Showing papers in "Annual Review of Immunology in 1991"
TL;DR: Dendritic cells are specialized to mediate several physiologic components of immunogenicity such as the acquisition of antigens in tissues, the migration to lymphoid organs, and the identification and activation of antigen-specific T cells.
Abstract: Dendritic cells are a system of antigen presenting cells that function to initiate several immune responses such as the sensitization of MHC-restricted T cells, the rejection of organ transplants, and the formation of T-dependent antibodies. Dendritic cells are found in many nonlymphoid tissues but can migrate via the afferent lymph or the blood stream to the T-dependent areas of lymphoid organs. In skin, the immunostimulatory function of dendritic cells is enhanced by cytokines, especially GM-CSF. After foreign proteins are administered in situ, dendritic cells are a principal reservoir of immunogen. In vitro studies indicate that dendritic cells only process proteins for a short period of time, when the rate of synthesis of MHC products and content of acidic endocytic vesicles are high. Antigen processing is selectively dampened after a day in culture, but the capacity to stimulate responses to surface bound peptides and mitogens remains strong. Dendritic cells are motile, and efficiently cluster and activate T cells that are specific for stimuli on the cell surface. High levels of MHC class-I and -II products and several adhesins, such as ICAM-1 and LFA-3, likely contribute to these functions. Therefore dendritic cells are specialized to mediate several physiologic components of immunogenicity such as the acquisition of antigens in tissues, the migration to lymphoid organs, and the identification and activation of antigen-specific T cells. The function of these presenting cells in immunologic tolerance is just beginning to be studied.
4,872 citations
TL;DR: This review has summarized and discussed the available information concerning the regulation and structure of the genes, the structure and biochemical properties of the polypeptide products, their receptors, signal transduction, cell sources, and in vitro as well as in vivo activities of these cytokines.
Abstract: A family consisting of at least ten distinct novel 8-10 kd cytokines has been identified over the past 12 years. These cytokines exhibit from 20 to 45% homology in amino acid sequence, are probably all basic heparin-binding polypeptides, and have proinflammatory and reparative activities. The cDNA for these cytokines are characterized by conserved single open reading frames, typical signal sequences in the 5' region, and AT rich sequences in the 3' untranslated regions. Those human cytokines known as interleukin 8, platelet factor 4, beta thromboglobulin, IP-10 and melanoma growth stimulating factor or GRO can be assigned to a subfamily based on their location on chromosome 4 and unique structural features, whereas the second subset consisting of LD78, ACT-2, I-309, RANTES, and macrophage chemotactic and activating factor (MCAF) are all closely linked on human chromosome 17. In this review we have summarized and discussed the available information concerning the regulation and structure of the genes, the structure and biochemical properties of the polypeptide products, their receptors, signal transduction, cell sources, and in vitro as well as in vivo activities of these cytokines.
1,930 citations
TL;DR: The autosomal recessive lpr and gld genes induce in mice multiple autoantibodies and the progressive accumulation of large numbers of non-malignant CD4- CD8- T lymphocytes, and the mechanism whereby these two genes induce autoimmunity and lymphoproliferation remains obscure.
Abstract: The autosomal recessive lpr and gld genes induce in mice multiple autoantibodies and the progressive accumulation of large numbers of non-malignant CD4- CD8- T lymphocytes. The clinical syndromes and immune abnormalities associated with these two nonallelic genes are nearly identical and are also highly dependent on background genes. MRL/lpr mice are particularly severely affected, and they develop a syndrome that is serologically and pathologically similar to human systemic lupus erythematosus (SLE). Abnormal cell marker expression in the aberrant lpr T lymphocytes includes surface antigens normally associated with activated T cells or even with B cells, and it occurs along with enhanced expression of certain oncogenes. The lpr gene results in intrinsic abnormalities of both T and B lymphocytes, yet its location and product are unknown. The gld gene is located on chromosome 1; its product is also unknown. Although many immunological abnormalities are known, the mechanism whereby these two genes induce au...
