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How To Bolster Your Immune System

How To Bolster Your Immune System

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The Immunity Crisis in America

Have you ever wondered WHY you get sick from different things, sometimes seemingly for no reason? Haven't you ever wished that you could find some way to stop yourself from getting sick and stay healthy all the time? Well, that might be more possible than you thought at first! Your immune system is an odd system, that many scientists are still struggling to understand. However, there have been some amazing breakthroughs! Once you get access to this detailed and helpful book, you will be able to find REAL and Applicable ways to improve your immune system and keep yourself from getting sick all of the time. This book teaches you everything that you never learned about your immune system Start learning what you can Really do to improve your immune system's health and keep your body healthier for longer! It's not hard at all Get started today!

Immunity Crisis Summary

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Apoptosis as an Antiviral Immune Response

Like all other living organisms, insects are constantly challenged by bacteria, fungi, and viruses. In vertebrate animals, immunity can be broken down into innate and adaptive immunity. Insects do not possess the adaptive immune response that is characteristic of vertebrates including antibodies and T cells. That does not mean, however, that insects are defenseless against invading microorganisms. Insects have robust innate immune systems that are in many ways similar to the innate immune mechanisms found in vertebrates. Over the past 10 15 years, enormous strides have been made in understanding the molecular basis for insect innate immunity against bacteria and fungi. Despite these advances, the understanding of how insects defend themselves against viruses has lagged behind. Work with baculoviruses has demonstrated that apoptosis can serve as an innate immune mechanism in insects. The importance of apoptosis in antiviral immunity in insects is only beginning to be understood, and...

Immune Response to Infection

PPVs, in common with other poxviruses, stimulate a vigorous immune and inflammatory response in their hosts, and have evolved to replicate in the presence of this response. In sheep experimentally infected with ORFV, studies in the skin and lymph draining into (afferent lymph) and out of (efferent lymph) local lymph nodes have demonstrated that activated CD4+ (helper) and CD8+ (cytotoxic) T cells, B cells, and antibodies are generated as part of the sheep-acquired immune response to infection. The cytokines generated in lymph in response to virus reinfection are typical oftype 1 antiviral cell-mediated immune responses and include interleukin (IL)-1 p, IL-2, tumor necrosis factor (TNF)-a, granulocyte-macrophage colony-stimulating factor (GM-CSF), inter

Interaction with the Immune System

PCV2 provides a valuable model for gaining insight into how ssDNA viruses interact with the host immune system and for understanding their pathogenesis. PCV2 is intriguing in its ability to persist in macrophages and dendritic cells without replication although its infectivity is retained. When natural interferon (IFN)-producing cells responded to an inducer of cytokine synthesis, their co-stimulatory function, which induces myeloid dendritic cell maturation, was clearly impaired in case of a concurrent PCV2 infection. Stimulation of the porcine immune system with IFN-a and IFN-g causes increased replication of PCV2 in vivo, while no changes were observed in IL-1-, IL-6-, tumor necrosis factor alpha (TNF-a)-, or IL-10-treated cells. With the circumstantial evidence compiled over the last years, one may assume that PMWS can be considered as an acquired immunodeficiency syndrome of pigs although direct evidence for this hypothesis is still missing.

Overview of the Immune System

The immune system includes several interacting components. Nonspecific immunity (protection against any invasion) is provided by the barriers of the skin and mucous membranes lining the lungs and gut. Additional nonspecific defenses are provided by the inflammatory response and the complement proteins in the bloodstream. We shall not deal further with these defenses.

Consequences of Immune System Cells Stimulation by Superantigens

The arachidonic acid lipid pathways. ,,, This SAgmediated hyperstimulation of the immune system of the host can overwhelm the host regulatory network and thereby assist pathogen evasion of the adaptive immune response. 18 Moreover, the excessive and aberrant activation of T cells causes damage to tissues and organs and cell apoptosis which may result in disease and even death. 13,22 Superantigen activity, particularly SPE A, has been found in acute-phase serum samples from strepto-coccal disease patients. 4

Psychological Stress and the Immune System

Early studies in the field examined the effects of stress on general components of the immune system, such as T-cells and natural-killer (NK) cells. More recent studies chose to measure another component of the immune system the cytokines, a system that is composed of molecules called interleukin. They are a group of naturally occurring proteins that are important in the activation of lymphocytes of the immune system. They were discovered in the 1970s, and several known types of interleukin (IL) are recognized as crucial constituents of the body's immune system. The most studied interleukins are interleukin-1 (IL-1) and interleukin-2 (IL-2). IL-1 is considered a proinflammatory and a pyrogenic agent, whereas IL-2 is considered an anti-inflammatory agent. The EFA has a differential effect on the production and the activity of ILs. For example, a diet based on n-3 PUFA abolishes the anorexia response to IL-1 (Endres, 1997, Calder, 1997, DePablo et al., 2000). DHA (n-3) administration...

Host Immune Responses

An early nonspecific containment phase (innate immunity) and a later HSV-specific effector phase (adaptive immunity) contribute to protection. Natural killer (NK) cells and rapid production of IFN type I provide a threshold of resistance to HSV-1 infection and were associated with the natural resistance of certain mouse strains. In mice, IFNa p inhibit the onset of IE gene expression, limit virus spread into the nervous system, and activate NK cells. Dendritic cells (DCs) are required for activation of NK cells and CD4+ and CD8+ T cells in response to HSV-1. Conventional CD11c+CD8a+ DCs are the principal antigen-presenting cells during acute HSV-1 infection. The plasmocytoid CD11c+B220+ DCs secrete large amounts of type I IFN in vitro after exposure to HSV-1 and help lymph node DCs to induce HSV-specific cytotoxic T cells (CTLs) optimally during a primary immune response. Various reports have incriminated or refuted the association of HLA with HSV infections.

Innate Immune Responses

Substantial evidence supports the view that cysteine proteases secreted by a range of pathogens specifically prevent cells of the innate immune response promoting Th1-adaptive immune responses.10,25-27 The mechanisms are varied and depend on the substrate specificity ofthe protease and ofthe location ofthe pathogen within the host. The innate immune system constitutes the first line ofhost defence during infection and plays a crucial role in the early recognition ofinvading pathogens. Unlike the adaptive immune response, the innate immune response is relatively nonspecific, relying on the recognition ofevolutionarily conserved structures on pathogens, termed pathogen-associated molecular patterns (PAMPs), through a limited number of pattern recognition receptors (PRRs).28 A number of different PRR families have been described but the best characterised is the family of TLRs. To date, 13 TLRs have been identified in humans and are distinguished by their recognition of distinct PAMPs...

Complementderived Dangertransmitters Shape Innate And Adaptive Immune Responses Following Physiological And

The immune system needs to distinguish between physiologic changes in the environment, e.g., physiologic cell death and the necessity to clear these cells without substantial inflammation and pathological changes that demand inflammation. In short, danger-sensing needs to translate into adequate dangertransmission that tailors the immune response. The complement system is well suited for this task as it releases a panel of bioactive cleavage fragments, the function of which is regulated by interaction with soluble and cell-bound proteins. Cleavage fragments of C3 (e.g., C3a, C3b, iC3b, C3dg) have the ability to act as danger-transmitters that instruct cells of the innate and adaptive immune systems through interaction with specific receptors (C3aR, CR1 CD35 , CR2 CD21 , CR3 CD11b CD18 , and CR4 CD11c CD18 , Likewise, cleavage products of C5 i.e., C5a as well as the membrane attack complex (C5b-9 MAC) can transmit humoral inflammation and translate humoral into cellular inflammatory...

The Secondary Immune Response and Duration of Immunity

One of the more striking variations in the immune response to FMD vaccines is the extent to which it is boosted by subsequent vaccinations. The increase in neutralising antibody titre may often exceed 1.5 log10 (Pay 1984) whereas little or no boosting of the immune response is apparent in the data from some other reports (Francis et al. 1983 Rocha et al. 1983), suggesting that the initial and subsequent vaccinations did not stimulate the development of immunological memory. This prompts the question of what variables impact on the secondary response and, by extrapolation, on the duration of protective antibody titres. Antigen pay-load has been studied by Rweyemamu and colleagues (Rweyemamu et al. 1984) using Al(OH)3 saponin FMD vaccines in cattle containing between 7 and 329,760 ng of 146S per dose. These authors concluded that the primary response was dose dependent but that there was no evidence of low dose tolerance or high dose immunological paralysis. Whereas the highest primary...

The Cognate Immune Response

As mentioned earlier, the innate and cognate immune systems are interlinked, so that many of the effects of leptin discussed in Section 4 will have implications for the behavior of responding lymphocytes. It is also clear that an organism mounts a coordinated immune response to an infectious pathogen that initially comprises innate immunity and then evolves, if appropriate to involve the cognate immune system. An important point of communication between the innate and cognate arms of the immune systems lies with macrophages and dendritic cells. These cells produce cytokines that polarize and activate T-cell responses and act as professional antigen-presenting cells by presenting peptide bound to major histocompatibility complex (MHC) molecules to T-cells along with high levels of costimulation. As leptin can effect the production of proinflammatory cytokines from macrophages (56) and dendritic cells (GM Lord, unpublished data) and also increase expression of MHC molecules and...

