Human Histocompatibility Antigens and Organ Transplantation

The success of organ transplantation depends not only upon the degree of skill employed in the execution of the technical procedure, but equally upon the proper antigenic matching of the donor and the recipient. Although there does not exist at the present time a perfect test for performing tissue typing—as in the case of blood transfusions—the most promising tests are those of leukocyte typing. This is possible because the histocompatibility antigens that determine the success or failure of tissue allografts are also found on the leukocytes. The problem concerns itself with developing an exact, specific, monosera test—simple and uncumbersome—that can be used to type the leukocytes and thus select a donor who corresponds antigenically to the recipient.     

Birth of the Major Histocompatibility Complex

Klein J, Sato A. Birth of the Major Histocompatibility Complex. Scand J Immunol 1998;47:199–209     

Chicken Major Histocompatibility Complex and Disease

The chicken MHC (B complex) initially described by Briles as controlling blood antigens, is now known to be composed of at least three regions, L, F and G. Two of these, F and G, were described on the basis of recombinants found in a study of over 10,000 chickens. On the basis of biochemical, tissue distribution and functional analyses, F corresponds to the murine H-2 K/D regions. The G region is unique to the chicken since the antigenic product is expressed only on erythrocytes and their progenitors. L was identified by serological studies and corresponds to the H-2 I region; the L antigen is expressed predominantly on B lymphocytes, monocytes and 10% of T lymphocytes, and differences in the L region result in variations in immune responsiveness. A number of functional similarities exist between the chicken MHC and that of other species such as regulation of graft rejection, graft-versus-host reaction (GVHR) and mixed lymphocyte reactions (MLR), mitogenic and immune responsiveness and resistance to RNA and DNA virus infection. The chicken MHC also controls the severity of autoimmune disease, as exemplified by the spontaneous thyroiditis of Obese strain (OS) chickens. It differs from mammalian MHC's by having a lower crossing-over frequency and no apparent gene duplication.     

Intrathymic Tolerance Induction: Determination of Tolerance to Class II Major Histocompatibility Complex Antigens in Maturing T Lymphocytes by a Bone Marrow-Derived Non-Lymphoid Thymus Cell

Two new experimental approaches were established to analyse the influence of the thymus on tolerance induction to major histocompatibility complex (MHC) antigens: The aim of the first experiment was to perform successful transplantation of adult allogeneic thymus tissue into nude mice, an attempt that has been unsuccessful in the past. Tolerance for the MHC genotype of a prospective thymus graft recipient (A) was induced in mice of strain B by injection of (A X B) splenocytes during the neonatal period. Adult thymic tissue obtained from these allogeneic donors (B) were grafted into the nude mice of strain A. The allogeneic thymus was accepted by the nude mice and immunoreconstitution was achieved. Subsequently the recipients developed tolerance to the MHC antigens of the allogeneic thymus donor as proved by mixed lymphocyte cultures and the acceptance of skin grafts. The second experiment was designed to determine which Ia-positive thymic compartment participates in conferring tolerance to MHC antigens in maturing T lymphocytes. Chimaeric thymus grafts were created by transplantation of neonatal thymus (A) into allogeneic nude mice (B) for a period of 8 weeks. The graft was populated with host bone marrow-derived Ia antigen-positive cells. The chimaeric thymuses consisting of type A epithelium but populated with both type A and B lymphocytes and non-lymphoid cells (i.e. Ia-positive macrophages and dendritic cells), were newly transplanted into nude mice of strain A. The engraftment lead to immunological reconstitution and the nude mice acquired tolerance to the MHC antigens expressed by the allogeneic Ia-positive cells populating the chimaeric graft. Irradiation of the chimaeric thymus prior to transplantation allowed transplantation of chimaeric thymus devoid of living thymocytes but still populated with functionally intact Ia-positive non-lymphoid cells. Transplantation of irradiated chimaeric thymuses resulted in immunoreconstitution and induced exactly the same allotolerance pattern as described above. The results demonstrate that not thymus epithelial cells but a bone-marrow-derived non-lymphoid thymus cell, most likely the Ia-antigen-positive thymic macrophage of dendritic cell, is responsible for the induction of tolerance to MHC antigens in developing T lymphocytes.     

Bordetella pertussis Proteins Dominating the Major Histocompatibility Complex Class II-Presented Epitope Repertoire in Human Monocyte-Derived Dendritic Cells

