bluuebunny/crossref_metadata_2025 huggingface dataset:
Enzymatic and extraenzymatic role of ecto‐adenosine deaminase in lymphocytes
Authors: Franco Rafael , Valenzuela Agustin , Lluis Carmen , Blanco Julià
Published: April 2006

Summary: Adenosine deaminase (ADA, EC 3.5.4.4) is an enzyme of the purine metabolism which has been the object of considerable interest mainly because the congenital defect causes severe combined immunodeficiency (SCID). In the last 10 years, ADA, which was considered to be cytosolic, has been found on the cell surface of many ceils and, therefore, it can be considered an ecto‐enzyme. There is recent evidence about a specific role of ecto‐ADA, which is different from bat of intracellular ADA. Apart from degrading extracellular adenosine (Ado) or 2′‐deoxyadenosLne (dAdo), which are toxic for lymphocytes, ecto‐ADA has an extraenzymatic function via its interaction with GD26. ADA/CD26 interaction results in co‐stimulatory signals in T cells. This co‐stimulation is blocked by HIV‐1, thus evidencing a role for ecto‐ADA in the pathophysiology of AIDS. The fact that, besides CD26, ADA can interact with different cell‐surface proteins opens new perspectives in the research for a role of ecto‐ADA in the function of the immune system and in the Interactions that take place between different cells in the development of the immune system. The most interesting aspect is the possible participation of the ecto‐enzyme in cell‐to‐cell contacts during ontogenesis and maturation of immunocompetent cells.
Dipeptidyl‐peptidase IV/CD26 on T cells: analysis of an alternative T‐cell activation pathway
Authors: von Bonin Arne , Hühn Jochen , Fleischer Bernhard
Published: April 2006

Summary: CD26 is a proteolytic enzyme (dipeptidyl‐peptidase IV) with a wide tissue distribution and a unique specificity that was already described 27 years ago. CD26 is expressed on a fraction of resting T cells at low density but is strongly upregulated following T‐cell activation. Recent results indicate that CD 2 6 is a muitifunctional molecule that may have important functions on T cells and in the immune system. It is associated with molecules of immunological importance such as the protein tyrosine phosphatase CD45 and adenosine deaminase (ADA) on the cell surface. Synthetic inhibitors of the enzymatic activity of CD26 have been shown to suppress certain immune reactions in vitro and in vivo. An interesting feature of CD26 is its ability to transmit a transmembrane signal to trigger functional programs in T cells. This triggering requires crosslinking of CD26 on a cell membrane. The enzymatic activity of CD2 6 is not obligatory for the activation of T cells via CD26. Since CD26 is a type II membrane protein with only six intracellular amino acids, it must deliver its signal via a signal‐transducing molecule. Signaling is dependent on the expression of the T‐cell receptor (TCR) complex with a special need for a functional ζ‐chain. In this context the ζ‐chain of the TCR complex is required for CD26‐mediated signaling but, in contrast to other co‐stimulatory molecules such as the CD2 molecule, is not sufficient for triggering the T cell.
The structure and function of CD26 in the T‐cell immune response
Authors: Morimoto Chikao , Schlossman Stuart F.
Published: April 2006

Summary: CD26 is a widely distributed 110 kD cell‐surface glycoprotein with known dipeptidyl‐peptidase IV (DPP‐IV) activity in its extracellular domain. This ectoenzyme is capable of cleaving amino terminal dipeptides from polypeptides with either L‐proline or L‐alanine in the penultimate position. On human T cells, CD26 expression appears late in thymic differentiation and is preferentially restricted to the CD4+ helper/memory population, and CD26 can deliver a potent co‐stimulatory T‐cell activation signal. The cDNA sequence of CD 26 predicts a type II membrane protein with only 6 amino acids in its cytoplasmic region, suggesting that, in addition to DPP‐IV enzyme activity, other signal‐inducing molecules may be associated with CD26, Considerable evidence exists that CD26 interacts, presumably in its extracellular domain, with bothCD45, a protein tyrosine phosphatase, and adenosine deaminase (ADA), each of which is capable of functioning in a signal transduction pathway. In addition, CD26 is the receptor for ADA, and ADA on the cell surface is involved in an important immunoregulatory mechanism by which released ADA binds to the cell‐surface ADA. This multifunctional molecule may be involved in cell migration and the HIV‐1‐associated loss of CD4+ cells though the process of programmed cell death. Thus, CD26 appears to play a key role in a number of aspects of lymphocyte function.
CD38: a new paradigm in lymphocyte activation and signal transduction
Authors: Lund Frances E. , Cockayne Debm A. , Randall Troy D. , Solvason Nanette , Schuber Francis , Howard Maureen C.
Published: April 2006