Inflammatory And Immune Responses

Dovid Scharf

Innate Immune Response Adaptive Immune Response In contrast, the molecules introduced into the body by acarine parasites may induce an adaptive immune response that is highly specific for a particular epitope (sequential or structural) on an immunogenic molecule (antigen) from the parasite. An epitope is the part of the antigen that receptors on B and T lymphocytes recognize. The adaptive immune response is stronger and quicker with successive exposures and involves T and B lymphocytes and memory cells of each type. It may be accompanied by an inflammatory reaction too that can be delayed. With the help of type 2 T-helper cells (Th2) B cells become plasma cells that produce antibody directed at the offending molecules from the mite. Activated Th1-type helper cells activate cytotoxic T cells (Tc) that perform functions that kill the parasite directly or damage it. Helper T cells release specific cytokines such as Interleukin 2 (IL-2), interferon Y (IFN-y), and other interleukins (IL-4,...

Brain Autoantigens in the Immune System

However, quite unexpectedly, several observations showed that CNS-specific autoantigens were also produced within the immune system, most prominently by thymus cells, mainly stroma, and that these ectopic autoantigens actively influenced the generation of the autoimmune T cell repertoire. At about the same time, two laboratories described a whole family of MBP and MBP-related genes in the immune cells (Pribyl et al. 1993 Grima et al. 1992). Both groups described MBP-like sequences in the thymus as well as in lymph nodes and the spleen. In particular, MBP expression by thymus stroma cells was unexpected. Then Kojima et al. showed directly for the first time the co-existence of CNS autoantigen and specific autoreactive T cells in the same rodent thymus. The autoantigen was the calcium binding protein S-1000, which is expressed in astrocytes, rather than in myelin

Bivalency in the Immune System

IgG and IgE antibodies, prime components of the immune system, are bivalent proteins containing two identical receptors (Fab sites Fig. 2.12) 21 . When binding bivalently to a surface (Fig. 2.12a) or to a soluble bivalent ligand (Fig. 2.12b), we postulate that the enhancement (P) for a given antibody is inversely proportional to the monovalent dissociation constant (K fflnlty) and directly proportional to the effective concentration (Ceff) of ligand near an available receptor (Fig. 2.12). If we assume Ceff to be constant for all antibodies (that is, that they have the same average distance between Fab sites), then greater enhancements will result from higher affinity (lower K fEnity) ligands. At cell surfaces, the enhancement for the binding of a polyclonal mixture of IgG with high monovalent affinity (average K ffinity 1 nM) to the surface of Bacillus sp. was 100 143 . Cremer and co-workers examined the binding of a polyclonal mixture of IgG to phospholipid mem-

Immune Response Prevention and Control

Cellular immunity is crucial for regression of papillo-mas. Dense infiltrates of T-lymphocytes can be observed in regressing warts in many animal species and immuno-suppression can result in severe papillomatosis. The early, noncapsid proteins are important antigens for cell- mediated immunity and these might prove to be effective therapeutic vaccines for existing infections. Vaccination with CRPV early viral gene products has been shown to clear papillomas in rabbits. However, one complication is that PVs encode several functions that enable them to evade the immune system they are able to inhibit inter-feron-dependent innate immunity and disrupt viral antigen presentation, which might also interfere with therapeutic vaccination.

Immuno Grid The Virtual Human Immune System Project

ImmunoGrid is a 3 year project funded by the European Union which began in February 2006 and establishes an infrastructure for the simulation of the immune system that integrates processes at molecular, cellular and organ levels. It is designed for applications that support clinical outcomes such as the design of vaccines, immunotherapies and optimization of immunization protocols. The first phase of the project concentrated on improving and extending current models of the immune system. We are now entering the second phase which will design and implement a human immune system simulator. Since the new models are orders of magnitude more complex than the previous ones, grid technologies will be essential in providing the necessary computer infrastructure. The final phase of the project will validate the simulator with pre-clinical trials using mouse models. The immune system is a complex and adaptive learning system which has evolved to defend the individual against foreign...

Interaction of the Microbiome with the Innate Immune Response in Chronic Wounds

Abstract Microbes colonizing and or infecting chronic wounds undoubtedly play a major and interactive role in impaired healing, especially in amplifying and perpetuating the host innate immune response. The development of molecular techniques to identify and quantify microbial organisms has revolutionized our view of the microbial world. These less-biased, high throughput methods greatly enable investigations regarding host-microbe interactions in the chronic wound environment. This review focuses on the mounting evidence implicating microbes and excessive inflammation in chronic wounds, as well as the challenges associated with understanding how microbes modulate wound healing and the innate immune response. Our bodies are colonized inside and out by microbes, estimated to exceed the number of eukaryotic cells of our bodies 10-fold. In most cases, these microbes are harmless and provide functions that we as humans have not had to evolve on our own (Gill et al. 2006). Despite constant...

Immune Response and Persistence

SIV-infected macaques typically produce high levels of antiviral antibodies and high-frequency cytotoxic T-lymphocyte (CTL) responses to the infecting virus. These immune responses persist for the lifetime of the infected host in both natural and experimental infection. SIV deletion mutants that are progressively more attenuated based on viral load measurements generate progressively weaker anti-SIV antibody responses. Anti-SIV CTL responses have been demonstrated as being major histocompatibility complex (MHC) restricted. Detailed investigation of CTL responses has been impeded by a lack of information regarding MHC types in different monkey species. However, a considerable amount of new information regarding MHC alleles and their cognate peptides is emerging for rhesus macaques. The importance of CD8+ lymphocytes in limiting the extent of SIV or SHIV replication has been definitively shown using CD8+ T-cell depletion. Extensive depletion of CD8+ cells was accomplished by intravenous...

Immune Response to SIV Infection

As SIV infection is lifelong, the host immune response cannot clear the infection but, in some cases, it can exert considerable control on the level to which SIV replicates. Before day 5 after mucosal SIV inoculation, there is little evidence of innate immune responses with only modest increases in type 1 interferon levels and interferon-stimu-lated gene levels at the site of inoculation. At days 6-7 PI, there is a dramatic and simultaneous increase in innate antiviral immune responses in all lymphoid tissues that coincides with the dramatic explosion of viral replication in these tissues. By days 10-14 PI, SIV-specific CD8+ T-cell responses are present in blood and in the mucosal sites of inoculation, with strong antiviral T-cell responses widespread by day 28 PI. This rapid increase in antiviral effector T cells occurs as viral replication and plasma vRNA levels decline from a peak at 14 days PI. The temporal relationship between the decline in plasma viremia and the appearance of...

Cytokines That Direct Immune Responses In The

Antigen-presenting cells (APCs) direct the quality of the emergent T cell response and have the capacity to subvert CNS immune responses toward inflammatory or noninflammatory outcomes, including whether CD4+ T cell activation generates a Th1 or a Th2 response. Although cell-surface interactions e.g., involving B7 family members or CD40, are known to play a role, the major influence on quality of T cell response is through release of specific regulatory cytokines by APCs. Macrophages that are induced with different colony-stimulating factors produce distinct cytokines and differentially elicit Th1 (APC1) vs. Th2 (APC2) responses 39 . Prominent among these are IL-12, IL-18, and IL-23, all of which are implicated in induction of Th1 immune responses and specifically interferon-gamma (IFNy) production, and IL-10, which directs Th2 responses. These cytokines are discussed in more detail below. A question that arises is how are these APCs directed to induce Th1 or Th2 It has been proposed...

Evasion of Host Immune Responses

Given the complexity of an antiviral immune response, there are many ways in which a virus can subvert this defense and persist in the host. Table 3 provides an outline of these strategies. As described above in EBV group I latency, HSV latency and HIV-1 Table 3 Viral strategies for evading the immune system3 Infection of sites not readily accessible to the Immune system latency, viruses can restrict the repertoire of genes they express or even become transcriptionally quiescent. This strategy renders the pathogen effectively invisible to the immune system. Lastly, cytokines and chemokines are important messengers for the coordination and orchestration of the immune response. TNF is targeted for example by poxvirus T2 protein that acts as a TNF receptor homologue. Secretion of this protein from infected cells results in the quenching of free TNF from the bloodstream. EBV BCRF-1, a homologue of IL-10, can block the synthesis of IFN-y and IL-2. Adenovirus VA RNA, HIV TAR RNA, and EBV...

Immunotherapy of EBVAssociated Malignancies

EBV-associated monoclonal tumors in otherwise immu-nocompetent individuals are known to be mostly invisible from an immunological point of view. In comparison, lymphoproliferative diseases after hematopoetic stem cell transplantation or solid-organ transplantation usually arise as polyclonal proliferations of EBV-infected immortalized cells that are subject to immune control. Immediate partial reconstitution of immune surveillance is the first action to take. Without treatment, benign polyclonal proliferations often progress to oligoclonality or monoclonality with greatly reduced chances for successful therapy.

Analyses of Immune Responses to Ontogeny Specific Antigens Using an Inbred Strain of Xenopus laevis J Strain

In this chapter, the procedures for specific detection of ontogenic emerging antigens during animal development are described. Anuran metamorphosis has provided us with a good experimental model for investigation of the mechanisms of tissue remodeling. The establishment of a syngeneic strain of Xenopus laevis described in this chapter has enabled us to perform a unique experiment to develop antibodies that specifically react to ontogenic antigens by immunizing syngeneic animals. This strategy was successful because the antibody repertoires produced in the adult frog serum were well subtracted by a number of common antigens expressed in syngeneic larvae. Here we show, using results of immuno-histochemical and T-cell proliferation analyses that adult frogs exhibit humoral and cellmediated immune responses to larva- or metamorphosis-specific antigen molecules in epidermal cells. Key Words Larval antigens epidermal cells skin metamorphosis tissue remodeling transformation antiserum...