1,214 citations
TL;DR: Studies that address the interactions between the foreign superantigens and MHC class-II molecules, the mechanism of T-cell stimulation, and the role that tolerance to self-superantigen plays in shaping the T- cell repertoire are reviewed.
Abstract: Superantigens combine with MHC class-II molecules to form the ligands that stimulate T cells via the Vβ element of the T-cell receptor. Two groups of superantigens have been described so far: first, endogenous murine products that include the MIs determinants, and second, bacterial products such as the Staphylococcal enterotoxins. Here, we review studies that address the interactions between the foreign superantigens and MHC class-II molecules, the mechanism of T-cell stimulation, and the role that tolerance to self -superantigens plays in shaping the T-cell repertoire. We speculate on the possible evolutionary significance of superantigens.
789 citations
TL;DR: Mice homozygous for the scid mutation (scid mice) are severely deficient in functional B and T lymphocytes; the mutation appears to impair the recombination of antigen receptor genes and thereby causes an arrest in the early development of B andT lineage-committed cells; other hematopoietic cell types appear to develop and function normally.
Abstract: Mice homozygous for the scid mutation (scid mice) are severely deficient in functional B and T lymphocytes. The mutation appears to impair the recombination of antigen receptor genes and thereby causes an arrest in the early development of B and T lineage-committed cells; other hematopoietic cell types appear to develop and function normally. The arrest in lymphocyte development is not absolute; some young adult scid mice are "leaky" and generate a few clones of functional B and T cells. By 10-14 months of age, virtually all scid mice are leaky. Scid mice readily support normal lymphocyte differentiation and can be reconstituted with normal lymphocytes from other mice and even partially reconstituted with human lymphocytes. They also support the growth of allogeneic and xenogeneic tumors. Thus, scid mice are of interest for studies of both normal and abnormal lymphocyte development and function. In addition, they can be used to study the function of nonlymphoid cell types in the absence of lymphocytes.
760 citations
TL;DR: This protein is of interest to immunologists and clinicians because of its role in regulation of the complement pathways and, therefore, inflammation in immune complex-mediated syndromes; to reproductive immunologists on account of its expression on sperm and at the maternal-fetal interface; and to tumor immunologists because ofIts high expression on malignant cells.
Abstract: Membrane cofactor protein (MCP; CD46) is a widely distributed C3b/C4b-binding cell surface glycoprotein which serves as an inhibitor of complement activation on host cells. The protein has been purified, multiple cDNAs cloned and sequenced, and the genomic organization determined. MCP belongs to a family known as the regulators of complement activation (RCA) gene cluster. The RCA members are related structurally [possess approximately 60 amino acid repeating motifs termed short consensus repeats (SCR)], functionally (bind C3b/C4b), and genetically (genes are tightly clustered on chromosome 1 at q3.2). Beginning at its amino-terminus, MCP is composed of four SCRs, a ser/thr/pro-enriched region, an area of undefined function, a transmembrane hydrophobic domain, a cytoplasmic anchor and cytoplasmic tail. On SDS-PAGE, MCP migrates as two broad forms with Mrs of 59,000-68,000 and 51,000-58,000. The quantity of each form expressed is inherited in an autosomal codominant fashion. This structural heterogeneity is partly explained by the expression of multiple cDNA/protein isoforms that arise by alternative splicing of ser/thr/pro-rich exons (sites of heavy O-glycosylation) and of cytoplasmic tails. This protein is of interest to immunologists and clinicians because of its role in regulation of the complement pathways and, therefore, inflammation in immune complex-mediated syndromes; to reproductive immunologists on account of its expression on sperm and at the maternal-fetal interface; and to tumor immunologists because of its high expression on malignant cells. The availability of monoclonal and polyclonal antibodies and molecular probes will be helpful in addressing questions about the biology of MCP in these and other areas.