Summary: CD38 is a type II transmembrane glycoprotein that is extensively expressed on cells of bematopoietic and non‐hematopoietic lineage. Although the intracellular domain of CD38 is not homologous to any known proteins, the extracellular domain of CD38 is structurally related to enzymes in the ADP‐ribosyl cyclase family. The structural homology between CD 38 and die cyclase family members extends to functional homology, as the extracellular domain of CD 38 can mediate the catalysis of β‐NAD+ into nicotinamide, ADP‐ribose (ADPR) and, to a lesser extent, into cychc ADPR‐ribose (cADPR). Extensive investigation in other systems has shown tbat cADPR is an important regulator of intracellular Ca2+ release. Since engagement of CD38 on bematopoietic cells with anti‐CD38 Abs has been shown to have potent effects on a number of in vitro cellular responses, we have speculated that cADPR might control CD38‐mediated signal transduction. However, it has been difficult to understand how a mediator which is typically an intracellular signaling molecule could potentiate its effects from an extracellular location, thus posing a dilemma which pertains to all ecto‐enzymes and the mechanisms by which they regulate signal transduction and cellular processes. This review describes the biologic properties ofmurineCD38, its role in humoral immunity, and its signal transduction properties in B lymphocytes. We suggest that signaling through CD38 represents a new paradigm in lymphocyte signal transduction and is predicated upon extracellular, rather than intracellular, crosstalk.
Ecto‐ATPase: an activation marker necessary for effector cell function
Authors: Dombrowski Kenneth E. , Ke Yong , Brewer Kenneth A. , Kopp Judith A.
Published: April 2006

Summary: Ecto‐ATPase, a transmembrane enzyme that catalyzes the hydrolysis of extracellular ATP (ATPJ to ADP and inorganic phosphate, is expressed upon cell activation, Ecto‐ATPase is inhibited by non‐hydrolyzable ATP analogues, which are competitive inhibitors of the catalytic reaction, and the ATP analogue affinity label, 5′‐p‐(fluorosulfonyl)benzoyl adenosine (5′‐FSBA), which irreversibly inhibits the catalytic activity. These nucleotide antagonists do not cross the cell membrane and are specific for ecto‐ATPase in T cells, B cells and NK cells. Inhibition of ecto‐ATPase by both reversible and irreversible nucleotide ant agonists results in the inhibition of antigen induced cytokine secretion and cytolytic activity of T cells. Likewise, granule release and cytolytic activity of NK cells as well as antibody secretion and spontaneous proliferation by B‐cell hybridomas are inhibited. Inhibition of ecto‐ATPase does not influence effector cell‐target cell conjugate formation, but acts, in part, by regulating the influx of extracellular calcium that is necessary to maintain cellular activation. Thus, further elucidation of ecto‐ATPase regulation and expression and its interaction with intracellular signal transduction events will provide a basis for understanding the role of the hydrolysis of ATPe by ecto‐ATPase in lymphocyte effector function.
Chemokine receptor trafficking and viral replication
Authors: Pelchen‐Matthews Annegret , Signoret Nathalie , Klasse Per J. , Fraile‐Ramos Alberto , Marsh Mark
Published: April 2006

Summary: Chemokines and chemokine receptors have emerged as crucial factors controlling the development and function of leukocytes. Recent studies have indicated that, in addition to these essential roles, both chemokines and chemokine receptors play critical roles in viral infection and replication. Not only are chemokine receptors key components of the receptor/fusion complexes of primate immunodeficiency viruses, hut chemokines can also influence virus entry and infection. Many viruses, in particular herpesviruses, encode chemokines and chemokine receptors that influence the replication of both the parent virus and other unrelated viruses. The cell surface expression of the chemokine receptors is regulated through their interaction with membrane trafficking pathways, ligands induce receptor internalization and downmodulation through endocytosis, and recycling is regulated within endosomes. Pan of the mechanism through which chemokines protect cells from HIV infection is through ligand‐induced internalization of the specific chemokine receptor co‐receptors. In addition, mechanisms may exist to regulate the trafficking of newly synthesized receptors to the cell surface. Here we discuss aspects of the mechanisms through which chemokine receptors interact with membrane‐trafficking pathways and the influence of these interactions on viral replication.
Evolutionary dynamics of HIV‐induced subversion of the immune response
Authors: Wodarz Dominik , Nowak Martin A.
Published: April 2006

Summary: Human immunodeficiency virus (HIV) disease progression is characterised by a slow but steady decline in the number of CD4+ T cells. It results in the development of AIDS when the immune response collapses and the virus grows uncontrolled. Pathogenicity of HIV may be due to viral escape from cellular immune responses as well as virus‐induced immune impairment. Here we discuss how the dynamic interactions between the virus population and the immune response may lead to the development of AIDS. In particular we argue that in vivo evolution of HIV may be the driving force successively weakening the immune system. This may lead to increased levels of viraemia as well as to the evolution of more virulent phenotypes which indicate progression to AIDS. These insights are important for understanding the disease process itself and for designing effective treatment regimes.
Measles: immunosuppression, interleukin‐12. and complement receptors
Authors: Karp Christopher L.
Published: April 2006

Summary: Measles virus, the first pathogen recognized to cause immunosuppression, induces profound and prolonged abnormalities in cellular immune responses in infected hosts. The ability of measles virus to specifically ablate monocyte/macrophage and dendritic cell production of interleukin (IL)‐12 provides a potentially unifying mechanism for many of these in vivo and in vitro abnormalities. Cross‐linking of the cellular receptor for measles virus, the complement regulatory protein CD46. is sufficient to inhibit IL‐12 production. CD46‐mediated downregulation of IL‐12 has turned out to be a specific instance of a more general pattern of tight inhibitory control over IL‐12 production effected by complement and phagocytic receptors on antigen‐presenting cells. Exploitation of these pathways by other intracellular pathogens is likely.
Human pathogen subversion of antigen presentation
Authors: Brodsky Frances M. , Lem Lawrence , Solache Alejandra , Bennett Elizabeth M.
Published: April 2006