Specific immunotherapy

Immunotherapy (desensitisation) has been used in the treatment of allergic diseases since 1911. Extracts of allergen to which the patient is sensitised are given in increasing concentration, starting with a very dilute solution, until tolerance is achieved. Allergen immunotherapy is specific to the allergen being Several studies evaluating the effectiveness of specific immunotherapy in food allergic diseases such as peanut and fish allergy produced conflicting results. The majority of the studies did not find evidence of protection in peanut allergic patients, and severe reactions during the treatment were common. However, some studies have supported the use of immunotherapy in the treatment of fish and egg allergy. The overall consensus is that specific immunotherapy has no place in the treatment of food allergy.

The Immune System and Stress

The immune system is the collection of organs, tissues, and cells responsible for the organism to resist attack by antigens or invasive foreign bodies, particularly microbes. In light of the research of the past few decades, the classic definition and conceptualization of the immune system has changed. The immune system, once considered a closed system (i.e., it reacts only to internal body events), is now recognized to be open and subject to activation by the nervous system. There are established strong relationships between the components of the immune system and behavior with reciprocal influences on each other. The recognition of these interactions gave rise to the label psychoneuro-immunology (PNI), a term probably first introduced by (Solomon, 1989). The popularity of PNI is easily attributable to the classic studies and writings of Ader and his associates (Ader et al., 1987) which have provided an impressive body of evidence that the nervous system is capable of modulating the...

PUFA and the Immune System

Repeated demonstrations that PUFA can modify the production and activity of various components of the immune system have left unexplained the mode of action by which it exerts its effects. Several mechanisms had been proposed, including the following membrane fluidity changes that might effect the capability of cytokines to bind to their respective receptors on the cell membrane lipid peroxidation decrease in free-radical-induced tissue damage prostaglandin production an indirect mechanism whereby prostaglandins that are derivatives of PUFA modify cytokine activity regulation of gene expression PUFA influences on the signal transduction pathways and on mRNA activity. The role of PUFA in immune function is complicated by the fact that n-3 and n-6 have differential effects on various immune components. A recent review (Zimmer et al., 2000) indicated that n-3 fatty acids induce a decrease in lymphocyte proliferation in humans and rats, a decrease in interleukin-1 (IL-1) production and a...

Exercise and Immune Function

Aging leads to a diminution of resting immune function, increasing the risk of infection, tumor development, and autoimmune diseases (Shephard and Shek, 1995). The production of IL-2 is decreased, sometimes with a decrease of total T-cell count, and often with changes in T-cell subsets and proliferative responses to mitogens. However, NK cell activity remains unchanged. In theory, moderate exercise training should help to reverse the adverse effects of aging upon the immune system. However, there have been relatively few studies comparing the immune responses of young and older individuals to acute exercise and to training. A single bout of moderate exercise seems to be well tolerated by the elderly. The NK cell response is as much as in younger individuals, but perhaps because of a low initial proliferative capacity, older subjects show less stimulation of lymphocyte proliferation by moderate activity and less suppression with exhausting exercise. Perhaps because resting immune...

The Effects Of Leptin On The Immune System 51 The Innate Immune Reponse

As mentioned earlier, the pattern of leptin release during an acute-phase response mirrors other cytokine gene expression, particularly IL-6 (11-13). It has been shown that LPS, IL-1, TNF-a, and other inflammatory stimuli increase gene expression and serum concentration of leptin as early as 6 h after the initial stimulus. The induction of gene expression makes leptin an ideal candidate to be a key player in an immune inflammatory response. It is of particular interest that LPS binds to a Toll-like receptor (TLR-4) on adipocytes and induces adipocyte expression of TLR-2 and secretion of leptin and other proinflammatory cytokines (102). TLR engagement provides an elegant mechanism whereby the production of leptin is induced at the start of an immune response before cognate recognition of a foreign antigen has occurred, which will, in turn, upregulate Th1 cognate immune responses if appropriate (see Section 5.2). This further illustrates the well-accepted concept of a critical interplay...

The Cell Mediated Immune Response in Starvation

As mentioned earlier, the cellular immune system seems particularly sensitive to undernutrition and starvation. The reasons for this are unknown and it has been hypothesized that much immunosuppression is the result of specific micronutrient deficiency. However, these deficiencies occur relatively sporadically, yet the type of immune impairment seen is fairly consistent, casting some doubt on this hypothesis. The immune phenotype seen in SII includes reduced delayed-type hypersensitiv-ity responses (DTH), which is a sensitive measure of T-cell-dependent in vivo immune responses. Furthermore, circulating peripheral T-cells are reduced, particularly na ve (CD45RA+) T-Cells (91). T cell antigen-specific responses are severely impaired and vaccination efficacy is poor (92). Antibody responses are relatively preserved, but production of interferon (IFN)-y is markedly reduced both in vitro and in vivo (93). Children seem particularly affected by SII because of the immaturity of their immune...

Starvation And Immune Responses 41 Models of Starvation in Normal Mice

Animal models have been set up to investigate the effects of food restriction on immune responses. It is important to define the terms of reference carefully when assessing the literature. Starvation is defined as withholding all food for a short defined period and allowing the animal free access to water. Following this short period of starvation, the animal is then allowed free access to food. A period of 48 h of food withdrawal is usually used in mice, because 24 h produces mild immunosup-pression only and 72 h causes unacceptable mortality. Most studies using rat models have employed 72-h food deprivation for similar reasons (14,81,82). Food restriction generally means reducing the calorific intake to approx 30-50 of normal. Starvation causes significant immune impairment (83). It has been shown that acute starvation in mice reduces the number of CD4+ T-cells and suppresses the development of T-cell-mediated immunity (84). Furthermore, starvation causes delayed repopulation of the...

Adaptive Immune Responses

Induction of Th2 Immune Responses and or Suppression of Th1 Responses In certain protozoan infections, cysteine proteases are critical for the induction of Th2 type immune responses. Leishmania are obligate intracellular parasites that live as nonmotile amastigotes within cells of the mononuclear phagocyte lineage of their mammalian hosts. The outcome of infection in leishmaniasis is determined by the Th1 versus Th2 nature ofthe effector response with parasites successfully establishing infection by driving a Th2 immune response.11 Inhibition of Leishmania mexicana cathepsin B, with a specific inhibitor, caused a switch in the polarisation of T-cell differentiation from a Th2 to a protective Th1 phenotype in mice.12,13 In addition, mutants of L. mexicana lacking cysteine protease activity induced less IL-4 and IgE in BALB c mice compared to wild type parasites.14 Finally, the delivery of recombinant cysteine proteases derived from either L. mexicana, or Trypanosoma cruzi, elicited...

The Adaptive Immune System

We find it useful to think of the immune system as a chemical sense organ, similar to the more familiar senses of taste and smell. They all function to identify novel materials, in a sense, which we then arrange to remove or inactivate. The immune system comes into play once foreign materials have achieved access to the interior. It is our cellular and molecular surveillance organ, and must not only distinguish between self and non-self, but also arrange for the inactivation, destruction, and removal of cells or molecules that it determines to be foreign. Foreign molecules are potential pathogens. The immune system makes no value judgments harmful or inert, if it is foreign, it should be removed.

Cell Mediated Adaptive Immune Responses to H pylori

The ability of the gastrointestinal tract to discern pathogenic bacteria from commensals is regulated through T-cell-dependent responses. CD4+ T-cells can be broadly divided into two functional subsets, type 1 (Th1) and type 2 (Th2) T-helper cells, each of which are defined by distinct patterns of cytokine secretion. Th1 cells produce IL-2 and IFN-y and promote cell-mediated immune responses whereas Th2 cells secrete IL-4, IL-5, IL-6, and IL-10 and induce B-cell activation and differentiation (82). The type of immune response to a particular microbial agent is governed by preferential expansion of one T-helper cell subset accompanied by a corresponding and relative down-regulation of the other (82). In general, most intracellular bacteria induce Th1 responses, whereas extracellular pathogens Although the acquired immune response to H. pylori is composed of both Th1- and Th2-type cells, cytokine profiles indicate a Th1 predominance, as the majority of H. pylori antigen-specific T-cell...

The Role of Membrane Complement Regulatory Proteins in Cancer Immunotherapy

Anti-tumor monoclonal antibody therapy represents one of the earliest targeted therapies in clinical cancer care and has achieved great clinical promise. Complement activation mediated by anti-tumor mAbs can result in direct tumor lysis or enhancement of antibody-dependent cellular cytotoxicy. Chemotaxis of phagocytic cells by complement activation products C5a is also required for certain cancer immunotherapy such as combined P-glucan with anti-tumor mAb therapy. However, high expression levels of membrane-bound complement regulatory proteins (mCRPs) such as CD46, CD55 and CD59 on tumors significantly limit the anti-tumor mAb therapeutic efficacy. In addition, mCRPs have been shown to directly or indirectly down-regulate adaptive T cell responses. Therefore, it is desirable to combine anti-tumor mAb therapy or tumor vaccines with the blockade of mCRPs. Such strategies so far include the utilization of neutralizing mAbs for mCRPs, small interfering RNAs or anti-sense oligos...

Evading the Immune Response

Viruses may use a number of strategies to evade the immune response. Evasion of cell-mediated immune responses Sanctuary sites Some sites are not easily accessible to the immune system for example, the brain and epididymis, which are separated from the blood by a barrier, and the kidney. HIV, for example, is present in the brain and semen. This may provide an explanation of why many HIV-infected individuals who generate strong cytotoxic T lymphocyte responses do not clear the virus. Herpes and measles viruses infect neurons and plasmodia infects red blood cells, neither of which express class I MHC. Even lymph nodes can act as a sanctuary. Infectious HIV has been found attached to FDCs in lymph nodes, even though neutralizing antibody was present.