594 citations
TL;DR: It is proposed that integrin avidity cycles may have an important role in the interconnected phenomena of locomotion, initial cell- cell adhesion, and cell-cell deadhesion.
Abstract: Lymphocytes adhere to other cells and extracellular matrix in the process of immunological recognition and lymphocyte recirculation. This review focuses on regulation of lymphocyte adhesion and the use of adhesion mechanisms by lymphocytes to obtain information about their immediate environment. The CD2 and LFA-1 adhesion receptors appear to have distinct roles in the regulation of adhesion and modulation of T lymphocyte activation. Adhesion mediated by interaction of CD2 with LFA-3 is dramatically altered by surface charge and adhesion receptor density in such a way that this pathway is latent in resting T lymphocytes but becomes active over a period of hours following T-cell activation. CD2 ligation can mediate or enhance T-cell activation, suggesting that signals from CD2/LFA-3 adhesive interactions are integrated with signals from the T-cell antigen receptor during immunological recognition. A model for the role of LFA-3 lateral diffusion in adhesion is presented, based on the lateral diffusion of different LFA-3 forms in glass supported planar membranes. Interaction of LFA-1 with ICAMs is also regulated by cell activation but in a different way than in interaction of CD2 with LFA-3. LFA-1 avidity for ICAMs is transiently increased by T-cell activation over a period of minutes. Cycles of avidity change are also observed for other T lymphocyte integrins which bind to extracellular matrix components. We propose that integrin avidity cycles may have an important role in the interconnected phenomena of locomotion, initial cell-cell adhesion, and cell-cell deadhesion. Recent observations on recirculation of T lymphocyte subpopulations are discussed in the context of general lessons learned from study of the CD2/LFA-3 and LFA-1/ICAM adhesion mechanisms.
543 citations
TL;DR: Molecular and genetic studies of HLA class-II genes provide new insights into the basis for MHC associations with autoimmunity and suggest a number of possible mechanisms critical for autoimmune triggering events involving class- II molecules.
Abstract: ty complex, autoimmunity, HLA class-II genes, disease associations, diabetes, rheumatoid arthritis Abstract Molecular and genetic studies of HLA class- II genes provide new insights into the basis for MHC associations with autoimmunity. Polymorphisms among class-II genes identif y specific haplotypes associated with auto immune diseases such as type-I diabetes, rheumatoid arthritis, celiac disease, and pemphigus vulgaris. In some cases, single genes within those haplot ypes are themselves implic ated in disease susc eptibility. Interactions, both cis and trans, between candidate susceptibility genes suggest a number of possible mechanisms critical for autoimmune triggering events involving class-II molecules. Amino acid sequence comparisons between products of candidate susceptibility genes and other class- II genes pinpoint a limit ed number of critical sites within HLA molecules which appear to be respon
517 citations
TL;DR: The location in which a particular antigenic peptide is produced is a function both of its route of introduction into the cell and its susceptibility to degradation, which contribute significantly to whether an antigen will be presented by class-I or class-II molecules.
Abstract: ty, antigen 'processing, antigen presentation, intracellular trafficking, invariant chain Abstract Histocompatibili ty molecules are peptide-binding proteins and present antigenic pep tides to T cells. In spite of similarity in structure and peptide specificity, class-I and class-II histocompatibili
351 citations
TL;DR: This review provides a summary of the characterization of gamma delta T cells found in epithelial tissues and speculates on the in vivo role of these cells.
Abstract: T cells bearing specific gamma delta TCR are the major lymphoid population in certain epithelial tissues. There are striking differences between these and peripheral T cells. The epithelial gamma delta T cells exhibit highly restricted V gene use, preferential pairing of TCR chains, and lack of diversity at the junctions creating populations of cells with virtually identical TCR in particular epithelia. Generation of certain epithelial gamma delta populations appears to be restricted to a discrete stage early in development. The restricted localization and expression of invariant antigen receptors may equip the epithelial gamma delta T cells to perform specialized functions which differ from those of circulating alpha beta and gamma delta TCR+ cells. This review provides a summary of the characterization of gamma delta T cells found in epithelial tissues and speculates on the in vivo role of these cells.