Summary: Many pathogens have co‐evolved with their human hosts to develop strategies for immune evasion that involve disruption of the intra‐cellular pathways by which antigens are bound by class I and class II molecules of che major histocompatibility complex (MHC) for presentation ro T cells. Here the molecular events in these pathways are reviewed and pathogen interference is documented for viruses, extracellular and intra‐cellular bacteria and intracellular parasites. In addition to a general review, data from our studies of adenovirus, Chlamydia tmchamatis and Coxiella burnetii are summarized. Adenovirus E19 is the first viral gene product described that affects class I MHC molecule expression by two separate mechanisms, intracellular retention of the class I heavy chain by direct binding and by binding to the TAP transporter involved in class I peptide loading. Coxiella and Chlamydia both affect peptide presentation by class II MHC molecules as a result of their residence in endocytic compartments, although the properties of the parasitophorous vacuoles they form are quite different. These examples of active interference with antigen presentation by viral gene products and passive interference by rickettsiae and bacteria are typical of the strategies used by these different classes of pathogens, which need to evade different types of immune responses. Pathogen–host co‐evolution is evident in these subversion tactics for which the pathogen crime seems tailored to fit the immune system punishment.
Cytotoxic T lymphocytes to endogenous mouse retroviruses and mechanisms of retroviral escape
Authors: Green William R.
Published: April 2006

Summary: Mouse retrovirus‐induced lymphoma/leukemia and immunodeficiency are useful models for analogous human diseases. Both ecotropic (mouse tropic) and recombinant retroviruses, including the polytropic mink cytopathic focus‐inducing type, have been studied for disease pathogenesis and as targets for humoral and cellular immunity, particularly cyto‐toxic T‐lymphocyte (CTL) responses. For AKR/Gross marine leukemia viruses (MnLV) we have defined an immunodominant CTL epitope in the β 15E transmembrane anchor envelope protein and three minor/subdominant epitopes. Evidence is presented for retroviral escape from CTL by selection following genetic recombination and point mutation both within and outside CTL epitope sequences, and via endogenous retrovirus‐infected cell downregulation of the generation of anti‐AKR/Gross MuLV CTL. As demonstrated in vivo in naturally occurring non‐responder strains by adoptive transfer, and in vitro by cell‐mixing experiments, a central non‐responsiveness mechanism appears to be peripheral inhibition mediated by infected cells expressing MHC‐presented viral peptides. Such inhibition requires Fas expression by antiviral T cells; occurs upon TCR‐mediated recognition of virus‐infected. Fas ligand‐expressing “veto” cells; and apparently leads to an antigen‐specific form of activation‐induced cell death of T cells. In the LP‐BMS MuLV isolate that causes murine AIDS (MAIDS) retroviral variation also leads to CTL escape – the BMS‐helper virus bas altered forms of the immunodominant and two minor/subdominant epitopes. In contrast, a novel immunodominant CTL epitope is recognized by MAIDS‐resistant, but not MAIDS‐susceptible, strains. This epitope is uniquely encoded in an alternative translational reading frame of the viral gag gene. It also appears that the LP‐BM5 MuLV have co‐opted the cells of the immune system for retroviral pathogencsis – CD40/CD40L (CD154) interactions are required both for the initiation and progression of MAIDS.
Interplays between mouse mammary tumor virus and the cellular and humoral immune response
Authors: Acha‐Orbea Hans , Finke Daniela , Attinger Antoine , Schmid Sandie , Wehrli Nathalie , Vacheron Sonia , Xenarios Ioannls , Scarpellino Leonardo , Toellner Kai‐Michael , MacLennan Ian C. M. , Luther Sanjiv A.
Published: April 2006

Summary: Mouse mammary tumor virus has developed strategies to exploit the immune response. It requires vigorous immune stimulation to achieve efficient infection. The infected antigen‐presenting cells present a viral superantigen on the cell surface which stimulates strong CD4‐mediated T‐cell help but CDS T‐cell responses are undetectable. Despite the high frequency of superantigen‐reactive T cells, the superantigen‐induced immune response is comparable to classical antigen responses in terms of T‐cell priming, T‐cell—B‐cell collaboration as well as follicular and extra‐follicular B‐cell differentiation. Induction of systemic anergy is observed, similar to classical antigen responses wbere antigen is administered systemically but does not influence the role of the superantigen‐reactive T cells in the maintenance of the chronic germinal center reaction. So far we have been unable to detect a cytotoxic T‐cell response to mouse mammary tumor virus peptide antigens or to the superantigen. This might yet represent another step in the viral infection strategy.
General and specific immunosuppression caused by antiviral T‐cell responses
Authors: Zinkernagel Rolf M. , Planz Oliver , Ehl Stephan , Battegay Manuel , Odermatt Bernhard , Klenerman Paul , Hengartner Hans
Published: April 2006

