bluuebunny/crossref_metadata_2025 huggingface dataset:
Recent advances in graft‐versus‐host disease (GVHD) prevention
Authors: Blazar Bruce R. , Korngold Robert , A. Daniel
Published: April 2006

Summary: In the 1970s and 1980s, GVHD prevention approaches were limited in number. Recent advances in our understanding of the requirements for T‐cell immune responses and for basic mechanism(s) involved in GVHD pathophysiology have led to exciting new strategies for GVHD prevention. This review focuses upon recent developments in GVHD prevention generated over the past S years. We have selected five different types of strategies to highlight including: 1) the in vivo targeting of GVHD‐reactive T cells using either intact and F(ab')2 fragments of monoclonal antibodies directed against T‐cell‐surface determinants or immunotoxins which consist of antibodies linked to toxins. 2) a comparison of the in vivo immunosuppressive effects of FK506 and rapamycin on T‐cell signaling, 3) the inhibition of T‐cell activation through blockade of costimulatory or adhesogenic signals. 4) shifting the balance between acute GVHD‐inducing T‐helper‐type I (Thl) T cells to anti‐inflammatory T‐helper‐type 2 (Th2)‐type T cells, and 5) the regulation of alloreactive T‐cell activation by treatment with peptide analogs which affect either TCR/MHC, CD4/MHC class II, or CD8/MHC class I interactions. Collectively, these approaches are illustratrative of the progress made in extending our GVHD prevention armamentarium.
Hematopoietic stem cell transplants from unrelated donors
Authors: Hansen John A. , Petersdorf Effie , Martin Paul J. , Anasetti Claudio
Published: April 2006

Summary: Transplantation of hematopoietic stem cells is now well established as life‐saving therapy for patients with several different genetic and acquired diseases. This has been possible largely because of the identification of HLA as the human major histocompatibility system and the application of new technologies for improving the accuracy of HLA typing and matching. Clinical advances including the development of more effective immune suppression therapy and improvements In supportive care have also been critically important. The lack of HLA‐identical sibling donors for most patients and the extensive polymorphism of HLA genes have necessitated establishing very large registries of HLA‐typed volunteers. With more than 3 million donors now available worldwide, the number of patients identifying HLA matches has increased substantially. Despite a higher incidence of graft‐versus‐host disease (GVHD). the results of unrelated donor transplants are favorable when performed under optimal conditions with a well‐matched donor. In order to provide transplants for all patients, improved methods for GVHD prophylaxis are needed that will make it possible to safely perform transplants even across limited degrees of HLA disparity.
Biology and adoptive cell therapy of Epstein‐Barr virus‐associated lymphoproliferative disorders in recipients of marrow allografts
Authors: O'Reilly Richard J. , Small Trudy N. , Papadopoulos Esperanza , Lucas Kenneth , Lacerda Joao , Koulova Lydia
Published: April 2006

Summary:Epstein‐Barr virus (EBV) is an ubiquitous herpesvirus which is carried as a latent infection of B lymphocytes and salivary gland epithelial cells in over 90% of normal adults. Latently infected IBV‐transformed B cells circulate at low frequency in the blood for the life of the host. These transformed B cells stimulate a heterogeneous and complex host cell response, ultimately leading to the development and maintenance of high frequencies of HLA‐restricted T cells specific for the EBV‐encoded nuclear antigens EBNA2–EBNA6 and the latency membrane proteins LMP‐1 and LMP‐2. Responses to latent EBV‐encoded proteins are hierarchical with responses to certain epitopes predominating, dependent upon the HLA genotype of the host. Profound suppression of T‐Cell immunity may permit the emergence of polyclonal, oligoclonal or monoclonal EBV antigen‐expressing lymphoproliferative disorders or malignant B‐cell lymphomas expressing these latent EBV antigens. Adoptive transfer of small numbers of peripheral blood mononuclear cells or HLA‐partially matched T cells from in vitro expanded EBV‐specific T‐cell lines derived from a seropositive marrow donor has induced durable regressions of bulky, widely metastatic monoclonal EBV lymphomas in a high proportion of cases. This review describes the current state of knowledge and hypothesis regarding the biology and immunology of EBV infection in the normal host, the features of donor, host and virus which contribute to the development of EBV‐associated lymphoproliferative diseases and the mechanisms whereby they are controlled by adoptive transfer of immune T cells.
Listeria monocytogenes in laboratory mice: a model of short‐term infectious and pathogenic processes controllable by regulated protective immune responses
Authors: Milon Geneviève
Published: April 2006

Summary:The mammalian immune system is an integrated network of tissues, leukocytes and effector and regulatory molecules. All these components operate i) to maintain the proper structure of and processes expressed by each tissue, and ii) to protect the hosts from those microorganisms that generally invade them as part of their life cycle. Among the invading microorganisms, Listeria monocytogenes (L. monocytogenes) can persist as a live organism independent of the host, and is, thus, able to drive short‐term infectious and pathogenic processes that are controlled by integrated innate and adaptive protective immune responses driven by CD8 and CD4 type 1 T lymphocytes acting on non‐T non‐B leukocytes. Although the effector functions and the fine specificity of T lymphocytes have been more and more characterized, an understanding of the precise regulation of both leukocyte traffic and T‐lymphocyte migration depends on knowledge of the early tissue distribution of L. monocytogenes, points that are addressed in this review.
Non‐specific resistance mechanisms to listeriosis: implications for experimental and naturally occurring infection
Authors: Czuprynski Charles J. , Haak‐Frendscho Mary
Published: April 2006