Immune Response

In infected birds, the only significant immune response is the appearance of type-specific neutralizing antibodies which apparently recognize the regions of Env involved in receptor recognition. Group specific responses against Env or other proteins are not usually observed in infected chickens, although inoculation of virus into mammals induces antibodies capable of recognizing all virion proteins in the absence of subgroup-specific reactivity. The limited immune response observed in infected chickens has been attributed to the presence of endogenous pro-viruses whose expression (even at a low level) can induce tolerance to antigens in common with infect ing virus. Indeed, it has been suggested that induction of tolerance might be a desirable feature for the animal, since it could prevent or limit immunopatho-logical sequelae of infection. Postinfection immune response seems to be of little consequence in preventing subsequent malignant disease, since the cells which will eventually...

Immune Responses

The humoral immune response has been analyzed in great detail for human rotavirus infection. Specific antibodies detectable in intestinal contents and feces (of immunoglobulin IgA, IgM class) and serum antibodies (IgG, IgA, IgM class) appear during the first week after onset of infection. Serum antibody levels cannot be used as predictors of immunity to reinfection. The level of ingested or persisting antibody in the intestinal lumen can be predictive of immunity. Longitudinal studies of rotavirus infection in children (in developed and developing countries) show that primary infection (symptomatic or asymptomatic) does not confer immunity to reinfections, which are frequent, but does result in clinical immunity to development of severe symptoms during reinfection (Fig. 8). Immunity to caliciviruses following infection appears to be influenced by the infecting agent. Sporadic pediatric infections (due to Sapporo viruses) are associated with long-lived immunity. However, immunity to...

Immunotherapy

Immune responses to infection are vital as evidenced by the fact that healthy, immunocompetent individuals resolve infection. An interesting correlation between administration of highly active antiretroviral therapy (HAART) and a decrease in cryptosporidiosis in AIDS patients has been observed. HAART does not directly affect the parasite but exerts its effects through enhancing the immune system of these patients. A picture is slowly emerging of the immune responses during infection. CD4+ T cells play an important role as well as CD8+ (a p and y 8) intraepithelial T cells. Cytokines involved in clearance include INFg, IL-12, and IL-15. 12,13

Host Immune Response

Very little is known about immunological defense by cellular immunity against HHV-6. The presence of HHV-6-specific T cell clones in seropositive individuals has been reported. Natural killer (NK) cells, a key component of the innate immune system, are known to play an important role against viral infections. Infections of PBMCs with HHV-6 and HHV-7 lead to upregulation of their NK cell cytotoxicity by inducing IL-15, which is one of the NK activity-enhancing cytokines. The cell type in PBMCs that has been identified as the source of IL-15 is the monocyte macrophage. In fact, it has been reported that HHV-6 interacts directly with monocytes and induces IL-15 in them. This enhancement of NK cell cytotoxicity following infection is consistent with the previous observation that NK activity increased during the acute phase of exanthem subitum. IL-15 production following viral infections may therefore represent a powerful host defense mechanism involved in restricting viral growth and in...

Viruses and Apoptosis

Induction of apoptosis later in the virus life cycle could assist the release of the newly produced virus particles, especially nonenveloped nonlytic viruses, from the cell. The presence of virus in apoptotic bodies, which are phagocytosed by other cells, helps the virus evade the host immune surveillance system and spread. Virus-induced apoptosis also contributes to the clinical manifestations and cytotoxicity associated with virus infections. The viral gene products involved in activating PCD and their targets in the cell are only starting to be identified (Table 2).

Preface to the First Edition

Part IV deals with the role of fats and oils in overall nutrition. The importance of antioxidants in nutrition and food preservation is presented. Excess fat intake is associated with many disease conditions. This section describes various omega fatty acids and their sources, the role of dietary fats in atherosclerosis, eicosanoids production, immune system, coronary heart disease and obesity. The various types of lipid-based synthetic fat substitutes are discussed.

Serologic Relationships and Variability

All attempts to demonstrate antigenic crossreactivity between EAV, LDV, PRRSV and SHFV have been unsuccessful. Even though antiviral antibodies are detected in infected animals by a week after infection, all four viruses can cause persistent infections. The mechanism by which these viruses evade clearance by the immune system is not known. Neutralization escape virus variants have been reported to arise during persistent LDV infections. Antiserum obtained from animals chronically infected with LDV and PRRSV contains infectious viral immune complexes. Plasma from LDV-infected mice has a higher nonspecific binding activity than plasma from uninfected mice virus-specific binding measured by an ELISA usually cannot be detected until the plasma has been diluted at least 1 400.

Models of Autoimmunity

Diabetes, particularly type I (insulin-dependent diabetes mellitus, IDDM) has been associated with viral infections. A potential mechanism described above is molecular mimicry. The principle here is that a virus encoding a crossreacting epitope is also present in the pancreas of the genetically susceptible individual. Infection with a virus having the crossreacting protein and or epitope could initiate a crossreacting immune response. Here, the cell in the pancreas that contains the peptide in association with MHC molecules would be recognized by T cells and attacked. Two laboratories, those of Oldstone and Zinkernagle, have constructed transgenic mice to test this hypothesis. Lymphocytic choriomeningitis virus (LCMV) glycoprotein (GP) or nucleocapsid protein (NP) genes controlled by the insulin promoter were inserted into the germ line. Such transgenic mice expressed the viral GP or NP protein in the islet cells of the pancreas. These mice therefore consider the viral protein as...

Future Perspectives

Some of the initial studies on molecular mimicry and virus-induced autoimmunity indicated that viruses share common sequences with host components. It has been demonstrated that some viruses have acquired host genes and modified these to subvert the immune system. Herpesviruses encode MHC-like molecules, Fc receptors, IL-10-like factor and complement regulatory proteins, and poxviruses have incorporated into their genome, IL-1 receptor, tumor necrosis factor (TNF) receptor, IFN-y receptors and complement control proteins. In addition, viral proteins need to perform specific functions in the cell to replicate its genome and assemble new virions. These functions use the existing cellular machinery and therefore mimic many of the host cells, which also perform similar tasks. The key question is still how are these infections which are associated with autoimmune disease able to initiate the pathway leading to self-reactive immune responses

Brief History of Hivaids

Although the first cases of acquired immune deficiency syndrome (AIDS) were recognized in the United States in 1981, phylogenetic analysis of human immunodeficiency virus (HIV) sequences suggest that HIV may have been initially transmitted to humans around 1930. By 1985, HIV had been identified in every region of the world and an estimated 1.5 million people were infected globally. Since then, unprecedented scientific advances have been made in the epidemiology, basic science, and treatment of this newly identified virus. Despite these advances, the global HIV pandemic has expanded rapidly. By 2007, an estimated 33.2 million people were living with HIV and greater than 20 million people had died of AIDS. AIDS is now the leading cause of death among people 15 59 years old and the world's most urgent public health challenge. The implementation of effective prevention strategies has proven challenging but there have been notable successes. In the US and Western Europe, extensive...

HIV Care and Treatment

The HIV epidemic intersects with other important diseases. By weakening the immune system, HIV predisposes to opportunistic infections such as tuberculosis (TB). Globally, more than 21 million people are co-infected with TB and HIV. Although TB infection remains latent (neither contagious nor symptomatic) in most people without HIV, with TB HIV co-infection the risk of progression to active, contagious disease increases 100-fold. TB and HIV synergistically worsen the burden of both diseases. The global TB incidence has increased, fueled by a rapid increase in HIV-associated TB in Africa. TB is also a leading cause of death among people living with HIV. Increased collaboration between TB-elimination and HIV-treatment programs is necessary to control both of these diseases.

Cis Regulatory Elements that Target AID to Immunoglobulin Loci

Somatic hypermutation (SHM) is a mutagenic process that randomly alters the DNA sequence of the immunoglobulin (Ig) genes by introducing point mutations and single nucleotide deletions and insertions. The mutagenic activity is focused on the variable (V) regions (referred to in this context as the rearranged VJ or VDJ exon) of the Ig gene loci that encode the antigen-binding sites of the Ig. This allows for the generation of Ig molecules with slightly altered affinity for the cognate antigen, and ultimately, in the context of a germinal center immune response, for the emergence of B cells with higher affinity for the antigen. Class switch recombination (CSR) is a somatic DNA recombination in the Ig heavy chain (IgH) locus that leaves the antigen-binding site intact, but replaces the initial C constant (C) region with another chosen from a set of distinct C regions residing in this locus. As the C regions encode the effector function of the Ig molecule, CSR allows for an optimal immune...

Rescue of Autoreactive B Cells by T Cell Independent Antigens of Type I TLRLigand AntigenComplexes

In the other way, autoantigen-TLR-ligand complexes might activate immature B cells to proliferation, rather than to apoptosis of the autoantigen-specific B cells, as, for example, LPS has been seen to induce such responses on a polyclonal level with immature B cells. Thereby, autoantigen-TLR-ligand complexes could compete with autoantigen-natural IgM-complement complexes for reactions leading either to survival and proliferation or to apoptosis of the autoantigen-reactive cells. This may well occur during the peak of a bacterial infection and might become chronic if the infection is chronic. A real danger of autoimmune disease (in the case of dsDNA IgG or chromatin to SLE) should only arise if the response of the rescued, matured, activated au-toreactive B cells is taken over by a helper T cell-dependent, or otherwise AiD-inducing action of the immune system.