Summary: Immunosuppression caused by the non‐cytopathic lymphocytic choriomeningltis virus (LCMV) (an RNA virus) is mediated by anti‐viral cytotoxic T cells that destroy LCMV‐infected cells, also of the immune system. While this immunopathological destruction of antigen‐presenting cells, macrophages and follicular dendritic cells and of some CD4+ T cells causes general immunosuppression and impairs immune response to third party antigens, it also enhances exhaustion/deletion of LCMV‐specific CD8+ T‐cell responses. LCMV seems in addition to infect neutralizing antibody‐producing B cells via the specific receptor; immunopathological LCMV‐specific CD8T T‐cell‐mediated elimination of these infected B cells (but not of uninfected internal virus antigen‐specific B cells) causes a highly specific immunosuppression that delays neutralizing antibody responses and thereby enhances virus persistence. Both generalized and specific immunosuppression by CD8+ T‐cell‐mediated immunopathology may be involved in human infections with HIV; hepatitis B virus or hepatitis C virus.
Tumor necrosis factor‐a and the progression of diabetes in non‐obese diabetic mice
Authors: Green E. Allison , Flavell Richard A
Published: April 2006

Summary: In the past decade, a wealth of information has accumulated through studies in non‐obese diabetic (NOD) mice regarding the molecular and cellular events that participate in the progression to diabetes in insulin‐dependent diabetes mellitus (IDDM). One molecule that has received considerable attention is the inflammatory cytokine tumor necrosis factor‐a (TNF‐α). TNF‐a has been demonstrated to have a positive or negative effect on the progression to diabetes in NOD mice, although the mechanism by which TNF‐α exerts these differential outcomes is unknown. Here we describe a new NOD model for analyzing the role of TNF‐α in IDDM, TNF‐α‐NOD mice, TNF‐cc‐NOD mice express TNF‐a solely in their islets from neonatal life onwards, and develop accelerated progression to diabetes. This rapid progression to diabetes is related to earlier and more aggressive infiltration of the islets with immune cells and an enhancement in the presentation of islet antigen in situ in the islets by islet‐infiltrating antigen‐presenting cells to T cells. Although adoptive transfer studies demonstrated that TNF‐α can enhance presentation of islet antigen to both effector CD4‐ and CD8+ T cells, further investigations in TNF‐α‐NOD mice deficient in either CD4+ or CD8 *‐ T cells demonstrated that diabetes progression is dependent on CD8+ T cells, with CD4+ T cells playing a lesser role. The data accumulating from TNF‐α‐NOD mice, described in this review, indicates novel pathways by which inflammatory stimuli can precipitate autoimmunity, and suggests newer approaches in the design of therapeutic treatments that prevent β‐cell destruction in IDDM.
Dissecting the role of CD4+ T cells in autoimmune diabetes through the use of TCR transgenic mice
Authors: Suri Anish , Katz Jondthdn D.
Published: April 2006

Summary: Insulin‐dependent diabetes mellitus (IDDM) is an Immunological disorder wherein autoimmune‐mediated destruction of islet cells in che pancreas results in persistent hyperglycemia. The non‐obese diabetic mouse model of IDDM has revealed che importance of multiple factors that impact upon che disease process; however, understanding of primary immune mechanisms leading to IDDM remains elusive. The emergence of transgenic mouse models for IDDM has made importance contributions towards clarifying many of these factors, including the cell types, che various effector molecules and the genetic elements Involved in the pathogenesis of IDDM, In this review, we will focus on the primary mechanism and mediators of islet β‐cell death, the impact of T‐helper lymphocytes on disease progression and the potential role of major histocompatibility complex class II molecules in conferring susceptibility to IDDM.
The central and multiple roles of B cells in lupus pathogenesis
Authors: Chan Owen T. M. , Madaio Michael R , Shlomchik Mark J. , Chan Owen I. M. , Madaio Michael P. , Shlomchik Mark J.
Published: April 2006

Summary: A standard view of B cells in systemic autoimmunity is that they promote lupus by producing autoantibodies (autoAb). However, this view is incomplete because recent studies have revealed that autoimmune disease can be dissociated from autoAb deposition. Furthermore, the spontaneous T‐cell activation and organ infiltration in systemic lupus erythematosus patients and animal models are difficult to explain entirely via a direct autoAb‐mediated mechanism. In this review, we describe work addressing the B‐cell functions of autoantigen presentation and autoAb production in lupus pathogenesis. In the JHD‐MRL‐Faslpr strain (JHD/lpr), a B‐cell‐deficient version of the lupus‐prone MRL‐Faslpr (MRL/lpr) mouse, spontaneous nephritis and dermatitis is abrogated, demonstrating that B cells have a primary role in disease. B cells play a similar role in Fas‐intact, lupus‐prone MRL mice. To address the role of autoantigen presentation, we analyzed transgenic mice which have B cells that cannot secrete immunoglobulin (mIgM transgenic mice). The restoration of B cells without antibody caused substantial interstitial nephritis and vasculitis although less marked than the intact MRL/lpr controls. To address the role of autoAb, we infused serum from aged MRL/lpr mice into JHD/lpr mice. At most, mild to no nephritis was observed in the infused mice. These results indicate that B cells are promoting autoimmunity in mechanisms other than autoAb secretion, and we describe a model depicting these B‐cell roles in the context of other inflammatory events in lupus.
Different modes of pathogenesis in T‐cell‐dependent autoimmunity: clues from two TCR transgenic systems
Authors: JI Hong , Korganow Anne‐Sophie , Mangialaio Sara , Höglund Petter , André Isabelle , Lühder Fred , Gonzalez Antonio , Poirot Laurent , Benoist Christophe , Mathis Diane
Published: April 2006

