Major Transplantation Antigens Research Articles

Speculations on the role of major transplantation antigens in cell-mediated immunity against intracellular parasites.

In three major fields of immunology—“academic” immunology, immunology of infectious diseases, and transplantation immunology—exciting features in common have been discovered over the past few years. As early as the 1950’s, possible links between the transplantation reaction and cell-mediated immunity to cell-bound antigens or intracellular parasites were postulated. For instance, Mitchison speculated that cellular immune recognition of antigen in delayed-type hypersensitivity (DTH) reactions probably occurred only when the antigen involved (e.g., tuberculin or chemical allergens) were present on the cell-membrane, thus resembling a foreign transplantation antigen (Mitchison, 1954). Lawrence, stimulated by Thomas’ surveillance hypothesis (Thomas, 1959), proposed that immune lymphocytes recognize not only foreign antigens on cell surfaces, since cell-mediated immunity originally evolved against intracellular parasites, but also recognized a self-component (Lawrence, 1959, 1974). This self-plus-X hypothesis was a very lucid speculation that foresaw many of the principles discovered since. All these discoveries now lead to the conclusion that thymus-derived lymphocytes (T-cells) seem to express a double specificity for foreign antigenic determinants and for cell-surface self determinants (For reviews see Paul and Benacerraf, 1977; Munro and Bright, 1976; Doherty et al., 1976; Shearer et al., 1976; Forman, 1976; Zinkernagel and Doherty, 1977a; Koszinowski et al., 1977a; Schrader et al., 1977; Katz, 1977; Langman, 1978).KeywordsMajor Histocompatibility ComplexIntracellular ParasiteHistocompatibility AntigenAssociative RecognitionLymphocytic ChoriomeningitisThese keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.

Major transplantation antigens, viruses, and specificity of surveillance T cells.

The altered-self hypothesis is an attempt to explain why thymus-derived lymphocytes (T cells) apparently lyse only virus-infected target cells with which they share major transplantation antigens (Zinkernagel and Doherty, 1974a-c; Doherty and Zinkernagel, 1974, 1975a). Specific T-cell-mediated lysis of cells infected with lymphocytic choriomeningitis virus (LCMV), ectromelia virus (mouse pox), or vaccinia- or paramyxovirus (Sendai) requires homology of the K or D regions but not the I region of the major murine histocompatibility (H-2) gene complex (Doherty et al., 1976a; Zinkernagel and Doherty, 1975; Blanden et al., 1975a; Doherty and Zinkernagel, 1976; Koszinowski and Thomssen, 1975; Zinkernagel, 1976a). H-2K and H-2D code for major histocompatibility (H) or transplantation antigens that are expressed independently on the cell surface and that are responsible for rapid allogeneic graft rejection (reviewed in Schreffler and David, 1975, and Klein, 1975).

Cells that express viral antigens but lack H-2 determinants are not lysed by immune thymus-derived lymphocytes but are lysed by other antiviral immune attack mechanisms.

Murine F9 teratoma cells do not express major transplantation antigens detectable by either serologic or alloreactive assays of thymus-dependent lymphocytes (T cells). Such cells can be infected with lymphocytic choriomeningitis virus or vaccinia virus, do express viral antigens on the cell surface, and can release infectious virus in amounts equivalent to those of other H-2 bearing murine cell lines. Immunologic injury of virus-infected F9 cells occurs after the addition of specific antiviral antibody and complement or of specific antiviral antibody and unsensitized lymphoid cells (antibody-mediated cell-dependent killing). In contrast, injury does not follow the addition of immune cytotoxic T cells. These results indicate that possession of H-2 antigens is not a requirement for a cell's infection by or production of virus. Further, expression of viral antigens on the cell's surface, although adequate for antibody-mediated immune injury, is by itself insufficient for direct T cell-mediated lysis. The major transplantation antigens thus probably represent the cell surface structures that are crucial for T-mediated cell wall damage that results in chromium release.

Cellular and humoral immune response analysis of bone-allografted rats

Long-term cellular and humoral immune responses were studied in inbred rats in which bone was allografted. Transplants were made across major histocompatibility barriers. Mixed lymphocyte culture tests and humoral cytotoxicity assays were performed in order to determine degrees of cellular and humoral immunity. Grafts of complete bone and of bone free of marrow elicited both types of immune response and it is proposed that transplantation antigens for both types of reaction exist in the bone tissue itself. A gene-dose effect was found. Allogeneic bone grafts gave a stronger reaction than semiallogeneic grafts, and second-set grafts triggered a hypersensitivity type of humoral immune response. This study suggests that until the host-bone graft immunological relationship is better understood, the graft tissue should be matched to the host for major transplantation antigens to help prevent unexpected failures in massive bone allotransplantation.

Differences between pig tissues in the expression of major transplantation antigens: possible relevance for organ allografts.

Evidence is presented that there are differences between pig liver and kidney parenchymal cells in the expression of major histocompatibility complex antigens. Analogues of I-region antigens of the mouse are detectable on kidney cells and some peripheral blood leukocytes (PBL) but not on liver, platelets, and other PBL. Such differences between liver and kidney may explain (a) the fate of these organs as allografts and (b) the donor-specific protection of kidney by liver. Other antigens peculiar to skin and kidney have been detected but require further characterization.