Release of First MLV Followed by Reports of pvMD

Further investigation revealed that the vaccinated animals that succumbed to pvMD responded with serum antibodies to the other components of the vaccine but did not respond to the BVDV component. This suggested that the susceptibility to pvMD might be correlated with failure of the immune system to recognize BVDV. Questions raised by pvMD lead to the elucidation of the etiology of MD.

Common Types Of Childhood Cancer Leukemia

Leukemia is identified as being either acute (growing quickly) or chronic (growing slowly). Children with leukemia are typically diagnosed with an acute form of the disease. Acute leukemia is divided into two types, (1) acute lymphocytic leukemia (ALL), also known as acute lymphoblastic leukemia (2) and acute myelogenous leukemia (AML), also known as acute myeloid leukemia, acute myelocytic leukemia, and acute nonlymphocytic leukemia. ALL is a cancer of the lymphoblasts (cells that help form an individual's immune system). AML is a cancer type that affects immature bone marrow cells (American Cancer Society, 2004).

Discharge And Home Healthcare Guidelines

In persons older than 12 months, the spores are unable to germinate in the gut because of the presence of gastric acid, and therefore the food-borne disease is caused by ingesting a preformed toxin. The spores, however, can germinate in the GI tract of infants younger than 1 year because infants have lower levels of gastric acid, decreased levels of normal flora, and an immature immune system. The GI environment in infants is conducive to toxin production, making infants particularly susceptible to the spores present in unprepared foods.

Genome Organization and Protein Expression

CSF virus (CSFV) is an enveloped virus with a diameter of c. 40-60 nm. The single-stranded RNA genome has a size of 12.3 kb. It has positive polarity with one open reading frame (ORF) flanked by two nontranslated regions (NTRs). The 5' NTR functions as an internal ribosomal entry site (IRES) for cap-independent translation initiation of the large ORF that codes for a polyprotein of about 3900 amino acids. The polyprotein is co- and post-translationally processed by viral and cellular proteases. From 11 viral proteins, four constitute the structure of the particle, namely three envelope glycoproteins (Erns, E1, and E2) and one core (C) protein. The remaining seven non-structural proteins are Npro, p7, NS2-3, NS4A, NS4B, NS5A, and NS5B. The main target for neutralizing antibodies is the viral envelope glycoprotein E2. To a lesser extent, the host's immune system produces neutralizing antibodies to Erns. This viral envelope glycoprotein occurs as a disulfide-bonded homodimer in the virus...

Polymicrobial Sepsis As A Model

In addition to suppressing TNF-a and IL-1, IL-10 can be immunosuppressive, in part through its ability to block Th1 and promote Th2-mediated immune response. This has been most evident in models where an endogenous IL-10 response to injury may contribute to the immunosuppression leading to secondary infections. For example, following a burn injury, mice are more susceptible to lethal cecal ligation and puncture. However, this increased susceptibility could be prevented by treating the mice with a monoclonal antibody against IL-10 in the interim between the burn injury and the cecal ligation and puncture. Similarly, an endogenous IL-10 response following cecal ligation and puncture was responsible for the decreased antimicrobial response and increased mortality resulting from lung exposure to Pseudomonas aeruginosa.

Pathogenicity and Clinical Features of Infection

Cellular immune response to non-LDV antigens is observed during the first 2 weeks following LDV infection. Thereafter, the immune response to other antigens is normal. In immunosuppressed C58 and AKR mice, neurovirulent isolates of LDV can induce a sometimes fatal poliomyelitis. In these mice, immunosuppression is required to delay antibody production until after virus has reached the central nervous system (CNS) and infected susceptible ventral motor neurons. LDV-infected neurons become the targets of an inflammatory response. In mice 6 months of age or older, paralysis of one or both hindlimbs and sometimes a forelimb is observed. In younger C58 mice, poliomyelitis is usually subclinical.

Bone Marrow Transplantation

The success of allogeneic transplantation in dealing with acute leukemia resistant to standard chemotherapy led investigators to use autologous transplantation against other cancers responsive to chemotherapy and radiation. Canellos (1985) compared the relative merits of allogeneic versus autologous BMT for treating non-Hodgkin's lymphoma. The former was limited by the few donors, patients in a gross state of relapse, infections from suppressed immune systems, the limiting effect of prior chemotherapy on whole-body irradiation, and graft-versus-host disease, a severe complication of allogeneic transplantation in which the donor cells attack the transplant recipient. Autologous BMT was more practical it not only obviated dependence on a limited number of donors and eliminated graft-versus-host disease GVHD, but also involved compromised stem-cell reserve and marrow contamination by malignant cells (p. 1452). Canellos emphasized that the use of ABMT with combination chemotherapy against...

Host Receptor Recognition Site

Animal viruses have to recognize a specific host cellular receptor for entry during infection. Host receptor binding is the initial step of virus life cycle and could be an effective target for preventing virus infection. Based on the atomic structure of animal viruses, it was found that the receptor recognition site is located in an area surrounded by hyper-variable regions of the antigenic sites. Usually, the area is in a depression (called the 'canyon') on the viral surface that may be protected from recognition by host antibodies. This structural feature is, for instance, present in human rhinovirus (also known as the common cold virus), and the active site of influenza virus hemag-glutinin (HA). The receptor-binding site on influenza virus HA does not have a deep depression, but it is surrounded by antigenic sites. The receptor-binding area on the surface of the viral capsid is conserved for recognition by the receptor, whereas the sites recognized by antibodies are distinct from...

Transmission and Tissue Tropism

Human CMV may be transmitted by direct person-to-person contact at any time shedding is occurring, but immune status dictates the likelihood of disease following transmission. There is no seasonal variation in infection rates. Primary infection of an immunocompetent host results in a viremia which disseminates virus to organs, including the salivary glands and kidneys. The more immunocompromised a host, the greater the likelihood of spread to additional organs, with or without disease. Congenital transmission may occur throughout gestation following primary maternal infection, although some believe disease risk is greatest during the first half of pregnancy. Seropositive mothers who reactivate virus during pregnancy are less likely to transmit virus because their own adaptive immune response probably reduces the virus load. Congenital infection is a consequence of CMV crossing the placenta, possibly via carriage in maternal leukocytes or replication in trophoblasts. Virus is also shed...

The Biological Functions Of

Kgp-null P. gingivalis strains lacked the black pigment characteristic for this species and were less virulent.46,53 In concert with the two Rgp members, Kgp also directly binds and cleaves fibrinogen and indirectly breaks down collagens via the activation of the matrix metalloproteinase system, resulting in an increased bleeding tendency and tissue damage at the infected periodontal site.54-57 Whilst the proteolytic activity of Kgp is important for generating peptides amino acids as the energy and carbon source suitable for the asaccharolytic nature of P. gingivalis, it is also utilized by P. gingivalis to manipulate and evade the host immune response via complex mechanisms,58-62 mainly involving the degradation of surface molecules of immune cells 63-66 and interference with the cytokine system of the host.61,67 In addition, Kgp can also bind host epithelial cells and other bacteria, providing a biological basis for the attachment and colonization of P. gingivalis.49,68...

Clinical Features of Infection

Acute EIA is most often associated with the first exposure to the virus, with fever and hemorrhages evident from 7 to 30 days after exposure. Acute disease is thought to be associated with massive virus replication in and destruction of infected macrophages. Horses in the initial phase of acute EIA will be seronegative, because the immune system has had insufficient time to respond to the viral antigens. During the peak of the febrile response in acute EIA, viremia of greater than 106 horse-infectious doses per ml of whole blood is often observed. The initial acute phase of EIA infection may not be seen by the veterinarian unless there is an epizootic of the infection in a group of horses. Even then, the horses must be under close supervision before the initial fever and anorexia are detected. Neither anemia nor edema is seen at this stage of disease.

Properties of Proteins

It is predicted that MCMV encodes 33-35 structural proteins including the major capsid protein (M86), the large tegument protein (M48), a minor capsid protein (M46), the upper (M82) and lower (M83) matrix proteins, large (M32) and small (M99) phos-phoproteins, and a fused protease-capsid assembly protein precursor (M80). The 28-kDa matrix phos-phoprotein induces a strong humoral immune response during MCMV infection of mice.

Prevention and Control

Combination immunotherapy with IFN-y TNF-a increases infected mouse survival rates and decreases virus replication in vitro, but not in vivo. Systemic immunotherapy with IL-2, but not IL-12, reduces the frequency of MCMV-induced retinitis in mice with MAIDS. Administration of the octapeptide thymic humoral factor (THF-y 2) enhances the immunocom-petence of spleen cells and restores MCMV-suppres-sion of T cell mitogenic responses and IL-2 secretion. Immunotoxins containing MCMV-specific IgG linked to deglycosylated ricin A chain or gelonin (ribosome-inactivating enzyme) inhibit MCMV replication. Immunomodulators such as BCH-527 (the hydrochloride salt of D-alanyl L-glutamine), lactoferrin, polyinosinic polycytidylic acid (poly(I C)), GLA-60 (synthetic lipid A subunit analogue), and iota-carra-geenan (i-CAR) mediate viral spread by modulating the immune response.