Summary: T lymphocytes constantly flirt with reactivity to self peptides, a price they pay for their ability to recognize foreign peptides presented by self‐MHC molecules, and autoreactivity in the T compartment occasionally gives rise to autoimmune disease. Pathology from T‐cell autoimmunity can manifest itself through radically different strategies, as we have observed recently in two transgenic models. In the BDC2.5 diabetes model, T cells express a transgene‐encoded T‐cell receptor (TCR) with reactivity against a pancreatic antigen. This leads to a massive, if often controlled, infiltration of the pancreatic islets. Target cell destruction then results from the local consequences of this local Immune/inflammatory process. On the other hand, the arthritic manifestations of the KRN transgenic model are indirect: the transgenic TCR confers a broad autoreactivity, through which T cells stimulate B cells to produce arthritogenic immunoglobulins. These molecules are then sufficient to produce the disease, even in the complete absence of any lymphocytes. Although important questions subsist in this model ‐ how the KRN T cells interfere with B‐cell tolerance, what the tar‐get of arthritogenic IgG is ‐ its implication is that an isolated T‐cell dysregulation may manifest itself through an Ig‐mediated disease.
On the role of tumor necrosis factor and receptors in models of multiorgan failure, rheumatoid arthritis, multiple sclerosis and inflammatory bowel disease
Authors: Kollias George , Douni Eleni , Kassiotis George , Kontoyiannis Dimitris
Published: April 2006

Summary:The specific role of the tumor necrosis factor (TNF)/TNF receptor (TNFR) system in disease pathogenesis still remains an unresolved puzzle. Recent studies in transgenic and knockout animals, where the pathogenic influence of genetically perturbed TNF expression has been evaluated, indicate that several pathways of TNF/TNFR action may contribute independently or in concert to initiate, promote or downregulate disease pathogenesis. Evidently, organ‐specific inflammatory or autoimmune pathology may ensue due co sustained activation by TNF of innate immune cells and inflammatory responses, which may consequently lead to tissue damage and co organ‐specific chronic pathology. However, more cryptic functions of this molecule may be considered Co play a significant pare in che development of TNF‐mediated pathologies. Direct interference of TNF with the differentiation, proliferation or death of specific pathogenic cell targets may be an alternative mechanism for disease initiation or progression. In addition Co these activities, there is now considerable evidence to suggest that TNF may also directly promote or downregulate the adaptive immune response. It is therefore evident that no general scenario may adequately describe the role of TNF in disease pathogenesis. In this article, we aim to place these diverse functions of TNF/TNFRs into context with the development of specific pathology in murine models of multiorgan failure, rheumatoid arthritis, multiple sclerosis and inflammatory bowel disease.
Autoaggression and tumor rejection: it takes more than self‐specific T‐cell activation
Authors: Ganss Ruth , Limmer Andreas , Sacher Torsten , Arnold Bernd , Hämmerling Günter J.
Published: April 2006

Summary: Establishment of self‐tolerance prevents autoaggression against organ‐specific self‐antigens. This beneficial effect, however, may In turn be responsible for tumor immune evasion. Thus, dissecting the mechanisms leading to the breakdown of self‐tolerance in autoimmune diseases might provide insights for successful antitumor immune therapies. In a variety of animal models, organ‐ or tumor‐specific immunity has been described, focusing on antigen‐specific T‐cell activation. Here, we discuss two trans ‐genic mouse models which demonstrate that both autoaggression and tumor rejection require more than activated, self‐reactive T cells. TCR transgenic mice, which are tolerant to a liver‐specific MHC class I antigen, Kb, can be activated to reject Kbb‐positive grafts, but fail to attack Kb‐expressing liver. However, autoaggression occurs when activated T cells are combined with “conditioning” of the target organ by irradiation or infection with a liver‐specific pathogen. Similarly, in a mouse model of islet cell carcinoma, neither co‐stimulatory tumor cells nor highly activated antitumor lymphocytes provoke an effective immune response against the tumor. Instead, a combination of activated lymphocytes and irradiation is required for lymphocyte infiltration into solid tumors. Both model systems provide evidence that although activated antigen‐specific lymphocytes are a prerequisite for autoaggression, effector cell extravasation and appropriate interaction with the target organ/tumor are equally important. Thus, we propose that the organ/tumor microenvironment is a critical parameter in determining the effectiveness of an anti‐self immune response.
Gene targeting in the analysis of mammalian apoptosis and TNF receptor superfamily signaling
Authors: Yeh Wen‐Chen , Hakem Razqallah , Woo Minna , Mak Tak W.
Published: April 2006