Summary: Use of murine listeriosis as an experimental model has greatly increased our understanding of the complex interplay of cells and mediators in non‐specific antibacterial resistance (innate immunity). Important contributions made with this experimental mode l include demonstrating the ability of inflammatory cytokines (i.e. IFN‐γ. IL‐1α, TNF‐α) to protect against bacterial infection, and illustrating the rapidity of the host cytokine response (detectable within 1 h of challenge) during bacterial infection. Most experimental studies of host defense against Listeria monocytogene (L. monocytogenes) have used a parenteral challenge (i.v. or i.p.). This ignores the pathogenesis of naturally occurring listeriosis, which usually results from ingestion of Listeria‐contaminated food products. In this review, we will include consideration of the host‐pathogen interactions that occur when L. monocytogenes invades through its natural portal of entry, the gastrointestinal tract. Although resistance to facultative intracellular pathogens, such as L. monocytogenes, was formerly thought to revolve exclusively around the T helper cell/macrophage axis, more recent evidence indicates that neutrophils are able to ingest and kill L. monocytogenes and prevent the unrestricted multiplication of listeriae in parenchymal cells. Exploring the mechanisms involved in this process will provide new insights into the communication between leukocytes and tissue cells in host defense.
Interleukin‐4 and listeriosis
Authors: Kaufman Stefan H. E. , Emoto Masashi , Szalay Gudrun , Barsig Johannes , Flesch Inge E. A.
Published: April 2006

Summary: Experimental infection of mice with Listeria monocytogenes (L. monocytogenes) has served as an appropriate model for analyzing Thl nil driven immune responses. Generally, Th2 responses are absent and IL‐4 is not detectable. Here, we describe experimental settings under which IL‐4 is detectable in listeriosis. Our data suggest that IL‐4 is rapidly produced after infection. This prompt IL‐4 burst seems to stimulate chemokine responses and, therefore, may participate in the regulation of the early antilisterial host response. Soon thereafter, lL‐4 production wanes. At least partially this seems to be caused by downregulation of IL‐4–producing CD4+ NK1+ TCRαβint lymphocytes by IL‐12. In the absence of IFN‐γ responsiveness, IL‐4 production is demonstrable during acquired immunity against L. monocytogenes, and this elevated IL‐4 production apparently contributes to disease exacerbation. In conclusion, the data are consistent with a detrimental role of IL‐4 in listeriosis and active control of IL‐4 synthesis by the antilisterial immune response. The rapid, but transient, IL‐4 burst in listeriosis probably contributes to host defense without impairing development of the acquired T‐cell response because of its shortness.
The cytokine stew and innate resistance to L. monocytogenes
Authors: Mocci Simonetta , Dalrymple Stacie A. , Nishinakamura Ryuichi , Murray Richard
Published: April 2006

Summary: The Listeria monocytogenes (L. monocytogenes) infection model has been a useful system to evaluate the cellular interactions leading to host immunity. The initiation of the innate immune response in naive animals and subsequent progression to acquired immunity represent an integrated system with numerous layers of complexity. Coincident with experimental infection is the induction of cytokines. Cytokines, which are soluble mediators of cell growth, maintenance and function, form a network of pleiotropic stimuli that serve as one of the main driving forces for the progressive development of cellular responses. A variety of in vivo approaches, such as injection of the recombinant cytokines themselves or antibodies lo neutralize their activity, have been used to define these stimuli. Perhaps one of the most useful tools is that of germline‐manipulated animals. One of the many cytokines implicated in resistance to L. monocytogenes Infection is interleukin (IL)‐6, a molecule associated with diverse infectious and pathophysiological disease states. This review concentrates on various cytokines (IL‐1, TNFα, IFN‐γ. IL‐12, IL‐10 and the colony‐stimulating factors (CSF)) thought to play a role during the innate host response to L. monocytogenes infection, with a special emphasis on studies using IL‐6‐deficient mice. Additionally, we show unpublished data obtained when the concepts learned from L. monocytogenes infection in IL‐6‐deficieni mice were applied :o other infection models.
Characterization of the murine H2–M3wt‐restricted CD8 response against a hydrophobic, protease‐resistant, phospholipid‐associated antigen from Listeria monocytogenes
Authors: Kurlander Roger , Nataraj Chandrasekaran
Published: April 2006