H ppzozinduced gastric inflammation

If a bacterial species is to persistently colonize a mammalian host, its most formidable challenge is to evade immune clearance. One mechanism through which H. pylori may persist is by limiting the bactericidal effects of pro-inflammatory molecules, such as nitric oxide (21). Another level of host defense that may be circumvented by H. pylori is innate immunity. Toll-like receptors (TLRs) are an evolutionarily conserved family of eukaryotic receptors that function in innate immunity via recognition of invariant regions in bacterial molecules termed pathogen- or microbe-associated molecular patterns (22-24). Although the bacterial ligands for TLRs are distinct, signaling pathways used by these receptors all appear to eventuate in NF-kB activation and pro-inflammatory gene expression (Fig. 2). It is becoming increasingly clear, however, that H. pylori has evolved strategies to avoid activation of this system. For example, TLR4 recognizes bacterial lipopolysaccharide (LPS), yet H. pylori...

Dermatologic Physical Exam

As the immune response becomes active during the second month, the primary burrows begin to show inflammation and become pruritic. General itching, especially bothersome at bedtime, increases and small intensely uncomfortable urticarial papules are present. Many cases show prominent immediate dermographism, which only adds to their discomfort. Persistent scratching causes excoriation, secondary infection, lichenification, and eczematous change. These patients often are simply unable to sit still during the examination process.

Therapeutic Approaches

Aging is associated with the decline in multiple areas of immune function, but, to date, no single mechanism has emerged as responsible for all of the observed changes. It is being increasingly acknowledged that autoimmune processes play a proinflammatory role in the development of many pathological conditions, such as atherosclerosis. It is likely that the mechanisms underlying age-related changes in immunity are multifactorial, with both genetic and environmental factors playing a significant role (Burns et al., 1997). The progression of and recovery from infectious diseases depends, at least in part, on immune responses and nutritional status in the elderly. Nutrition therapy may improve the immune responses of elderly people, particularly those with total-, protein-, fat-, or micronutrient-energy balances on prescribed low protein or fat diets (Lesourd, 1997). Micronutrient supplementation improves the immune status in the aged individuals. Episodes of disease in the aged leads to...

Nutrition Intervention

Immune system in the elderly, even in the apparently healthy independent-living elderly (Lesourd, 1999). Protein-energy malnutrition is associated with decreased lymphocyte proliferation, reduced cytokine release, and decreased antibody responses to vaccines. Deficits in zinc, selenium, and vitamin B6 in the elderly compound the depression of the immune system. The elderly do not have an adequate supply of fats for proliferation of lymphocyte and macrophage populations, antibody production, and hepatic synthesis of acute-phase proteins. Fat oxidation is reduced in the elderly at rest, during exercise, and in response to meal ingestion, as a result, in part, to the loss of fat-free mass, decreased intrinsic fat oxidation in muscle, and hormonal factors. These changes in fat oxidation are only partially corrected with training (Calles-Escandon and Poehlman, 1997). Lipids are known to have modulatory effects on the cellular immune system at the biochemical and molecular levels, including...

The Antibody Component

By virtue of their high levels of specificity and binding affinities, antibodies are the ideal choice of agent for drug detection. Antibodies are produced by the immune system as weapons to eliminate invading pathogens (1). Antibodies to a specific DOA can be produced by immunizing animals with the selected DOA conjugated to a carrier protein. A carrier protein is necessary because small chemicals (DOAs) by themselves are usually not immunogenic enough (as a hapten) to elicit an antibody response (2-6). Common protein carriers for this purpose include bovine serum albumin (BSA) and keyhole limpet hemocyanin (KLH). However, this technique is not as simple as it sounds and is not for the amateur protein chemist. The type of linker used, the length of the linker used, the molar ratio of the drug to the carrier protein, and the type of carrier protein to be used are only some of the factors that must be carefully considered to achieve effective conjugation.

H pylori Contact Mediated Cytokine Release and the Development of Acute Inflammation

Pro-inflammatory cytokine expression is often regulated at the mRNA level by soluble transcription factors and the human IL-8 gene contains several motifs within its promoter region including binding sites for NF-kB, NF-IL6, AP-1 (which is composed of the binding elements c-fos and c-jun), and a recently identified novel element that is homologous to an interferon-stimulated responsive element (ISRE) (Fig. 3) (54-57). NF-kB constitutes a family of transcription factors sequestered in the cytoplasm, whose activation is tightly controlled by a class of inhibitory proteins termed IkBs (58). Multiple signals, including microbial contact, stimulate phosphorylation of IkB by IkB kinase P (IKKP), which leads to proteasome-mediated degradation of phospho-lKB, thereby liberating NF-kB to enter the nucleus where it regulates transcription of a variety of genes, including immune response genes (Fig. 3) (59). Stimulation and activation of NF-kB does not require protein synthesis, thereby allowing...

Baculovirus Anti Apoptotic Genes P35 and Its Relatives

The P35 protein is a remarkable molecule. This baculo-virus protein is the most widely acting apoptosis inhibitor known it can inhibit apoptosis in nematodes, insects, and mammals. As such, P35 has proven to be a highly useful tool to investigators studying apoptosis in a wide variety of systems ranging from developmental events in Drosophila to immune system function in mice. Thanks to structural biology, we know a great deal about how P35 functions as a stoichiometric caspase inhibitor.

Summary And Conclusion

It would seem that modulation of lipid intake and exercise training may mediate and reverse some of the age-associated depression in the immune system. As human aging generally is accompanied by a reduction in the level of physical activity and impaired responsiveness of the immune system, there may be a relationship between these concurrent changes and the increased incidence of, and mortality from, cancer, autoimmune disorders, and chronic infectious diseases with age. The studies on the immune system of centenarians suggest that the immune system in this population may not be declining with age, instead it is being constantly remodeled and reshaped as required. Appropriate fat and protein intake may improve immune function. Lipids modulate immune function by several factors and mediators. Both the quantity and type of dietary lipids are known to have modulatory effects on the cellular immune system at biochemical and molecular levels. The mechanisms by which lipids modulate the...

Of Influenza Viruses By The Innate Immune

2 Recognition and Immune Responses to RNA 294 23. PORE FORMERS OF THE IMMUNE SYSTEM 325 5 Function of the three Pore Formers of the Immune System 339 24. PATHOGEN-SPECIFIC INNATE IMMUNE RESPONSE 342 1.1 PAMP-Triggered Plant Immune Responses 359 1.2 Effector-Triggered Plant Immune Responses 359

Anti Inflammatory and Cytoprotective Mechanisms

The cell-based activities of APC appear to require its interaction with the endothelial protein C receptor (EPCR) (Figure 4.5). EPCR, first identified as a receptor on the endothelium 93 , plays an important role in the conversion of zymogen protein C into APC. However, in addition to its role in APC generation, mounting evidence suggests its role in the signaling responses of APC at the endothelium (Figure 4.6) 68-71,92 . In addition, EPCR-dependent cell signaling can function through the protease-activated receptors (PAR-1, PAR-2, and PAR-3) 71,94 . EPCR appears to be restricted to the endothelial-leukocyte interface of the innate immune system, and is expressed on monocytes, natural

Danger Transmission Through Tlrs

Many exogenous or endogenous molecular patterns, either derived from pathogens such as LPS, glycolipds, and teichoic acid, or from tissues such as modified LDL or necrotic cells, can be recognized by complement-derived danger sensors and TLRs, suggesting that complement receptor pathways may intersect with TLR pathways. The first evidence of a regulatory link between the complement system and TLR-mediated immune responses was provided by reports demonstrating that activation of CR354 and the complement regulator molecule CD4658 by C3 cleavage products promote efficient control of TLR-induced synthesis of IL-12 from human monocytes. Further, the C5 cleavage fragment C5a was found to downregulate LPS or Staphylococcus Cowan strain 1 (SAC)-induced synthesis of IL-12 in human monocytes but not in monocyte-derived DCs121,122. In contrast, ablation of C5 in murine macrophages led to reduced IL-12 production in response to IFN-y + SAC stimulation, suggesting that C5a enhances IL-12...

Mechanism Of 5fu Action

Fas, a type I integral membrane protein, belongs to the tumor necrosis factor receptor (TNFR) superfamily and expresses an intracellular death domain (DD) required for rapid signaling from the receptor. Following ligation of the natural ligand, Fas ligand (FasL), or agonistic anti-Fas antibodies to Fas, an apoptotic signal is induced (37). Fas and FasL are known regulators of apoptosis in cells of the immune system including activation-induced cell death (38) and apoptosis induced by cytotoxic T cells (39). Fas is expressed in tissues that posses a high rate of cell turnover including epithelial tissues (40), and has demonstrated functional activity in cell lines derived from a variety of different histiotypes

Hypothesis on the Cause and Mechanism of Autoimmune Disease

Tis, adrenalitis, insulitis T1D, and others 15 . In IPEX, a high incidence of T1D and its early onset (within 1 year in the majority of cases 21 , see above) could be attributed to so severe a deficiency or dysfunction of natural Treg. Notably, thorough depletion of natural Treg from the normal immune system can induce novel autoimmune diseases that have been postulated to be of autoimmune etiology in humans, but with little evidence. For example, autoimmune neuritis or autoimmune myocarditis, resembling human CIDP (chronic inflammatory demyelinating polyneuropathy) or giant cell myocarditis, respectively, can be induced in NOD and BALB c mice, respectively ( 25 , Ono et al., unpublished data). Third, this possible mechanism of autoimmune disease implies that a single causative agent or a single genetic abnormality affecting the Treg-mediated control, or the balance between Treg and self-reactive effector T cells, may lead to the occurrence of different autoimmune diseases, frequently...