Summary: Apoptosis, or programed cell death (PCD), is che subject of much current investigative interest. Developing embryos and many adult organ systems require che tight coupling of cellular proliferation and PCD Co ensure proper organogenesis and optimal tissue function. Over the past decade, our knowledge of the genetic basis underlying the execution of apoptosis in mammals has progressed enormously, thanks largely to groundbreaking studies performed in the nematode Caenorhabditis elegans. In contrast, the components of the signaling apparatus that links che various death stimuli and the receptors they stimulate to the execution mechanism remain relatively unknown, it is only in the past 4 years that studies of signal transduction via members of the tumor necrosis factor (TNF) receptor superfamily have identified a plethora of novel, signaling proteins, including molecules that are directly involved in apoptosis signaling, and others that regulate che induction of cell death. This two‐part review focuses on the biology of apoptosis and signaling through members of the TNF receptor superfamily as revealed by the study of gene‐targeted “knockout” mice. These genetic mutant animals are invaluable tools not only for confirming or refuting a proposed function of a particular gene in an in vivo setting, but also for uncovering novel functions for a gene that were not anticipated from conventional in vitro experiments. In the field of apoptosis, as for many other areas of biomedical research, knockout mice and cell lines can be used as models for studying human disease, with the ultimate goal of developing therapeutic strategies.
Cell‐based vaccines for the stimulation of immunity to metastatic cancers
Authors: Ostrand‐Rosenberg Suzanne , Pulaski Beth A. , Clements Virginia K. , Qi Ling , Pipeling Matthew R. , Hanyok Laura A.
Published: April 2006

Summary: We are developing vaccines for inducing immunity lo metastatic cancers. Although primary tumors are frequently cured by surgery, chemotherapy, or radiation therapy, metastatic lesions often do not respond lo these treatments or proliferate after conventional therapy is terminated. Vaccine therapy for established metastases as well as prophylactic vaccine treatment to prevent outgrowth of latent metastatic tumor cells would therefore be beneficial. Our goal is to activate CD4+ and CDS+ T lymphocytes; however, we have focused on activating tumor‐specific CD4+ T‐helper lymphocytes because of their pivotal role as regulatory cells and in the generation of long‐term immunological memory. The vaccines are based on the premise that tumor cells express potentially immunogenic antigens that could be targeted for T‐cell activation, and that if appropriately genetically modified, tumor cells could be antigen presenting cells for these antigens. To facihtate direct antigen presentation to CD4+ T cells, tumor cells have been transfected with syngeneic major histocompatibility complex class II, co‐stimulatory molecule, and/or superantigen genes. In vivo studies in three mouse tumor models demonstrate that vaccination protects against future challenge with wild‐type tumor, cures some solid primary tumors, reduces established metastatic disease, and extends mean survival time. Antigen presentation studies demonstrate that m vivo vaccine efficacy is directly related to in vitro antigen presentation activity. The relevance of antigen presentation activity of the vaccines is further confirmed by in vivo studies demonstrating that during the immunization process, the vaccines directly present tumor‐encoded antigens to CD4+ T lymphocytes. Adaptation of these vaccines for the treatment of human metastatic cancers is discussed.
Live attenuated AIDS viruses as vaccines: promise or peril?
Authors: Ruprecht Ruth M.
Published: April 2006

Summary: Live attenuated viruses can provide vaccine protection against various viral illnesses, A number of live attenuated strains of the simian immunodeficiency virus (SIV) or related lentiviruses have been evaluated in primate models as vaccine candidates against AIDS, Impressive efficacy was observed for some viruses, most notably SIV strains with deletions in the nef gene. Sterilizing immunity was seen against homologous and heterologous virus challenge, against cell‐free and cell‐associated challenge, against intravenous and mucosal challenge, and against challenge as early as 3 weeks and as late as 2.25 years after just one immunization. However, these promising efficacy results are overshadowed by safety problems. such as reversion of the vaccine strain to a pathogenic virus encoding full‐length nef or residual virulence of multiply deleted vaccine strains. Strategies aimed at decreasing the replicative capacity of nef‐deleted vaccine strains to increase the safety profile have significantly curtailed vaccine efficacy. Nevertheless, studies of live attenuated vaccine strains should proceed and should focus on determining the correlates of vaccine protection and the molecular determinants for virulence and attenuation.
Approaches to improve engineered vaccines for human immunodeficiency virus and other viruses that cause chronic infections
Authors: Berzofsky Jay A. , Ahlers Jeffrey D. , Derby Michael A. , Pendleton C. David , Arichi Tatsumi , Belyakov Igor M.
Published: April 2006

Summary: We used several approaches to develop enhanced vaccines for chronic viral infections such as human immunodeficiency virus (HIV) and hepatitis C virus (HCV), I) Selected epitopes were used to avoid potentially harmful immune responses. 2) Linkage between helper and cytotoxic T‐lymphocyte (CTL) epitopes was found to be important, 3) We developed an “epitope enhancement” approach modifying the sequences of epitopes to make more potent vaccines, including examples for HIV and HCV epitopes presented by murine class II and human class I major histocompatibility complex (MHC) molecules, 4) CTL avidity was found to be important for clearing viral infections in vivo, and the mechanism was examined. High‐avidity CTLs, however, were found to undergo apoptosis when confronted with high‐density antigen, through a mechanism involving tumor necrosis factor (TNF), TNF‐RII, and a permissive state induced through the T‐cell receptor. 5) We employed cytokines in the adjuvant to steer immune responses toward desired phenotypes, and showed synergy between cytokines, 6) Intrarectal immunization with pep‐tide vaccine induced mucosal and systemic CTL, Local mucosal CTL were found to be critical for resistance to mucosal viral transmission and this resistance was enhanced with mucosally delivered interleukin‐12, 7) We used an asymmetry in induction of mucosal and systemic immune responses to circumvent pre‐existing vaccinia immunity for use of recombinant vaccinia vaccines.
Genetic vaccination strategies for enhanced cellular, humoral and mucosal immunity
Authors: Ramsay Alistair J. , Kent Stephen J. , Strugnell Richard A. , Suhrbier Andreas , Thomson Scott A. , Ramshaw Ian A. , Raima Alisiarr J. , Kent Stephen J. , Strugnell Richard A. , Suhrbicr Andreas , Thomson Scott A , Ramshaw Ian A.
Published: April 2006