Summary: Mice infected with Listeria monocytogenes (LM) generate protective CD8 cells of varying specificity. One subset, unlike conventional LM‐immune CDS cells, can respond to antigen‐presenting cells (APC) treated with heat‐killed LM (HKLM), These cells proved to have surprisingly uniform specificity, recognizing a product we designated HKLM‐associated antigen (HAA) presented by the non‐classical dass Ib product H2–M3′. HAA proved to be extremely hydrophobic and the bioactive portion of the molecule was highly protease‐resistant, leading us initially to speculate that it might be a non‐peptide. Recent studies, however, identify HAA as a complex containing lemA, a listerial protein bearing the immunogenic amino terminal peptide sequence fMIGWII, tightly associated with bacterial cardiolipin. A variety of cell types can process and present exogenous HAA/lemA. and the phospholipid component appears essential for this processing. Endosomal acidification and proteolysis are required for processing, but the site where antigen binds to H2–M3wt within APC remains uncertain. HAA/lemA‐immune effectors are unusually cross‐reactive. We could readily detect H2–M3wt‐restricted responses to APC incubated with unrelated N ‐formylated peptides, and bacteria, HAA‐like products represent an intriguing new set of bacterial antigens recognizable by immune CD8 cells.
Acquired immunity to an intracellular pathogen:immunologic recognition of L. monocytogenes‐infected cells
Authors: Bouwer H. G. A. , Barry Ronald A. , Hinrichs David J.
Published: April 2006

Summary: Listeria monocytogenes (L. monocytogenes) is a pathogenic bacterium, and subclinical infection in mice is utilized as a prototypic model to investigate the development and expression of acquired resistance to facultative intracellular organisms. A key virulence factor of L. monocytogenes is the hemolysin listeriolysin O (LLO), and BALB/c mice immunized with hemolysin‐secreting strains of L. monocytogenes develop specific acquired resistance, while mice immunized with hemolysin‐negative strains or non‐viable preparations of L. monocytogenes do not develop a protective immune response. Adoptive transfer studies show that L. monocytogenes‐Immune CD8+ T cells mediate acquired resistance. The L. monocytogenes‐immune CD8+ population is cytotoxic, and target cells infected with hemolysin‐secreting strains of L. monocytogenes are lysed, while target cells infected with hemolysin‐negative strains or non‐viable preparations of L. monocytogenes are not lysed. MHC dass la and Ib molecules present I. monocytogenes‐derived peptides, and we have identified Qa‐1b, a T‐region‐encoded MHC class Ib molecule, as a restriction element for L, monocytogenes‐specific CD8+ CTL. MHC class Ib‐restricted CTL are stimulated following infection with L. monocytogenes and are a significant component of the total MHC class I‐restricted CTL population. These findings support the observation that cytoplasmic L. monocytogenes‐derived antigens are endogenously processed and presented in association with MHC class Ia and Ib molecules to CD8+ effector cells, and that both populations of effector cells contribute to the immune response to this intracellular pathogen.
Recombinant Listeria monocytogenes as a live vaccine vehicle and a probe for studying cell‐mediated immunity
Authors: Jensen Eric R. , Shen Hao , Wettstein Felix O. , Ahmed Rafi , Miller Jeff F.
Published: April 2006

Summary: The ability of Listeria monocytogenes (L. monocytogenes) to enter the cytosol of host cells allows secreted proteins lo efficiently enter the endogenous antigen‐processing pathway leading to presentation by MHC class I molecules. L. monocytogenes has recently been exploited as a live vaccine vehicle for the induction of immunological memory against heterologous antigens. We have established a genetic system for site‐specific integration of antigen expression cassettes into the imam genome which allows regulated expression and secretion of heterologous proteins. The ability of recombinant strains to stimulate long‐term immunological memory and CD8+ T‐cell‐mediated protective immunity was investigated using the lymphocytic choriomeningitis virus (LCMV) murine infection model. Vaccination of mice with recombinant Listeria strains expressing LCMV antigens induced LCMV‐specific CD8+ T cells which protected mice against LCMV challenge. We have also used a cottontail rabbit papilloma‐virus model to test the ability of recombinant Listeria strains to stimulate protective antitumor immunity in domestic rabbits. These studies have demonstrated the protective efficacy of recombinant L. monocytogenes vaccines and have established an experimental system for systematic analysis of cytotoxic T cell induction by an intracellular bacterium.
Listeria monocytogenes: a potent vaccine vector for neoplastic and infectious disease
Authors: Weiskirch Larry M. , Paterson Yvonne
Published: April 2006

Summary: Listeria monocytogenes (L. monocytogenes) is a promising candidate vaccine vector that naturally infects antigen‐presenting cells, and targets antigen delivery to both the class I MHC pathway of endogenous antigen presentation and the class II pathway of exogenous antigen presentation. At the same time, L. monocytogenes stimulates the innate immune response (o produce cytokines that enhance antigen‐presenting function and induce a Th1–type cytokine profile associated with cell‐mediated immune responses, Immune responses with these features are considered to be particularly important for clearance of viruses, tumors, and intracellular infections. In this review, we describe the development of methods to transform L. monocytogenes to express and secrete foreign antigens and the studies that have demonstrated that genetically engineered L. monocytogenes mutants are highly effective vectors for the induction of potent immune responses against viral antigens and tumor cells. In addition, we discuss the strengths and weaknesses of L. monocytogenes as a vaccine vector.
What can we learn about human immunodeficiency virus infection from a study of lymphocytic choriomeningitis virus?
Authors: Klenerman Paul , Zinkernagel Rolf M.
Published: April 2006