Isolation of Dendritic Cells from Human Afferent Lymph

The skin acts as a mechanical, physicochemical, and immunological control and defense system. The efficient operation of the skin immune system involves cytokine production and adhesion molecule expression by both infiltrating and resident cutaneous cells, and thus depends upon a system of cell homing, based on interactions between cell-surface properties and soluble mediators. they possess different morphological, phenotypic, and functional properties when isolated from these distinct sites. The lymph cannulation system described in this chapter enables the isolation of skin-derived DC that are migrating to regional lymph nodes so that they may be analyzed. The investigation of these cells in human afferent skin lymph is a unique opportunity to learn about the local immunity and especially about the induction of an immune response. 6. Brand, C. U., and Braathen L. R. (1996) Investigation of skin derived lymph an approach to get insight into the skin immune system. Dermatology....

Virus Replication

EBV expresses at least three genes during the lytic cycle that are capable of modulating the host immune response. Two of these encode homologues of human interleukin 10 (hIL-10) and the receptor for colony-stimulating factor 1 (CSF-1). EBV IL-10 (vIL-10), encoded by the BCRF1 gene, displays a colinear homology of 78 with hIL-10, and is functionally equivalent in many (but not all) respects to its cellular counterpart. Because hIL-10 has numerous immunosuppressive effects, expression of vIL-10 is viewed as a mechanism to potentiate EBV infection and establishment of the carrier state. The EBV CSF-1 receptor homologue, encoded by the BARF1 gene, is a secreted protein able to bind and neutralize soluble CSF-1, though a role for CSF-1 in the host defense against EBV infection has not been defined. The third EBV gene, BZLF2, encodes gp42, a glycoprotein that plays an important role in the infection of B lymphocytes through interaction with the cell-surface class II antigen HLA-DR....

Cannabinoid Receptors Cbrs

A second cannabinoid receptor (CBR2) was subsequently found in the immune system, but not in the brain. In this text it is only the brain receptor (CBR1) that will be discussed. It clearly lies at the heart of the well-known effects that extracts of the plant Cannabis sativa (cannabis marijuana) have on the human brain mind. The CBR1 receptor is concentrated in the basal ganglia, the hippocampus and the cerebellum, areas that are consistent with behavioural effects of the drug. It is also found in the spinal cord and in the peri-aqueductal grey matter (PAG). This tissue surrounds the central canal of the spinal cord and brain stem and holds the pain pathways as they course up to the brain. Closer examination of the anatomy indicates that CBR1 is located in the presynaptic membrane. We shall discuss its molecular physiology in Section 16.6.

Molecular Mechanisms of Pathogenesis

Since these viruses are of only minor veterinary importance, recent research has focused on the elucidation of the determinants for viral virulence, particularly with respect to the strategies that these viruses employ to subvert the immune system of the infected host. Particular attention has been paid to the mechanism(s) underlying the immune dysfunction caused by MYX infection in Oryctolagus rabbits. To date, at least two classes of viral gene products have been directly implicated in the immunomodulation induced by these viruses 2. 'Viroceptors' are viral proteins that mimic cellular receptors and function by sequestering important host cytokines that normally participate in the antiviral immune response. Leporipoxviral-encoded receptorlike molecules have been discovered for tumor necrosis factor (TNF) and interferon g (IFN-g), and may exist for other antiviral lymphokines as well. SPV encodes a novel homolog of cellular chemokine receptors, and the leporipoxviruses express...

APC Mechanism and Sepsis

Given these data, the mechanism of APC's efficacy in the treatment of sepsis is also likely to require the EPCR-dependent effects that have been described in preclinical studies above, both suppressing endothelial activation and modulating the innate immune system. The ability of APC to suppress molecules such as ICAM, VCAM, and E-selectin may be important in light of the critical early role of cell adhesion in the inflammatory response and in sepsis 201-204 . Under normal circumstances, the vascular endothelium controls a number of regulatory mechanisms to modulate coagulation, inflammation, and vascular function to maintain homeostatic balance in the local environment 72,205 . During infection or inflammatory insult, the endothelium becomes activated, begins to initiate the expression of proinflammatory cytokines, chemokines, and cell surface adhesion molecules required for leukocyte adhesion and migration (reviewed in 67,206-208 ). This adaptive response plays a critical role in...

Cardiovascular System

Blood makes up about 7 of human body weight. In females this averages about 4.5 L of blood males about 5.5 L. When a tube of blood is centrifuged, the upper 55 of the volume will be a pale yellow liquid called plasma. Plasma is 90 water, with 10 solutes including proteins and electrolytes nutrients such as glucose, amino acids, and lipids and waste products such as urea and bilirubin, a waste product that gives plasma, as well as urine and feces, their color. About 96 of the plasma proteins consist of albumins and globulins. These have overlapping functions, including control of osmolarity and the transport of insoluble lipids, vitamins, metals, hormones, and so on. Globulins are an important component of the immune system, discussed in Section 9.7. The rest of the protein is fibrinogen, involved in blood clotting. The dominant electrolytes are sodium and chloride. Intercellular fluid is similar in composition to plasma. Just 0.1 of the blood volume is composed of white blood cells,...

Clinical Development of Drotrecogin Alfa Activated for Severe Sepsis

Severe sepsis has been extremely challenging to dissect both in terms of defining its patho-physiology, and in defining targets for therapeutic intervention. Severe sepsis (sepsis associated with acute organ dysfunction) and septic shock (sepsis associated with hypotension) represent the more severe complications of an uncontrolled immune response to infection and are the most common causes of death in noncoronary intensive care units, with estimated mortality rates ranging between 30 and 50 209 . The last decade has seen a significant advance in understanding this complex disorder, focused on the tight interplay and coupling of inflammation, microvascular coagulation, and endothelial cell dysfunction. In line with this changing view, studies with rhAPC were initiated, and early phase studies demonstrated a treatment benefit 210,211 . This prompted the initiation of the PROWESS trial, a phase III, placebo-controlled, international, blinded, randomized, 28-day all-cause mortality...

Generation of Murine Bone MarrowDerived Dendritic Cells

Dendritic cells (DC) are the most potent antigen-presenting cells (APC) of the immune system. Derived from stem cells in the bone marrow, DC migrate to the tissues where they become sentinels of the immune system. DC possess the unique ability to initiate primary T-cell responses and can also stimulate and modulate both B and T lymphocytes during an ongoing immune response (1-3). Located in most tissues, DC are able to capture and process efficiently a wide variety of antigens. In response to danger-signaling cytokines and micro-bial products they up-regulate, their expression of co-stimulatory molecules, display high levels of peptide-bearing major histocompatibility complex (MHC) molecules on their cell surface and migrate to secondary lymphoid organs including the spleen and lymph nodes. In this draining lymphoid tissue they liase with and activate antigen-specific T cells (1). The capacity to activate naive as well as memory T cells is a property not shared by other APC. DC,...

Tolllike Receptors Natural Killer Cells and Innate Immunity

The innate immune response relies on the rapid recognition of microbial pathogens to provide the first phase of protection against infections. Innate immune cells such as macrophages, dendritic cells and natural killer (NK) cells respond to pathogen-associated molecular patterns (PAMPs) as well as host-derived factors. In the last decade receptors for many of the PAMPs have been discovered. Much of the focus in the field of Toll-like receptors (TLRs) has been given to recognition of pathogens via TLRs expressed on antigen presenting cells (APCs). NK cells are ancient lymphocytes that have very close crosstalk with APCs. In recent years, there has been an interest in the avtivation of NK cells, similar to APCs, via direct stimulation with microbial PAMPs. This review focuses on TLRs and activation of NK cells by TLR ligands. We will review the evidence for direct and or indirect activation of NK cells by TLR ligands agonists. As the first line of defense against pathogens and...

Immunity And The Lymphatic System

The immune system consists of defenses against foreign matter that gains entry to the body. It consists of the lymphatic system plus components of numerous other systems of the body. Many toxic pollutants either stimulate or suppress the immune system. The lymphatic system consists of lymph, lymphatic vessels, lymphocytes, and lymphoid tissues and organs. Lymph is a fluid similar to plasma. Lymphatic vessels are similar in structure to veins. They conduct lymph from peripheral tissues to the veins. Capillaries deliver more liquid to tissues than they carry away. The rest forms intercellular fluid that collects as lymph. The most important lymphoid organs are the lymph nodes, the spleen, and the thymus. The lymph nodes contain immune system cells that remove pathogens from the lymph before they reach the bloodstream. The tonsils are lymph nodes positioned to respond to infections arriving by way of the mouth or nose. The thymus produces T cells (described below). The spleen performs...

Pathology and Histopathology

The principal difference between the benign fibroma syndrome described above and the devastating disease caused by MYX in Oryctolagus rabbits is that the latter virus efficiently propagates in host lymphocytes and is able to circumvent the cell-mediated immune response to the viral infection. The subcutaneous tumors consist of proliferating undifferentiated mesenchymal cells, which become large and stellate with prominent nuclei ('myx-oma' cells). In surrounding tissue there can be extensive proliferation of endothelial cells of the local capillaries and venules, often to the point where complete occusion leads to extensive necrosis of the infected site. The overlying epithelial cells can show hyperplasia or degeneration, depending on the virus strain, and poxviral inclusion bodies are frequently observed in the prickle-cell layer. In some MYX strains, primary and secondary skin tumors can undergo extensive hemorrhage and internal lesions may be found in the stomach, intestines, and...