Summary: In this article, we describe several novel genetic vaccination strategies designed to facilitate the development of different types of immune responses. These include: the consecutive use of DNA and fowlpoxvirus vectors in “prime‐boost” strategies which induce greatly enhanced and sustained levels of both cell‐mediated immunity and humoral immunity, including mucosal responses; ii) the co‐expression of genes encoding cytokines and cell‐surface receptors, and the use of immunogenic carrier molecules, for immune modulation and/or Improved targeting of vector‐expressed vaccine antigens; acid iii) the expression of minimal immunogenic arnino acid sequences, particularly cytotoxic CD8+ T‐cell determinants, in “polytope” vector vaccines. The capacity to modulate and enhance specific immune responses by the use of approaches such as these may underpin the development of vaccines against diseases for which no effective strategies are currently available.
The search for a vaccine against schistosomiasis ‐ a difficult path hut an achievable goal
Authors: MeManus Donald Peter
Published: April 2006

Summary: The search for an effective vaccine against schistosomiasis, a parasitic disease currently affecting over 200 million people, remains a desirable but as yet challenging and elusive goal. Progress in the area has been relatively slow but research demonstrating the ability of humans to acquire natural immunity to schistosome infection, together with the successful use in animals of attenuated vaccines, supplemented with encouraging results obtained with defined antigens, suggests that development of a vaccine is achievable. Noteworthy also are recent immune correlate findings which shed light on the complex, putatively protective immune responses in buinans, which have improved the prospects of success. With the first human clinical trial having been completed with a schistosome vaccine candidate, this review examines current progress aimed at achieving the objective of a safe and effective vaccine for widespread use against schistosomiasis. The review emphasises work undertaken in the author's laboratory and those of his chief collaborators in the search for a vaccine against schistosomiasis japonica, a disease of major public health significance in The People's Republic of China and The Philippines. Schistosomiasis vaccines should not be considered as the panacea for schistosomiasis control as, when available, it is generally envisaged that they would be used as one component of an integrated strategy complementing currently available and effective tools such as chemotherapy, improvements to sanitation, piped water supply, effective sewage draining and health education.
Evidence for a unique N‐linked glycan associated with human infertility on sperm CD52: a candidate contraceptive vaccinogen
Authors: Diekman Alan B. , Norton Elizabeth J. , Klotz Kenneih L. , Watkodk V. Anne , Herr John C.
Published: April 2006

Summary: A major objective in developing a sperm antigen‐based contraceptive vaccine for humans is the discovery of sperm surface immunogens that are functionally relevant and sperm specific. The latter criterion is deemed essential to avoid the possibility of inducing autoimmune disease upon vaccination. This review presents evidence that a unique carbohydrate epitope is synthesized in the human epididymis, is attached to the core peptide of CD52, a lymphocyte differentiation marker, and is subsequently inserted into the sperm membrane via a glycosylphosphatidylinositol anchor. This unique CDS2 glycoform is localized to the entire sperm surface, functions as a potent target for agglutitiating and cytotoxic antibodies, and is one of the few well‐defined sperm surface glycoproteins indicated in human antibody‐mediated infertility.
Class IMHC molecules: assembly and antigen presentation
Authors: Solheim Joyce C.
Published: April 2006

Summary: Several years ago, the only factor known to be necessary for the assembly and surface expression of class I MHC was pjm; even for β2m, it was unclear at what point in class I maturation its role was played. Recent experiments that employed attachment of an endoplasmic reticulum (ER) retention signal to β2m have shown that the point of time at which β2m is required is while the class I heavy chain is in the ER. Later association between β2m and class I is not vital in order for properly folded class I to be expressed at β2m cell surface. After crystallization of the first class I MHC molecule, it was reahed that not only is antigen presented by class I, but that antigen is presented in the form of a peptide that stabilizes the class I structure and allows its transit to the cell surface. Class I allelic differences influence interactions with both peptide and β2m, with likely consequences for the ability of the class I heavy chains to present antigen through alternative pathways. Furthermore, it is now also clear that formation of appropriate disulfide bonds in the class I heavy chain is needed before class I can bind peptide antigen securely, a process that may he assisted by an ER chaperone. Many different proteins that are resident in the ER, such as calnexin, transporter associated with antigen processing (TAP), caheticulin, and tapasin, have been found to be integral to class I assembly. TAP, tapasin, and calreticulin hind preferentially to the open form of class I, which can be distinguished with the use of a monoclonal antibody specific for this form. Calreticulin and calnexin contrast in their interactions with class I, despite other similarities between these two chaperones. Overall, class I MHC assembly is now understood to involve the interplay of multiple intra‐ and intermolecular events in a defined chronological order which ensure continual reporting of cellular contents to cytotoxic T lymphocytes.
The nature of the MHC class I peptide loading complex
Authors: Cresswell Peter , Bangia Naveen , Dick Tobias , Diedrich Gundo
Published: April 2006