The role of cytotoxic T lymphocytes (CTL) in human immunodeficiency virus (HIV) infection remains elusive. Since the discover) 10 years ago of high levels of specific CTL in this disease, same have argued that they play an important role in virus control, minis that they drive disease progression through destruction of T helper cells, and others st ill that they play no obvious role at all. By contrast, the central role of CTL in murine lymphocytic choriomeningitis virus (LCMV) infection has been very clearly worked out through the use of in vivo depletion and adoptive transfer experiments, as well as knockout and transgenic mice. To interpret the possible roles for CTL in HIV, we have therefore made a comparison between what is known about CTL and their interaction with virus‐infected cells in these two infections. This illustrates a potential critical role for these cells in both control of HIV replication and immune‐mediated pathology, but one that is highly dependent on virus dose, distribution and dynamics.
Co‐evolution of human immunodeficiency virus and cytotoxic T‐lymphocyte responses
Authors: Goulder Philip , Price David , Nowak Martin , Rowland‐Jones Sarah , Phillips Rodney , McMichael Andrew
Published: April 2006

After more than a decade of intensive research, the precise of human immunodeficiency virus (HIV)‐specific cytotoxic T lymphocytes (CTL) in determining the course of the infection remains open to argument. It is established that HIV‐specific CTL appear early in the infection and are temporally associated with the clearance of culturable virus from the blood; that CTL are generally detectable at very high levels throughout the asymptomatic phase and decline at the time of progression to AIDS; and that CTL‐mediated killing is sufficiently fast to prevent production of new virus by HIV‐infected cells. However, viral turnover is throughout the course of the infection, and –infected individuals progress inexorably to disease in spite of the CTL response. In order Co address the question of whether CTL play an active part in influencing the course of HIV infection, one approach has been to seek evidence for CTL‐mediated selection pressure on the virus. Several clear examples of CTL epitope‐specific mutations selected to fixation are described. We argue that CTL escape is a common event which occurs at all stages of the Infection. Detailed longitudinal studies are required to detect CTL escape and to nd the complexities contributed by factors SUC h as a polyvalent CTL response and the presence of epitope variants which antagonise the CTL response. In conclusion, there is strong evidence of a dynamic process in which CTL impose important selection constraints upon HIV fro m which the virus attempts to escape; ultimately, at the time of disease progression, the tenuous control of CTL over the virus is lost.
Host factors in the pathogenesis of HIV disease
Authors: Cohen Oren J. , Kinter Audrey , Fauci Anthony S.
Published: April 2006

Host factors play an important role in determining rates of disease progression in human immunodeficiency virus (HIV)‐infected individuals. HIV is able lo subvert the host immune system by infecting CD4+ T cells that normally orchestrate immune responses and by inducing the secretion of proinflammatory cytokines that the virus can utilize to its own replicative advantage. The recognition that certain chemokine receptors serve as necessary co‐factors for HIV entry into its target cells as well as the fact that ligands for these receptors can modulate the efficiency of HIV infection has expanded the number and scope of host factors that may impact the pathogenesis of HIV disease. This area of investigation will no doubt yield novel therapeutic strategies for intervention in HIV disease; however, caution is warranted in light of the enormous complexity of the pleiotropic cytokine and chemokine networks and the uncertainty inherent in manipulating these systems.

HIV‐infected long‐term non‐progressors represent an excellent model to study potential host factors involved in HIV disease pathogenesis. Genetic factors certainly have a major impact on the immune responses mounted by the host. In this regard, a polymorphism in the gene for the HIV co‐receptor CC chemokine receptor 5 (CCR5), which serves as a coreceptor for macrophage (M)‐tropic strains of HIV, affords a high degree of protection against HIV infection in individuals homozygous for the genetic defect and some degree of protection against disease progression in HIV‐infected heterozygotes. HIV‐specific immune responses, including cytotoxic T‐lymphocyte (dX) responses and neutralizing antibody responses, also appear to play salutary roles in protecting against disease progression.
Effector CD4+ and CD8+ T‐cell mechanisms in the control of respiratory virus infections
Authors: Doherty Peter C. , Topham David J. , Tripp Ralph A. , Cardin Rhonda D. , Brooks James W , Stevenson Philip G.
Published: April 2006