328 citations
TL;DR: This work has shown that the rate determining step may be a conformational change that results in the entrapment of the peptide, and developed a variety of binding assays that allow study of the detailed kin etics and specificity of the interaction.
Abstract: on correla Abstract The MHC class-I and class-II molecules are highly polymorphic membrane proteins, which bind and transport to the surface of cells peptide fragments of intact protei ns. The peptide-MHC complexes are recognized by the antigen-specific receptor of T lymphocytes and are the basis by which the cellular immune system distinguishes self from nonself. In order to perf orm this function, MHC proteins simultaneously display a large spectrum of struc turally divergent peptides for a sufficiently long period of time for the T cell repertoire to scan the cell effecti vely. Consis tent with the protein's biological role, the rates of association and dissociation at physiolog ical pH are very slow relative to other known receptor-ligand interac tions. The mechanism by which the proteins do this is still poorly understood, but recent experimental results indic ate that the rate determining step may be a conformational change that results in the entrapment of the peptide. A variety of binding assays have been developed that allow study of the detailed kin etics and specificity of the interaction. The optimal peptide length for binding is between 8 and 12 amino acids with the central 5-7 residues contributing the majority of the specific contacts. Determining the conf ormation of bound pep tides has been hampered by the inh erent ability of the receptor to bind manifold sequences. Consequently, strategies employing monos ubstituted analogs have had
TL;DR: Studies on the gene structure, on the transcript, and on perforin protein are reviewed, including intracellular trafficking, to refute the concept that the homologous restriction factors of complement also restrict the lysis of homologyous cells by perforIn.
Abstract: Studies on the gene structure, on the transcript, and on perforin protein are reviewed, including intracellular trafficking. Perforin transcription is tightly regulated and specific for CTL and NK. Two independent pathways for perforin induction exist, only one of them being IL-2 independent. Perforin expression in vitro and in vivo correlates with the functional expression of cytotoxicity in viral infection, transplant and tumor rejection, and in autoimmunity. Perforin together with granzymes is localized in cytolytic granules. However, the trafficking of those two proteins is quite different. Since the properties of perforin containing granules encompass the characteristics of secretory granules and of lyzosomes, the term granulosomes is used to describe this unique organelle. Evidence is reviewed to refute the concept that the homologous restriction factors of complement also restrict the lysis of homologous cells by perforin.
TL;DR: Transcriptional regulation of the immunoglobulin (Ig) genes is one of the best-studied systems for understanding tissue-restricted gene control and it appears that the coordinate action of a select constellation of these transactivators conveys the information for tissue-specific expression of the Ig genes.
Abstract: Transcriptional regulation of the immunoglobulin (Ig) genes is one of the best-studied systems for understanding tissue-restricted gene control. Dissection of the Ig genes reveals that each contains multiple regulatory elements that are preferentially active in B lymphocytes. These include a promoter and one or more enhancer elements. Biochemical analysis and cloning of the genes for transactivator proteins has uncovered a variety of distinct proteins that are often members of gene families. The transactivators themselves are under complex regulation at the transcriptional level as well as by interactions with other proteins in the cell. It appears that the coordinate action of a select constellation of these transactivators conveys the information for tissue-specific expression of the Ig genes.
TL;DR: Insight is provided into lympho-stromal interaction and the role of thymic microenvironments in positive and negative selection of the T-cell repertoire, and the potential influence of T cells on the development ofThymicmicroenvironments is discussed.