T helpers may be sensitized by antigen-specifically altered structures, which are coded by the I region of the H-2 gene complex.

We have shown that virus immune cytotoxic cells are specific for virus-altered structures (1–4). These structures are coded for in the H-2K or the H-2D. Accordingly, virus immune cytotoxic CBA/H (H-2k) T cells sensitized in vivo will react in vitro only with ‘altere’ H-2k, not with ‘altere’ H-2d. The alteration can be envisaged as biochemical modifications of the protein or carbohydrate part of the private specificity of major transplantation antigens or of structures coded very closely to them. Alternatively, it could be formation of a complex of these structures and viral antigens (1–4). Structures coded for in the I region of the H-2 complex could not be shown to be relevant at the effector level (2, 3). However, this H-2 region may be involved in the initial sensitization and/or proliferation step(s). The requirement for compatibility at H-2K or H-2D of in vitro T cell-mediated cytotoxicity against virus infected target cells is apparently not due to an inherent incapacity of these T cells to interact with allogeneic infected target cells.

Subunit structure of H-2 alloantigens.

HISTOCOMPATIBILITY antigens carry the immunological determinants involved in tissue transplant rejection1. Recent evience has shown that papain-solubilised HL-A antigens are composed of two polypeptide chains2,3. The smaller of the solubilised HL-A polypeptide chains has been shown4,5 to be identical to β2-microglobulin and it has also been shown that β2-microglobulin is physically linked to the HL-A antigens on the cell surface6–9. These findings raised the question of whether the major transplantation antigens from other species are composed of subunits. This communication shows that mouse H-2 alloantigens are linked to a small polypeptide chain which is homologous with human β2-microglobulin.

Human lymphocyte-dependent antibody mediated cytotoxicity and direct lymphocyte cytotoxicity against non-HL-A antigens.

EXPRESSION of the major transplantation antigens in humans is generally considered to be controlled by the genes of the HL-A region1–4. Skin, kidney and bone marrow transplants usually survive longer when donors and recipients are HL-A identical than when they are not5–7. However, the fact that grafts are still rejected with HL-A identity and negative mixed lymphocyte reactivity (MLR)8–11 strongly suggests the presence of minor transplantation antigens. The major problem to date has been the development of in vitro assay systems to detect these antigens.

CELLULAR REQUIREMENTS FOR THE REJECTION OF SKIN ALLOGRAFTS IN RATS

The role of bone marrow-derived cells in the rejection of skin allografts in rats was investigated. Lewis rats, rendered tolerant of BN antigens and bearing healthy grafts, were thymectomized, irradiated with 900 rad, and injected with varying doses of either normal isologous bone marrow, normal lymph node cells, and/or lymph node cells presensitized to BN antigens. In some experiments rats were also adoptively sensitized to tuberculin. Results showed that, although necessary for the elicitation of tuberculin skin reactions, bone marrow cells are not needed for the rejection of previously tolerated skin allografts. Rats receiving lymph node cells alone rejected their grafts in about 6-7 days. In addition, rats injected with bone marrow alone also rejected their grafts, although significantly later than did lymph node cell recipients, indicating that rat marrow contains a population of cells capable of reacting to transplantation antigens. These cells were found capable of reacting to major transplantation antigens but not minor as they were ineffective in causing the rejection of Ag-B compatible Fischer skin grafts. From experiments utilizing bone marrow from neonatally thymectomized donors and cells treated with an antiserum to rat T cells, these competent cells in the marrow were shown to be thymus derived.

Transplantation antigens in rhesus monkeys.

WE read your interesting editorial1 dealing with our work on the major transplantation antigens of rhesus monkeys, the RhL-A system. Your communication ends: “The previously held concept of H-2 genetic structure is now very much open to doubt. If further work shows that the RhL-A system also consists of two segregant series of antigens it is bound to undermine even more the concept of H-2 as a system of multiple, pseudoallelic antigens”.

Allergic Encephalomyelitis: Passive Transfer Across Major Histocompatibility Barrier

SummaryPassive transfer of allergic encephalomyelitis by injection of living, immunized lymph node cells into normal recipients constitutes a graft of lymphoid cells. It has been accomplished previously when histocompatibility barriers were absent, minor, or undefined. Treatment with an immunosuppressive drug and cells bearing donor-type antigens has now made passive transfer possible despite differences in major transplantation antigens between Lewis donor and BN recipient rats.

Comparison of soluble human and mouse transplantation antigens.

The molecular and chemical characteristics of membrane components bearing the major transplantation antigen systems in mouse (H-2) and man (HL-A) were compared and found to be strikingly similar. Kinetics of papain solubilization from cell membranes, gel filtration, and electrophoretic patterns of the alloantigenic components were found to be nearly identical. Comparable size heterogeneity of the solubilized materials was also demonstrated. Some differences in amino acid and carbohydrate content of the purified H-2 and HL-A alloantigenic materials were found. The general pattern of distribution of the amino acid residues, however, appears to be quite similar and indicate compositional relatedness in these materials. These physical and chemical similarities in the characteristics of molecules bearing the transplantation antigens are in accord with biologic studies indicating a comparable functional immunologic role for the mouse H-2 and human HL-A antigen systems. These studies support the view that the genes determining these major transplantation antigen systems may have evolved from a common precursor.