Knowledge of naturally processed Bordetella pertussis-specific T cell epitopes may help to increase our understanding of the basis of cell-mediated immune mechanisms to control this reemerging pathogen. Here, we elucidate for the first time the dominant major histocompatibility complex (MHC) class II-presented B. pertussis CD4⁺ T cell epitopes, expressed on human monocyte-derived dendritic cells (MDDC) after the processing of whole bacterial cells by use of a platform of immunoproteomics technology. Pertussis epitopes identified in the context of HLA-DR molecules were derived from two envelope proteins, i.e., putative periplasmic protein (PPP) and putative peptidoglycan-associated lipoprotein (PAL), and from two cytosolic proteins, i.e., 10-kDa chaperonin groES protein (groES) and adenylosuccinate synthetase (ASS). No epitopes were detectable from known virulence factors. CD4⁺ T cell responsiveness in healthy adults against peptide pools representing epitope regions or full proteins confirmed the immunogenicity of PAL, PPP, groES, and ASS. Elevated lymphoproliferative activity to PPP, groES, and ASS in subjects within a year after the diagnosis of symptomatic pertussis suggested immunogenic exposure to these proteins during clinical infection. The PAL-, PPP-, groES-, and ASS-specific responses were associated with secretion of functional Th1 (tumor necrosis factor alpha [TNF-α] and gamma interferon [IFN-γ]) and Th2 (interleukin 5 [IL-5] and IL-13) cytokines. Relative paucity in the natural B. pertussis epitope display of MDDC, not dominated by epitopes from known protective antigens, can interfere with the effectiveness of immune recognition of B. pertussis. A more complete understanding of hallmarks in B. pertussis-specific immunity may advance the design of novel immunological assays and prevention strategies.     

Co-Stimulatory Blockade and Tolerance Induction in Transplantation

Recipients of organ and tissue transplants require lifelong immunosuppression to prevent rejection. Better understanding of the processes culminating in allograft rejection has led to novel approaches to modulating the immune response. Co-stimulatory signals between antigen-presenting and -responding cells are essential for a normal alloimmune response, and blockade of these pathways during initial graft-host interaction may be used to ameliorate or prevent a destructive response from proceeding. A large number of experimental studies now support this concept, and early clinical trials have been initiated. Despite some early difficulties and many unanswered questions, co-stimulatory blockade has major potential as a future immune-modulating mechanism for use in clinical transplantation.     

Curli,Fibrous Surface Proteins of Escherichia coli,Interact with Major Histocompatibility Complex Class I Molecules

Curli are thin, coiled fibers expressed on the surface of Escherichia coli that bind several matrix and plasma proteins such as fibronectin, laminin, plasminogen, tissue plasminogen activator, and H-kininogen. In this work, we examined the interactions between curli-expressing E. coli and human major histocompatibility complex class I (MHC-I) and class II (MHC-II) molecules. Curliated E. coli was found to interact with an MHC-I-expressing lymphoma cell line as shown by scanning electron microscopy, whereas the binding to a mutant variant of this cell line expressing small amounts of MHC-I molecules was significantly lower. Moreover, curli-expressing E. coli bound purified radiolabeled MHC-I but not MHC-II molecules, whereas an isogenic curli-deficient mutant strain showed no affinity for either MHC-I or MHC-II. Purified insoluble curli could also bind ¹²⁵I-labeled MHC-I molecules, and in Western blot experiments the 15-kDa curlin subunit protein bound intact MHC-I molecules as well as β₂-microglobulin, the light chain of MHC-I molecules. A direct interaction between monomeric MHC-I molecules and a bacterial surface protein has previously not been reported. The binding of curli to MHC-I molecules, which are present on virtually all cells in higher vertebrates, will provide curliated E. coli with ample opportunities to interact with a great variety of hosts and host cells. This should facilitate the adaptation of E. coli to different ecological niches, and in human infections the interaction between curli and MHC-I molecules could contribute to adherence and colonization.Some Escherichia coli strains belonging to different clinical types (enterotoxigenic, enterohemorrhagic, and sepsis isolates) express fibrous surface proteins called curli (3, 23). Similar surface organelles designated thin aggregative fimbriae are also found in Salmonella enteritidis (6–8). Curli fimbriae in E. coli consist of polymers of a single 15-kDa protein encoded by the curlin subunit gene csgA (23), which is highly homologous to the AgfA subunit in thin aggregative fimbriae (6, 10). For simplicity, curli fimbriae are referred to here as curli. The production of curli in E. coli requires expression of two csg operons (15), and the polymerization of the curlin subunit to insoluble curli is dependent on the presence of a specific nucleator protein encoded by the csgB gene (16). The csgA and csgB genes are cotranscribed (1), and they show 25% sequence identity at the protein level. A prominent and noteworthy property of curli polymers is their ability to specifically interact with numerous human proteins such as the matrix proteins fibronectin and laminin (23, 24) and proteins of the fibrinolytic and contact-phase systems (3, 26). This ability should facilitate the adaptation of curli-expressing bacteria to different niches in the infected host.Major histocompatibility complex (MHC) class I (MHC-I) molecules are highly polymorphic transmembrane glycoproteins (for references, see reference 14). They function as receptors that present foreign peptides to cytolytic T cells, resulting in the destruction of the presenting cell, i.e., a virus-infected cell. Structurally, MHC-I molecules are composed of a 40-kDa heavy chain which has three extracellular globular domains, a short transmembrane domain, and a cytoplasmic domain (5). The 12-kDa light chain, β₂-microglobulin (β₂m), is noncovalently associated with the three extracellular globular domains of the heavy chain. β₂m and these domains all exhibit the typical immunoglobulin (Ig) fold (28), and consequently MHC-I molecules belong to the Ig superfamily of proteins. Numerous Ig-binding bacterial surface proteins have been isolated and characterized (for references, see reference 18). However, none of these or any other defined microbial surface protein has been reported to interact directly with monomeric MHC-I molecules. As these Ig-related surface proteins are found at the surface of all nucleated mammalian cells, this is somewhat surprising. Thus, it would appear a plausible microbial strategy to adhere to these abundant surface proteins during, for instance, the initial colonization of the host. This notion and the multipotent protein-binding property of curli stimulated us to analyze a possible interaction between MHC-I molecules and curli. The results demonstrate that curliated E. coli, purified curli, and the curlin subunit protein indeed have affinity for MHC-I molecules.     