Immunological Abnormalities of the obob and dbdb Mouse

Impaired cellular immune function was noted nearly 20 yr ago in both ob ob and db db mice, long before the discovery of leptin (76-80). Leptin-deficient ob ob mice and receptor-defective db db mice have been found to exhibit defective cell-mediated immunity and lymphoid atrophy analogous to that observed in chronic human undernutrition, in which leptin levels are low. In one study, skin graft rejection from a fully allogeneic mouse strain was delayed when grafted onto db db mice compared with wild-type controls (77). These mutant mouse strains also show increased susceptibility to pathogens, most notably to coxsackie virus. In one study, infection of db db mice with coxsackie virus caused 100 mortality, as opposed to less than 10 mortality in the wild-type control group (80). Of note, there seemed to be a discrepancy between the in vivo and in vitro results in that cellmediated immune responses were significantly impaired in vivo, but in vitro T-cell responses were less affected (77)....

Functions of Viral Proteins

The functions of the individual viral proteins encoded by animal viruses are somewhat analogous to their HPV counterparts. The E5 protein of BPV-1 is the primary transforming protein and promotes proliferation of infected cells. It is a membrane protein that can transform fibroblasts by inducing constitutive, ligand-independent activation of the p-type platelet-derived growth factor receptor (PDGF-Rp), and by interfering with Golgi acidification. BPV-4 E5 also transforms fibroblasts and disrupts gap junction-mediated intercellular communication. Many PV E5 proteins downregulate surface expression of major histocompatibility complex (MHC) class I molecules, which helps the virus to evade the host immune system.

Functions of Papillomavirus Proteins

The most prominent target of E6 is the cell-cycle regulator and tumor suppressor p53. E6 and p53 form a trimeric complex including a protein called E6AP. E6AP is a ubiquitin ligase and the trimeric association results in p53 degradation. As a consequence, p53 is lost as inducer of the cdk inhibitor p21CIP, and the cell cycle of the infected cell is set free to undergo G1 S transition, creating an environment favorable to viral DNA replication, and establishing a prerequisite for oncogenic transformation. p53 is also known to be an inducer of apoptosis, and p53 elimination by E6 protects against this mechanism, which would otherwise eliminate infected cells and terminate PV replication. Yet other functions of E6 include the modulation of transcription by affecting the cofactor CBP p300, effects on the immune response by interactions with the interferon regulatory factor-3, and alterations of cell shape and signaling by reaction with hDlg in a manner similar to a pathway that is induced...

Food Intake Regulation by Central Complement System

Complement C3a and C5a are released from C3 and C5, respectively, on activation of the complement system and play an important role in immune response. C3a, C5a and their receptors have been revealed to be present in the central nervous system (CNS) as well as the peripheral immune system. We found that centrally administered C3a suppresses food intake, while C5a stimulates food intake, and their food intake regulation may be associated with the prostaglandin system. We propose that complement C3a and C5a are regulators not only of the immune system but also of the CNS.

Experimental Erectile Dysfunction

Erectile capacity was evaluated by measuring the intracavernous pressure response to cavernous nerve stimulation (ranging from 0.5 to 10 mA). In the first series of experiments, ANOVA revealed increased engorgement pressure in treated animals. A second series of experiments further examined the dose dependence and duration of gene transfer. The intracavernous pressure response to submaximal (0.5 mA) and maximal (10 mA) nerve stimulation was evaluated 3 or 4 months postinjection of a single dose of pcDNA-hSlo ranging from 10 to 1000 g. ANOVA again revealed that hSlo overexpression was associated with increased nerve-stimulated pressure responses compared with responses in corresponding control animals. Histological studies revealed no immune response to the presence of hSlo. Polymerase chain reaction analysis documented that expression of both plasmid and transcript were largely confined to the corporal tissue. In the third series of pharmacological experiments, hSlo gene transfer in...

Self versus Modified Self Discrimination

The apparent contradiction between the two opposing functional effects of PTX3 might be resolved if the context of the protein production is taken into account. In fact, on one hand cell-bound PTX3 might serve to enhance the elimination of apoptotic cells before loss of their cell-membrane permeability and release of self-antigens and alarmins (Jaillon et al. 2009). On the other, rapid production and secretion of PTX3 during inflammation might avoid capture of apoptotic cells in a pro-inflammatory setting that is likely to trigger an immune response against self antigens (Jeannin et al. 2008). Data obtained in vivo actually support the hypothesis that PTX3 plays a protective role in a murine model of systemic lupus erythemato-sus (Lech et al. 2011).

Hematological Disorders Associated with EBV

Immunosuppression significantly increases the risk to develop EBV-associated malignant diseases because of the immortalizing and transforming properties of the virus. More than 90 of posttransplantation lymphoproliferative disorders (PTLD) are related to EBV. PTLD is variable with respect to morphology and clonality. In general, monoclonal tumors are more aggressive than polyclonal ones, likely because of additionally acquired genetic mutations enabling immune escape. Polyclonal proliferation often progresses to oligoclonality or mono-clonality without intervention.

Management Of Ebvassociated Diseases

Most cases of infectious mononucleosis do not require therapeutic intervention. In cases of clinically severe IM and life-threatening forms of SCAEBV, intravenous application of the nucleoside analog acyclovir or gancy-clovir may be necessary to reduce active viral replica-tion. 4 In addition, but not alone, antiphlogistic drugs to reduce the unspecific effects of the cellular immune response may be beneficial. Tonsillectomy is frequently used and was found to reduce symptoms of IM possibly

Concluding Remarks and Future Directions

Despite the debate surrounding direct vs. indirect NK cell activation via TLR ligation, the evidence supports the fact that NK cells are highly sensitive to the presence of pathogens and their various PAMPs, and can be easily stimulated to respond efficiently and effectively to tumors and virus infected cells. Different ligands have varying abilities to influence the cytolytic functions, cytokine induction, receptor up-regulation and proliferation of NK cells, with varying capacities within NK cell subsets, as well as between species. Additional cytokines or chemokines may be required in many instances for successful NK cell functions, however, they may not induce responses on their own in a physiologically relevant manner. Many of these NK cell functions can be up-regulated or synergized when coupled with one or more relevant cytokine. To determine the effects of the TLR ligands on NK cells, it is absolutely important to examine several aspects of NK cell activity, cell phenotypes...

Generation of Mouse Dendritic Cell Lines

Dendritic cells (DC) are now recognized as major players in the control of immune responses (1), since they direct both the quality and the extent of the adaptative response. Thus, DC represent a very appropriate means for the manipulation of harmful or protective immunity (2-4). As DC are present in both lymphoid and nonlymphoid tissues, but in relatively low numbers, it is difficult to obtain large numbers of these cells with a high degree of purity. For many types of studies it would be beneficial to have reliable methods to generate and, therefore, to grow large numbers of homogeneous DC. In particular, the molecular basis for the unique immunostimula-tory properties of DC, the precise mechanism of antigen handling, and the biochemical pathways of signal transduction have all been only marginally investigated. Furthermore, a complete characterization of DC physiology and the identification of DC-specific genes are a necessary prerequisite for an optimal use of DC in immunotherapy...

Structure and Function of the Respiratory System

Bronchial Circulation 268 Pulmonary Vascular Pressures 269 Pulmonary Vascular Resistance 269 Distribution of Blood Flow 271 Control of Pulmonary Blood Flow 272 Lung Fluid Balance 273 Nonrespiratory Functions of the Lung 273 Airway Defense Mechanisms 273 Immune System Defense Mechanisms 275 Biosynthetic Functions 276

Immunomodulation by ORFV

In general, PPV infection is mild and localized with more severe disease only occurring in stressed or otherwise immune-impaired individuals. An intriguing feature of PPVs is the ability to repeatedly infect animals despite an apparently typical antiviral immune response to infection. This may in part be a result of the action of viral-encoded immune modulators that are a feature of large DNA viruses. There are now several examples of these that have been identified within the terminal regions of the genome of ORFV. ORFV IL-10 (vIL-10) is the product of an early viral gene and the predicted protein is very similar to ovine IL-10 over the C-terminal two-thirds of the molecule while differing substantially at the N-terminus (80 amino acid sequence identity overall). The vIL-10 exhibited similar anti-inflammatory and immunostimulatory activities to ovine IL-10. Both cytokines suppressed TNF-a production from macrophages and suppressed IFN-g production from peripheral blood cells. Both...

Properties of the Proteins

Polymerase, with protein priming, reverse transcriptase, and RNase H activity, carries out viral DNA synthesis. The 305 amino acid PreCore core protein is processed and secreted from the infected cell, as the viral c-antigen. The function of the e-antigen is unknown. It has been conjectured that this core related protein protects infected cells from the antiviral immune response.

PPVs as Vectors and Immunomodulators

ORFV could prove useful as a vector for delivering micro-bial antigens to the immune system. Proof of concept for this has been obtained with protective immunity generated to pseudorabies virus and Borna disease virus infection of rodents. The restricted host ranges ofthe PPVs and lack of systemic spread even in immuno-compromised animals make them good viral vector candidates. Furthermore, inactivated ORFV particles have been shown to exhibit nonspecific immuno-modulatory effects that enhance immunity to a variety of pathogens in several species. This is thought to be mediated by IFN and a type 1 immune response that is downregulated at later stages by IL-10, among other cytokines. This feature of ORFV continues to be exploited commercially.

Environmental Toxicity

We have previously reviewed the potential for combined or sequential effects of chemical and pathogen exposure on the susceptible host 2 , potentially through modulation of immune function. The likelihood that microbicides or their DBPs are involved in such processes would depend on their immuno- or genotoxicity and on the risks of exposure to them. However, it is clear that several demographic trends 27 , including increased urbanization, raise the frequency of exposure to both chemicals and pathogens, and therefore the risks of such combined or sequential exposures.