Abstract: Intrathymic T-cell differentiation requires a symbiotic interaction between thymic microenvironments and developing T cells. This paper attempts to provide insight into lympho-stromal interaction and reviews the architecture of thymic microenvironments, the phenotype of thymic microenvironments, the in vitro culture of thymic microenvironments, and the supportive role of thymic microenvironments in T-cell differentiation. Moreover, we discuss experimental manipulation of thymic microenvironments in vivo and in vitro, using monoclonal antibodies directed to cell surface determinants on stromal cells or their ligands on lymphoid cells. Finally, new types of experimental mouse models are considered with special reference to the role of thymic microenvironments in positive and negative selection of the T-cell repertoire, and the potential influence of T cells on the development of thymic microenvironments.
TL;DR: The vertebrate B-cell repertoire is capable of generating up to 10(9) different antibody molecules using relatively few germline immunoglobulin (Ig) gene segments, but chickens have only single functional V and J segments for the heavy and light chain loci, and chicken Ig gene rearrangement occurs only during a brief period of embryonic development.
Abstract: The vertebrate B-cell repertoire is capable of generating up to 10(9) different antibody molecules using relatively few germline immunoglobulin (Ig) gene segments. To generate diversity, humans and mice depend on combinatorial and junctional variations that occur during the gene rearrangement events that produce complete heavy and light chain Ig genes. This gene rearrangement process goes on continuously in the bone marrow, where each developing B cell assembles a unique heavy and light chain Ig gene from families of functional V, D, and J gene segments. In contrast, chickens have only single functional V and J segments for the heavy and light chain loci, and chicken Ig gene rearrangement occurs only during a brief period of embryonic development. A specialized organ involved in avian B-cell development, the bursa of Fabricius, provides the microenvironment necessary for the amplification of B cells that have undergone productive Ig gene rearrangements. Within the bursa, B cells also acquire somatic diversity within the rearranged V gene segments of the heavy and light chain Ig loci. Somatic diversification of chicken V gene segments occurs by intrachromosomal gene conversion, a DNA recombination process which involves unidirectional transfer of nucleotide sequence blocks from families of V region pseudogenes into the functional rearranged VH and VL genes.
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TL;DR: Although memory T and B cells use different mechanisms to elaborate memory, there are a number of interesting analogies: lymphokines vs antibodies and affinity maturation of B cell antigen receptors vs upregulation of adhesion molecules on T cells.
Abstract: Three remarkable and unique features of the immune system are specificity, diversity, and memory. Immunological memory involves both T and B cells and results in a secondary antibody response that is faster, of higher affinity, and results in the secretion of non-IgM isotypes of Ig. In this review we discuss the properties of memory T and B cells, their specific receptors, and the events which occur both in the nucleus and on the cell surface during generation and activation of these cells. Although memory T and B cells use different mechanisms to elaborate memory, there are a number of interesting analogies: lymphokines vs antibodies and affinity maturation of B cell antigen receptors vs upregulation of adhesion molecules on T cells. Finally, we discuss the importance of these cells in health and disease and suggest what impact additional information about these cells might have on the manipulation of the immune response.
TL;DR: The aim of this chapter is to explore the immunological dominance of hsp65 and its role in autoimmunity--benign and pernicious.
Abstract: The immunology of the 65 kd heat shock protein (hsp65) is paradoxical. Microbial and mammalian hsp65 molecules are 50% identical in amino acid sequence and immunologically cross-reactive, so microbial hsp65 looks like self; yet hsp65 is a dominant antigen in infection. Immunity to hsp65 can cause autoimmune diabetes in mice and may be related to autoimmune arthritis in rats and humans, so immunity to hsp65 should be forbidden; yet healthy persons manifest T-cell responses to self-hsp65. The aim of this chapter is to explore the immunological dominance of hsp65 and its role in autoimmunity--benign and pernicious.
TL;DR: Understanding how B cell accessory molecules regulate key interconnections during development may provide insights into the control and management of diseases with B-cell dysfunctions.