Summary: Peptide binding to major histocompatibility complex (MHC) dass I molecules occurs in the endoplasmic reticulum (ER). Efficient peptide binding requires a number of components in addition co the MHC class I‐β2 microglobulin dimer (β2m). These include the two subunits of the transporter associated with antigen presentation (TAP1 and TAP2), which are essential for introducing peptides into the ER from the cytosol, and tapasin, an MHC‐encoded membrane protein. Prior to peptide binding, MHC class I‐β2m dimers form part of a large multisubnnit ER complex which includes TAP and tapasin. In addition to these specialized components two soluble ‘house‐keeping’ proteins, the chaperone calreticulin and the thiol oxidoreductase ERp57, are also components of this complex. Our current understanding of the nature and function of the MHC class I peptide loading complex is the topic of this review.
The role of endoplasmic reticulum‐associated protein degradation in MHC class I antigen processing
Authors: Wang Ye , Chen Di , Androlewicz Matthew J.
Published: April 2006

Summary: The processing and presentation of secretory glycoprotein antigens by the MHC class I processing pathway presents an interesting topological problem. That is, how do the luminal glycoprotein antigens gain access to the class I processing machinery located in the cell cytosol? Current data indicate that the retrograde transport of glycoproteins from the endoplasmic reticulum (ER) to cytosol represents the major pathway for ER‐associated protein degradation, and most likely represents a major pathway for the processing of glycoprotein antigens by MHC class I molecules as well. There is now a growing list of viral and tumor glycoprotein antigens that undergo retrograde transport from the ER to the cytosol and processing by the ubiquitin‐proteasome pathway of degradation. We review here some general aspects of this “ER degradation” pathway, and how it relates to the processing and presentation of class I‐associated viral and tumor antigens. In particular, we analyze the role of oligosaccharide trimming and ER molecular chaperones in this process. We would like to emphasize that the class I processing machinery has adapted a common cellular pathway for its use, and that this could lead to the identification of unique characteristics with regard to ER degradation and antigen processing.
Molecular interactions between extracellular components of the T‐cell receptor signaling complex
Authors: Garcia K. Christopher
Published: April 2006

Summary: The structural and biochemical basis of antigen recognition by the T‐cell receptor (TCR)‐CD3 signaling complex has been illuminated greatly over the past few years. Structural biology has contributed enormously to this understanding through the determination of crystal structures of many of the individual components of this complex, and some of the complexes, A number of general principles can be derived for the structure of the aP TCR and its interaction with peptide–major histocompatibility complex (pMHC) in class 1 systems, as well as interaction of the CDS co‐receptor with MHC, Large buried surface areas within the protein–protein interfaces, and varying degrees of shape complementarity appear critical for modulating the stability of the multicomponent, low‐affinity macromolecular complexes consisting of TCR, pMHC, CDS or CD4, and CD3 γ, δ, ɛ and ζ, Significant structural alterations in TCR and pMHC, upon complex formation, hint at an as yet unclear role for conformational change in both recognition and activation. Subtle chemical alterations in key peptide residues which contact the TCR can have dramatic agonist or antagonist effects on receptor activation, which correlate only loosely with the TCR/pMHC complex affinity, implying an ability of the signaling complex to “sense” for differences in the interface. The stoichiometry of an activated TCR signaling complex is stain an unresolved issue, as is the structure and disposition of the CD3 components. However, functional experiments are bridging this gap and providing us with preliminary working models of the multimeric assemblies.
Get into the groove! Targeting antigens to MHC class II
Authors: van Bergen Jeroen , Ossendorp Ferry , Jordens Reina , Mommaas A. Mieke , Drijfhout Jan‐Wouter , Koning Frits
Published: April 2006

Summary: The activation of MHC class Il‐restricted helper T cells is paramount to adaptive immune responses. Vaccine development could therefore benefit from improved ways of targeting antigens into MHC class II molecules. In recent years, the natural pathways of MHC class II antigen presentation have been exploited to achieve this goal, First, antigenic proteins and peptides have been modified to facilitate receptor‐mediated uptake by professional antigen‐presenting cells. Second, DNA constructs containing specific targeting seqtiences have been used to direct endogenously synthesized antigens to the MHC dass II compartments. Both strategies proved to be highly effective. We review these data and describe how this knowledge is currently applied to the design of vaccines that activate helper T cells in vivo.
Alternative pathways for processing exogenous and endogenous antigens that can generate peptides for MHC class I‐restricted presentation
Authors: Reimann Jörg , Schirmbeck Reinhold
Published: April 2006

Summary: The concept of distinct endogenous and exogenous pathways for generating peptides for MHC‐I and MHC‐II‐restricted presemation to CD4+ or CD8+ T cells fits well with the bulk of experimental data. Nevertheless, evidence is emerging for alternative processing pathways that generate peptides for MHC‐I‐restricted presentation. Using a well characterized, particulate viral antigen of prominent medical importance (the hepatitis B surface antigen), we summarize our evidence that the efficient, endolysosomal processing of exogenous antigens can lead to peptide‐loaded MHC‐I molecules. In addition, we describe evidence for endolysosomal processing of mutant, stress protein‐bound, endogenous antigens that liberate peptides binding to (and presented by) MHC‐I molecules. The putative biological role of alternative processing of antigens generating cytotoxic T lymphocyte‐stimulating epitopes is discussed.