The rules for T‐cell‐mediated control of viruses that infect via the respiratory mucosae show both common themes and differences depending on the nature of the pathogen. Virus‐specific CD8+ cytotoxic T lymphocytes (CTLs) are the key effectors of virus clearance in mice infected with both negative strand RNA viruses (influenza and Sendai) and a DNA virus, the murine γ‐herpesvirus68 (MHV‐68). Recently completed experiments establish that these activated CD8+ T cells indeed operate primarily via contact‐dependent lysis, Perform‐mediated cytotoxicity seems to be the preferred mode, though a Fas‐based mechanism can apparently serve as an alternative mechanism. Immune CD4+ T cells functioning in the absence of the CD8+ subset cannot eliminate MHV‐68 from lung epithelial cells, are somewhat less efficient than the CD8+ CTLs at clearing the RNA viruses, and are generally ineffectual in mice that lack B lymphocytes. Though cytokine secretion by CD4+ and CD8+ T cells in the virus‐infected king may promote both T‐cell extravasation and macrophage activation, such processes are not alone sufficient to deal consistently with any d these infections. However, CD4+ T help is mandatory for an effective B‐cell response, and can operate lo promote the clonal expansion of virus‐specific CD8+ T cells in the lymph nodes and spleen. Furthermore, a concurrent CD4+ T‐cell response seems to be essential for maintaining continued CD8+ T‐cell surveillance and effector capacity through the persistent, latent phase of MHV‐68 infection in B cells. Thus, the evidence to date supports a very traditional view: CD8+ T cells function mainly as killers and the CD4+ T cells as helpers in these respiratory virus infections.
Antiviral immune responses modulate the nature of central nervous system (CNS) disease in a murine model of multiple sclerosis
Authors: Drescher Kristen M. , Pease Larry R. , Rodriguez Moses
Published: April 2006

The spectrum of disease is influenced by factors related to both the pathogen and the host, as well as the end points used in defining disease. In this article, the issue of disease resistance versus susceptibility will be examined in the framework that genetic manipulation of either the pathogen or the host immune response alters the balance from disease protection towards pathogenesis. The response of the host may trigger both a protective and a pathogenic immune response. The failure CO mount protective immune response predisposes the pathogen to persistence, which then becomes the target for immunopathology. This review will examine the factors involved both in virus‐mediated pathogenesis and in disease protection in the Theiler's model d human multiple scler manipulating the character of the virus pathogen and the specificity of the immune response, the entire spectrum of human demyelinating disease is reproduced.
On the mystique of the immunological self
Authors: Silverstein Arthur M. , Rose Noel R.
Published: April 2006

Since the time of Paul Ehrlich 100 years ago, we have known that the immunological apparatus somehow inhibits most damaging autoimmune responses while permitting a response to exogenous immunogens. With the discovery of tolerance, the concept of immunological surveillance, and especially with the discovery of HLA restriction of T‐cell recognition, the term “the immunological self” and the phrase “self‐nonself discrimination” have gained wide currency. Immunology has been called The Science of Self, and self‐nonself discrimination has been assigned as the driving force for its complex evolution. The concept of self has thus been given such mystical trappings since the time of Macfarlane Burnet that recent workers have felt free to pronounce it the central paradigm of modern immunology, and to claim to overthrow it! In this article, we challenge some of the more egregious claims about the immunological self by recalling important historical findings, by reviewing the mechanisms of Darwinian evolution, and by remembering that the general pathology of immunogenic inflammation shows that the immune response cannot discriminate between the benign and the noxious.
Cell death and longevity: implications of Fas‐mediated apoptosis in T‐cell senescence
Authors: Mountz John D. , Wu Jianguo , Zhou Tong , Hsu Hui‐Chen
Published: April 2006

Summary: Two prominent features of immune senescence are altered T‐cell phenotype and reduced T‐cell response. We have previously shown that T‐cell senescence is greatly reduced in CD2‐fas transgenic mice, in which the Fas apoptosis molecule is constantly expressed on T cells. Using a different experimental approach, the relationship between T‐cell senescence And apoptosis was analyzed on human peripheral blood mononuclear cells. The results indicate that there was increased apoptosis of CD45RO− (CD45RA+) T cells upon activation. We propose that this could account for the increase in CD45RO+“memory” T cells with aging in humans. T‐cell responsiveness remained high in CD2‐fas transgenic aged mice, but there was no increase in overall life span of these mice. Increased T‐cell responsiveness was associated with an increased acute‐phase response and serum amyloid A deposition in the glomerulus of aged CD2‐fas transgenic mice. Therefore, restoration of the T‐cell immune function using a CD2‐fus transgene produced undesirable side‐effects transgenic mice. In addition to its role in activation‐Induced cell death. Fas‐mediated apoptosis may be important in deleting T cells in response to DNA damage. It may also inhibit cell‐cycle progression by cleaving various kinases and DNA repair enzymes. We observed that cell lines derived from human premature aging diseases have a higher sensitivity to Fas mediated apoptosis. The implications of these observations are discussed.
Human T‐cell clones in long‐term culture as a model of immunosenescence
Authors: Pawelec Graham , Rehbein Arnika , Haehnel Karin , Merl Andrea , Adibzadeh Medi
Published: April 2006

Summary: We have consistently observed that like other normal somatic tissue cells, human T lymphocytes manifest a finite proliferative capacity in culture in vitro. When measured in population doublings (PD), this averages about 35 PD for T‐cell clones (TCC) derived from mature peripheral T cells of young adults and about 20 PD more for TCC derived from T‐cell precursors in their bone marrow. We believe that alterations in surface marker phenotypes and corresponding functional changes observed in these human TCC as they progress through their finite lifespans in vitro can provide valuable information on processes of T‐cell immunosenescence in vivo. They may also provide a model system for studying ways of modulating the ageing process to delay or prevent immunosenescence in the elderly and the chronically infected or possibly to accelerate immunosenescence in organ transplantation.
Thymic aging and T‐cell regeneration
Authors: Mackall Crystal L , Gress Ronald E.
Published: April 2006