Abstract: Human B lymphocyte differentiation is regulated by signals transmitted after binding of cytokines to their specific receptors and/or cross-linking of cell-cell adhesion receptors. In addition to surface immunoglobulin (sIg) receptors for antigen, a number of B cell-associated surface molecules have now been identified which may regulate activation and adhesion of B cells. These include members of the Ig supergene family such as CD19, CD22, B7/BB1, and BMC1, cell surface enzymes such as CD10, CD73, and CDw75, and proteins with multiple transmembrane domains such as CD20 and CD37. In this review we describe how several of these accessory molecules may affect signaling via antigen receptors and influence primary vs secondary immune responses. For instance, signaling via either CD21 or CD22 can augment responses to anti-Ig; the B cell activation marker B7/BB1 may function to trigger T cells via its ligand, CD28, to produce cytokines which in turn stimulate B cells; and the receptor, CD40, may transmit a signal to protect germinal center B cells from undergoing programmed cell death. Understanding how B cell accessory molecules regulate key interconnections during development may provide insights into the control and management of diseases with B-cell dysfunctions.
TL;DR: The CD4-gp120 interaction is an obvious target for AIDS therapeutics because it leads to progressive destruction of the CD4+ subset of T lymphocytes, resulting in immunodeficiency and AIDS.
Abstract: Infection by the human immunodeficiency virus (HIV) leads to progressive destruction of the CD4+ subset of T lymphocytes, resulting in immunodeficiency and AIDS. The selectivity of CD4+ cell destruction is due to the specific binding of gp120, the external envelope glycoprotein of HIV, to CD4, initiating viral entry. Binding of gp120 to CD4 on the cell surface may also lead to CD4+ cell depletion by inappropriate immune targeting, and may interfere with CD4+ cell function and ontogeny by disrupting CD4-mediated cell signaling. The CD4-gp120 interaction is thus an obvious target for AIDS therapeutics.
TL;DR: The SCID-hu mouse is a heterochimeric small animal model designed to support hematopoietic differentiation and function in vivo and is now possible to study systematically the infective process of HIV and to address questions about the efficacy of novel antiviral compounds or vaccines in vivo.
Abstract: The SCID-hu mouse is a heterochimeric small animal model designed to support hematopoietic differentiation and function in vivo. Multiple organs of the human hematolymphoid system have been successfully engrafted into the immunodeficient C.B-17 scid scid mouse, including fetal liver, thymus, lymph node, and skin. Co-implantation of human fetal liver and human fetal thymus results in long-term, multilineage human hematopoiesis in vivo. Mature human lymphocytes within the SCID-hu mouse are phenotypically and functionally normal. HIV infection of the SCID-hu mouse reflects a tropism similar to that found in humans: only human organs with CD4+ cells are infected. Viral replication can thereafter be monitored with assays that are safe, reproducible, and quantitative. Given this small animal model, it is now possible to study systematically the infective process of HIV and to address questions about the efficacy of novel antiviral compounds or vaccines in vivo.
TL;DR: CD4+ T lymphocytes initiate and regulate both the specific and nonspecific effector mechanisms of allergic immune responses, and the use of molecular genetic probes and monoclonal T cells demonstrates the functional importance of both the HLA-D RAB1 and -DRAB3 gene products in T-cell recognition of allergen.
Abstract: CD4+ T lymphocytes initiate and regulate both the specific and nonspecific effector mechanisms of allergic immune responses. The definition of immunogenic components within allergens has allowed the specificity of the T-cell repertoire to be examined, and the refinement of their molecular structure is now facilitating the mapping of functional epitopes. Nevertheless, the immunological mechanisms that distinguish between atopic and nonatopic states remain unclear; as knowledge of the complex network of cytokines in the regulation of immune responses unfolds, this problem may be resolved. Population genetics indicates that susceptibility to allergic disease is partly determined by products of the major histocompatibility gene complex. The use of molecular genetic probes and monoclonal T cells demonstrates the functional importance of both the HLA-DRAB1 and -DRAB3 gene products in T-cell recognition of allergen. Collectively, this information has made it possible to develop in vitro models examining the modulation of responsiveness to allergens.