Studies of Monoclonal Antibodies Specific for Major Histocompatibility Complex Products of the Rat

Polyclonal syngeneic, allogeneic, and xenogeneic and monoclonal syngeneic anti-anti-idiotypic antibodies have been produced against previously described monoclonal anti-idiotypic antibodies with specificity for monoclonal RT1 alloantigen-specific antibodies. The anti-anti-idiotypes could again be shown to be highly specific for the monoclonal anti-idiotype used for the induction of the anti-anti-idiotypic antibodies and to carry the same, or a very similar, idiotype as the original monoclonal idiotypic antibody used to induce the monoclonal anti-idiotypic. Among the 30 syngeneic and allogeneic and the five xenogeneic polyclonal anti-anti-idiotypic antisera and the three monoclonal anti-anti-idiotypes, only one polyclonal antiserum showed binding capacity to the corresponding RT1-encoded antigenic determinants on spleen cells. All the other antibodies were idiotypic but not antigen binding.     

Workshop on the Major Histocompatibility Complex in Infectious Disease Epidemiology

A workshop, sponsored by the National Institute of Allergy and Infectious Diseases, on the use of histocompatibility phenotype as a variable in epidemiologic studies of infectious diseases was held in Bethesda, Maryland on March 2 and 3, 1978. The Workshop chairman was J. Thomas Grayston and the group chairmen and rapporteurs were John E. Craighead, R. Gordon Douglas, David T. Karzon, Wilma B. Bias, W. Paul Glezen and Andre J. Nahmias. Those presenting were D. Bernard Amos, Rene R. P. de Vries, Robert Elston, William D. Hillis, Jogn B. Robbins, Pablo Rubenstein, Julius Schachter, Paul I. Terasaki, Jon J. van Rood and Edmond J. Yunis. Other participants included E. Russell Alexander, Philip S. Brachman, Mary J. Carter, Richard G. Cornell. John R. David, Earl L. Diamond, Roger Detels, David Drutz, Bo Dupont, King K. Holmes, Adel Mahmoud, William H. Marine, Robert W. McCollum, Kenneth McIntosh, Max R. Mickey, Arnold S. Monto, John N. Neff, Roger D. Rossen and Donovon J. Thompson. The organizing committee consisted of David W. Alling, Carl Cohen, George T. Curlin, Raphael Dolin, Bernard W. Janicki, Albert Z. Kapikian, Eric A. Ottesen, Fred J. Payne, and Ethan M. Shevach.     

Studies of Monoclonal Antibodies Specific for Major Histocompatibility Complex Products of the Rat

Sixteen monoclonal anti-idiotypic antibodies were prepared against RT1 antigen-specific monoclonal antibodies by means of an inhibition assay. Three (110-3, 112-89, and 133-4) were produced against antibody 3-8C2 (19), three (178-60, 181-14, and 184-38) against antibody 11/23/5, and three (144-3, 144-33, and 146-31) against antibody 1-5A4. One monoclonal anti-idiotypic antibody (21-39) was directed against antibody 1-8D2 and six (CE1-3, CE2-1, CE7-2, CE8-46, CE9-35, and CE10-2) against antibody 3-12A1. The anti-idiotypic antibodies were all highly specific for the respective monoclonal antibody used for the induction of the anti-idiotype and did not cross-react with other monoclonal antibodies.     

Studies of Monoclonal Antibodies Specific for Major Histocompatibility Complex Products of the Rat

Polyclonal anti-idiotypic antibodies against monoclonal antibodies with specificity for RT1-encoded antigens were induced in syngeneic, allogeneic, and xenogeneic hosts. The immune response to the idiotypic determinants on monoclonal antibodies was T-cell-dependent. The anti-idiotypic antibodies, independent of whether they were induced in syngeneic, allogeneic, or xenogeneic (after proper absorption) hosts, showed an exquisite specificity for the monoclonal antibody used for the induction. No cross-reactivity with other monoclonal antibodies could be observed.     

Studies of Monoclonal Antibodies Specific for Major Histocompatibility Complex Products of the Rat

Sixteen monoclonal antibodies against antigens coded for by the RT1 complex of the rat have been produced. Fourteen are specific for the a haplotype: six recognize class II and eight class I antigens. Two are specific for the 1 haplotype, one reacting with class I and the other with class II antigens. By means of these monoclonal antibodies four independent clusters of antigens for class I antigens of the a haplotype and three for class II antigens could be defined. The three antigenic sites of class II antigens reside on the same heterodimer. The monoclonals described here are characterized with regard to Ig class and subclass, pI, and complement-activating capacity.