Summary: Studies of Tcell regeneration using animal models have consistently shown the importance of the thymus for T‐cell regeneration. In humans, recent studies have shown that declines in thymic T cell regenerative capacity begins relatively early in life, resulting in a limited capacity for T‐cell regeneration by young adulthood. As a result, adult humans who experience profound Tcell depletion regenerate T cells primarily via relatively inefficient thymic‐independent pathways, resulting in prolonged CD4 depletion, CD4+ and CDS+ subset alterations, limited TCR repertoire diversity and a propensity for activation induced cell death. These limitations in T‐cell regeneration have significant clinical implications in the setting of HIV infection and bone marrow transplantation and may also contribute to immunologic abnormalities associated with normal aging. While the mechanisms responsible for thymic aging are not well under stood, current evidence suggests that changes within the thymus itself are primary, while age‐related changes in marrow T‐cell progenitors and inhibitory factors within the extrathymic host milieu contribute to a lesser extent. The development of therapies which can reverse thymic aging are critical for improving outcome in clinical settings of T‐cell depletion, and could potentially improve immunologic function in normal aged hosts.
CD8+ T‐cell clones in old mice
Authors: Ku Chia Chi , Kotzin Brian , Kappler John , Marrack Philippa
Published: April 2006

Summary: Most old mice and human beings contain large clones of CD8+αβ TCR+ T cells. In mice clones bearing Vβ7 appear more frequently in animals infected with mouse hepatitis virus than in uninfected animals. This property is controlled by some non MHC gene in the animals. The frequency of old mice containing such clones is affected by the origin of the animals. Although the clones are relatively anergic to acute stimuli in vitro, they can divide in vivo since in old animals they divide and turnover with about the same kinetics as other, non‐clonally expanded CD8+T cells. Moreover the clones expand slowly but inexorably after transfer into recipient animals. These data suggest that the CDS+αβ TCR clones arise because they are specific for some exogenous or auto antigen to which the cells are continuously exposed in vivo.
The effect of aging on IgD receptor expression by T cells and its functional implications
Authors: Swenson Christina D. , Thorbecke G. Jeanette
Published: April 2006

Summary: Exposure to oligomeric or aggregated (a), but not to mono‐merle (m), IgD causes a rapid (within 1 h) upregulation of IgD‐R expression on CD4+ T cells from young, but not from aged, mice and on both CD4+ and CD8+ T cells from all young and from =65% of aged humans. In normal young (but not in IgD−/‐) mice, this increase in IgD‐R expression is associated with a marked increase in primary and secondary antibody responses, transferable to both aged and young mice with T cells from aIgD pretreated donors. In both species, immunization causes a rise in the IgDR+ expression in vivo in the young. In mice, mIgD abolishes both the Induction of IgD‐R expression and augmentation of immune responses, suggesting that interaction between IgD‐R+ T and IgD+ B cells is needed. In aged humans, the ability of peripheral blood lymphocytes to exhibit IgD‐R expression in response to aIgD in vitro or to influenza vaccine in vivo is strongly correlated to the individual's ability to produce antibody. In T cells from aged mice, but not from aged IgD‐non‐responder humans, IgD‐R are able to come to the cell surface if an additional signal has been supplied, such as by (ionomycin/thapsigargin + aIgD). Agents which induce IgD‐R and augmentation of antibody production in aged and young mice include phosphatidylcholine and dehydroepiandrosterone sulfate. The immunoaugmenting effect of pretreatment with these agents appears Indeed due to IgD‐R+ T cells, because it is abolished by mIgD.
Primary and secondary alterations of immune reactivity in the elderly: impact of dietary factors and disease
Authors: Wick Georg , Grubeck‐Loebenstein Beatrix
Published: April 2006

Summary: The function of the immune system declines with age. It is the aim of the present review to demonstrate that it makes sense to distinguish between primary and secondary alterations of immune reactivity in the elderly. Primary changes occur as the result of an age‐dependent intrinsic decline of immune responsiveness. They also occur in healthy persons, i.e. persons, selected according to the criteria of the SENIEUR protocol of the European Community's Concerted Action Program on Aging (EURAGE). T lymphocytes are hereby more severely affected than B cells or antigen presenting cells, possibly due to the involution of the thymus, which is almost complete at the age of 60. Secondary immunological changes occur as the result of environmental factors including diet, drug intake, physical activity etc. or arc alternatively due to underlying diseases. In this article, the effects of high lipid intake as well as the impact of diseases, such as for instance Alzheimer's disease and atherosclerosis, will be addressed. The results underline the complexity of immunological alterations to be expected in old age. Changes in the aging immune system represent an opportunity for increased frequency and severity of disease and endanger the protective effect of vaccination.
The modular architecture of leukocyte cell‐surface receptors
Authors: Cambell Ioin D.
Published: April 2006