TL;DR: Molecular identification proved Mta, the maternally transmitted antigen of mice, to be a model minor histocompatibility (H) antigen that consists of a peptide, MTF, that is presented on the cell surface by an H-2 class-I molecule, HMT.
Abstract: Molecular identification proved Mta, the maternally transmitted antigen of mice, to be a model minor histocompatibility (H) antigen. It consists of a peptide, MTF, that is presented on the cell surface by an H-2 class-I molecule, HMT. MTF is derived from ND1, a mitochondrially encoded protein, and the amino-terminal N-formyl-methionine is essential for binding to HMT; conservative substitutions at the sixth residue causes MTF to be a minor H antigen. HMT is encoded by the M3 gene at the telomeric end of the H-2 complex. The peptide-binding site of HMT is hydrophobic, and allelic forms of the mature protein differ by only three amino acids. Homologues and analogues of the mouse Mta system have recently been identified in rats.
TL;DR: In myeloid leukemia and myelodysplastic syndromes, CSF treatment, particularly G-CSF, has proved effective for certain patients in improving neutrophil, platelet, and occasionally red cell production while reducing blast cells.
Abstract: Colony stimulating factors and interleukins regulate proliferation, differentiation, and functional activation of hematopoietic cells of multiple lineages. These hematopoietic growth factors are proving effective in vivo in stimulation of granulopoiesis in clinical situations associated with myelosuppression. G-CSF and GM-CSF promote accelerated granulocyte recovery following chemotherapy, or allogeneic or autologous bone marrow transplantation, in patients with cancer. In congenital defects of granulocyte production or in acquired disorders such as idiopathic neutropenia or aplastic anemia, CSF administration can lead to recovery of functioning granulocytes. This has resulted in a reduction in the morbidity and mortality associated with these diseases and now permits both a dose and a schedule intensification of chemotherapy. In myeloid leukemia and myelodysplastic syndromes, CSF treatment, particularly G-CSF, has proved effective for certain patients in improving neutrophil, platelet, and occasionally red cell production while reducing blast cells. The recombinant growth factors are generally well tolerated with few limiting toxicities at dose levels that effectively stimulate hematopoiesis.
TL;DR: The introduction of cloned genes into the germline of mice has been proven to be a powerful tool to investigate the role of the respective gene products within the immune system and peripheral mechanisms could be identified that induce and maintain self-tolerance.
Abstract: The introduction of cloned genes into the germline of mice has been proven to be a powerful tool to investigate the role of the respective gene products within the immune system. Here we summarize the transgenic mouse models that have been established with major histocompatibility complex (MHC) class-I genes. Foreign class-I alleles can be expressed in transgenic mice according to their normal expression patterns as authentic self molecules and can function in T-cell responses in the same way as endogenous class-I molecules. Since this is also true for most of the introduced human HLA class-I alleles, there is great interest in establishing mouse models for HLA-linked diseases. A new field of experimental approaches concerning self-tolerance has been opened by tissue specific expression of MHC antigens under specific promoters. Besides negative selection in the thymus, peripheral mechanisms could be identified that induce and maintain self-tolerance.
TL;DR: The experience in training immunologists for a period of over 30 years is described and the circumstances in which selected discoveries were made in his laboratory and the events and reasoning that led to these findings are analyzed.
Abstract: Dr. Benacerraf describes his experience in training immunologists for a period of over 30 years. He then analyzes the circumstances in which selected discoveries were made in his laboratory and the events and reasoning that led to these findings. The following topics are discussed: The phagocytic activity of the reticulo-endothelial system. The pathogenesis of immune complex diseases. The impact of activated macrophages on tumor rejection. The evidence that T-cell immunity is specific for internal protein determinants generated by antigen processing. The maturation of the antibody response in terms of antibody affinity. The discovery of Ir gene control of specific immuner esponses and the role of MHC molecules as presenters of peptide antigens to T cells. The generation of alloreactivity. Lastly, he addresses the administration of science and, particularly, the problems related to the transfer of technology to industrial partners.