Summary: Cells of the immune system have a large number of protein receptors on their surfaces, with a wide range of binding functions. They are, however, constructed from a limited set of protein structural units, which are recognisable at the sequence level. The 3D structure of many of these domains, or modules, is now known. These modular units and their structures are reviewed here. The ways in which they are assembled into multidomain receptor chains and oligomeric complexes of receptors are also discussed.
Comparison of the conformations of two intact monoclonal antibodies with hinges*
Authors: Harris Lisa J. , Larson Steven B. , Skaletsky Eileen , McPherson Alexander
Published: April 2006

Summary: Structures of two intact monoclonal antibodies were solved by X‐ray diffraction analysis revealing, in both cases, the dispositions of all segments, as well as the structures of the hinge polypeptides. An IgG1, whose antigen is the drug phenobarbital, assumed a completely different conformation when compared with an IgG2a specific for canine lymphoma cells. Though neither IgG displays global two‐fold symmetry, both maintain two pseudo dyad axes, one relating Fab segments, and the other the halves of the Fc. In both IgGs, the Fc segment is obhquely disposed with respect to the plane of the Fabs, making an angle of 128° in the IgG2a. and 107° in the IgG1, Hinge angles of the IgG1 are notably different at 78° and 123°, and unique as well from IgG2a values of 66° and 113°, Elbow angles within the IgG1 Fabs are the same at 155°, but non‐identical in IgG2a where they took on values of 143° and 159°, The IgG2a has an angle of 172° between Fabs so that it exhibits a “distorted T” shape, whereas that angle in the IgG1 is a much more acute 115° producing a “distorted Y”, CH2 domains appear, in both antibodies, to be the most independently mobile of the paired IgG domains. This perhaps reflects their importance in modulating effector functions through exposure of binding loci on the CH2, at the CH2‐CH3 interface, and on lower hinge polypeptides. Hinges in both antibodies contain disulfide‐linked cores bounded by fluid regions above and below, which provide mobility to the Fabs and Fc respectively. The conformations seen in these two structures are undoubtedly only two among many but they illustrate the modes of flexibility inherent to the IgG architecture.
IgG‐Fc‐mediated effector functions: molecular definition of interaction sites for effector ligands and the role of glycosylation
Authors: Jefferis Roy , Lund John , Pound John D.
Published: April 2006

Summary: The Fr region of human IgG expresses interaction sites for many effector ligands. In this review the topographical distributions often of these sites are discussed in relation to functional requirement. It is apparent that interaction sites localised to the inter‐CH2‐CH3 domain region of the Fc allow for functional divalency, whereas sites localised to the hinge proximal region of the CH2 domain are functionally monovalent, with expression of the latter sites being particularly dependent on glycosylation. All x‐ray crystal structures for Fc and Fc‐ligand complexes report that the protein structure of the hinge proximal region of the CH2 domain is “disordered”, suggesting “internal mobility”. We propose a model in which such “internal mobility” results in the generation of a dynamic equilibrium between multiple conformers, certain of which express interaction sites specific to individual ligands. The emerging understanding of the influence of oligosaccharide/protein interactions on protein conformation and biological function of IgG antibodies suggests a potential to generate novel glycoforms of antibody molecules having unique profiles of effector functions.
Paradoxical behavior of asymmetric IgG antibodies
Authors: Margni Ricardo A. , Borel Ileana Malan
Published: April 2006

Summary: Changes in the quantity and quality of antibodies occur in the course of an immune response. This review describes the physicochemical and biological properties of asymmetric antibodies as well as their functions, beneficial or harmful to the host, according to the nature of the antigen and the particular situation in which they act. Asymmetric antibodies have two paratopes, one of high affinity, with K0 similar to that of symmetric antibodies, and the other one with an affinity for the antigen 100 times lower. Functional univalence is due to steric hindrance present in one of the paratopes by the carbohydrate moiety attached to the Fd fragment of the Fab region, so these antibodies are unable to form large antibody‐antigen complexes and cannot trigger reactions, such as complement fixation, phagocytic activity and antigen clearance. When asymmetric IgG antibodies are specific for self‐antigens, they prove beneficial for the host by exerting regulatory functions. In allergic manifestations, in autoimmune diseases and especially during pregnancy, despite the fact that the antigens responsible for the process are foreign to the host, they also perform beneficial activity During pregnancy, the placenta secretes molecules or factors that regulate the synthesis of these antibodies, thus favoring fetal protection.
Recognition surfaces of MHC class I
Authors: Jones E. Yvonne , Tormo Jose , Reid Scott W. , Stuart David I.
Published: April 2006

Summary: Recent crystallographic results have provided dose to atomic resolution views of the recognition events mediated by MHC class I molecules. The specificity‐conferring interaction of MHC class I/peptide with a T‐cell antigen receptor (TCR) appears dependent on certain key interactions with the MHC scaffold. These interactions, in particular those of the TCR Va domain, define a standard orientation for TCR binding. Previous studies on biologically significant variations in the TCR recognition surface presented by a series of MHC/variant peptide complexes can be reassessed in the light of this TCR‐building mode. The interaction of CDS with MHC class I resembles that between antibody and antigen in the use of loops from the CD8 structure. The interaction is of very low affinity and buries equivalent surface area to that between the TCR and MHC class I but while the TCR/MHC interface shows poor surface shape complementarity the match in the conservative interaction between MHC and CDS is precise.
Structural specializations of immunoglobulin superfamily members for adhesion to integrins and viruses
Authors: Wang Jia‐huai , Springer Timothy A.
Published: April 2006

Summary: The circulation and migration of leukocytes are critical for immune surveillance and immune response to infection or injury. The key step of leukocyte recruitment involves the adhesion between immunoglobulin superfamily (IgSF) proteins on endothelium and integrin molecules on leukocyte surfaces. Some of the IgSF members are subverted as virus receptors. Four crystal structures of N‐terminal two‐domain fragments of these IgSF proteins have been determined: intercellular adhesion molecule‐1 (IC.AM‐l), ICAM‐2, vascular adhesion molecule‐1 (VCAM‐1), and mucosal address in cell adhesion molecule‐1 (MAdCAM‐1), An acidic residue near the bottom of domain 1 plays a key role in integrin binding. For ICAM‐1 and ICAM‐2, this glutamic add residue is located on a flat surface, complementary to the flat surface of the 1 domain of the integrin to which they bind, lymphocyte function‐associated antigen‐1 (LFA‐1). For VCAM‐1 and MAdCAM‐1, the acidic residue is aspartic acid, and it resides on a protruded CD loop which may be complementary to a more pocket‐like structure in the a4 integrins to which they bind, which lack I domains. A number of unique structural features of this subclass of IgSF have been identified which are proposed to consolidate the domain structure to resist force during adhesion to integrins. Different mechanisms are proposed for the different CAMs to present the integrin‐binding surface toward the opposing cell for adhesion, and prevent ds interaction with integrins on the same cell. Finally, CD4 and ICAM‐1 are compared in the context of ligand binding and virus binding, which shows how human immunodeficiency virus and rhinovirus fit well with the distinct structural feature of their cognate receptors.
CD2 and the nature of protein interactions mediating cell‐cell recognition
Authors: Davis Simon J. , Ikemizu Shinji , Wild Martin K. , van der Merwe P. Alton
Published: April 2006

Summary: Rapid progress has recently been made in characterising the structures of leukocyte cell‐surface molecules. Detailed analyses of the structure and interactions of CD2 were the first involving a molecule that has not been directly linked to antigen recognition in the manner of antigen receptors or co‐receptors. It seems highly likely that the properties of ligand binding by CD2 are relevant to the general mechanisms of cell‐cell recognition. As an example of biological recognition, the defining characteristic of cell‐cell contact is that it involves che simultaneous interaction of hundreds, if not thousands, of molecules. Affinity and kinetic analyses of ligand binding by CD2 indicated that the protein interactions mediating cell‐cell contact, whilst highly specific, are much weaker than initially anticipated, probably due to the requirement that such contacts be easily reversible. Simultaneously, in addressing the mechanism of this mode of recognition, structural and mutational studies focussed on the role of charged residues clustered in the ligand‐binding face of CD2, yielding the concept that electrostatic complementarity, rather than surface‐shape complementarity, is the dominant feature of specific, low‐affinity protein recognition at die cell surface by CD2. The crystallographic analysis of the CD2‐binding domain of CD58 strongly supports this concept.
Toward a predictive understanding of molecular recognition
Authors: Weng Zhiping , DeLisi Charles
Published: April 2006

Summary: T cells circulate in blood and the lymphatic system, continually engaging cells through transient non‐specific adhesion. In a normally functioning immune system, these interactions permit sufficient time for T‐cell receptors (TCRs) to sample major histocompatibility complex (MHC)‐pep‐tide complexes for the presence of foreign antigen, with detection of the latter to some extent being triggered by a longer dwell time of the receptor on the complex. Precisely how this incremental stability, which may be relatively small, leads to activation is unclear, but it appears to be related to diffusion‐mediated formation of ternary complex dimers.

The formation of stable dimers can explain the high sensitivity of the response, but leaves a number of questions un addressed, including the following; i) How can high sensitivity be reconciled with high specificity, and how can a short TCR dwell time be reconciled with a comparably short time for ternary complex pair formation? ii) What is the nature of the early signals on the plasma membrane that determine alternative responses e.g. proliferation at one extreme and apoptosis at the other’ iii) What arc the cell‐surface correlates of biphasic dose response functions i.e. of responses that peak as a function of dose and then descend?

This paper has two loosely coupled goals. One is to review and assess the mathematical and computational methods available for analyzing reactions with and between mobile membrane‐bound receptors. These methods range from phenomenological to mechanistic, the latter being based on the details of atomic structure. The other is to apply these methods to address biological questions, such as those raised above, part of whose answer may lie in the kinetic competition between alternative reaction paths.