William R. Duncan

The role of class I and class II MHC antigens in the rejection of vascularized heart allografts in mice.

We have examined the role of entire major histocompatibility complex (MHC) disparity, individual class II or class I alloantigens in the rejection of vascularized heart allografts. Our results demonstrate that entire MHC, as well as both class II and class I disparities, may induce acute heart graft rejection or severe and irreversible heart muscle destruction. However, in 1 of 2 combinations differing at class II and 1 of 5 differing at class I, hearts have shown a good function > 100 days postgrafting. Furthermore, each donor-recipient combination has demonstrated a unique pattern of heart allograft function as well as a degree of heart muscle damage. In conclusion, these data suggest that the rejection process depends upon multiple factors such as the immune-response-gene-regulated immuno-responsiveness of the recipient as well as the expression of alloantigens on heart grafts during the induction and effector phases of the immune response.

Hamster immune responses in infectious and oncologic diseases

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Alloimmune Reactions Among Recently Wild Syrian Hamsters and Classical Inbred Strains Include Alloantibody Production

Partially inbred lines of Syrian hamsters, the descendants of animals caught wild in Syria within the past decade, have been studied to determine their immunogenetic relationships to the long established domestic inbred strains. These new sources of hamster genes display strong alloimmune reactions when confronted with tissues from the domestic inbred strains and vice versa: acute skin graft rejection, strong mixed lymphocyte reactions, and intense graft-versus-host reactions. While these forms of reactivity have also characterized the disparities among the domestic inbred strains, no evidence of alloantibodies specific for putative transplantation antigens has ever been found in hamsters. We report, for the first time, that immunization of recently wild hamsters with tissues from domestic inbred strain donors elicits high titer cytotoxic antibodies directed at alloantigens. Similarly, animals of the domestic inbred strains produce comparably strong alloantibody responses when immunized with tissues from the recently wild hamsters. Availability of these alloantisera will make the possibility of defining the major histocompatibility complex equivalent in this species much more likely.

Analysis of the major histocompatibility complex in Syrian hamsters. II. Linkage studies.

SUMMARY The genetic control of the histocompatibility antigens that induce strong alloreactions in Syrian hamsters was examined. Genetic studies revealed that the alloantigens involved in skin graft rejection, graft-versus-host reactions, and mixed lymphocyte reactions are under dominant single gene control and that these genetic loci are closely linked. These data suggest that this strong histocompatibility locus (i) may represent the major histocompatibility complex equivalent in this species, and this locus or group of loci has been called Hm-1. In addition, studies concerning the genetic control of the immune response to bovine serum albumin suggest that the high response is under dominant, single gene control; however, this gene is not linked to Hm-1.

The role of TDTH and Tc populations in organ graft rejection. I. Functional analysis of graft-infiltrating T cells.

To analyze the role of T cell subpopulations in the rejection of organ allografts, we developed a new model for obtaining large numbers of graft infiltrating cells (GICs). We isolated W3/25+ Th/DTH and OX8+ Ts/c from vascularized, irradiated rat spleen allogfrafts. W3/25+ GICs obtained from spleen allografts transplanted to normal recipents were highly effective in eliciting cardic allograft rejection when transferred to sublethally irradiated recipients, however, the OX8+ subset was incapable of eliciting rejection. On the other hand, when OX8+ GICs were obtained from spleen allografts transplanted to previously immunized recipients, they were as efficient as the W3/25+ Th/DTH Subset in eliciting cardiac allograft destruction. These results indicate that the W3/25+, OX8- T cell is required for the rejection of primary organ allografts, but that the rejection of a secondary allograft by an immune recipeint may be mediated, independently, by both W3/25+ and OX8+ cells.

Immunochemical detection of hamster class II MHC homologues by murine anti-Iak sera

Syrian hamster la-like cell-surface glycoproteins have been identified by immunoprecipitation of radiolabeled hamster lymphocyte lysates with cross-reacting murine anti-Iak alloantisera. Two components of 39 000 and 29 000 daltons were discerned by polyacrylamide gel electrophoresis in SDS (SDS-PAGE). Absorption of the antisera with mouse or hamster lymphoid cells demonstrated the cross-reactive anti-Iak antibodies to be specific for hamster Ia homologues. These molecules were also shown to have radiolabeling characteristics similar to Ia antigens of the mouse and guinea pig. These studies suggest that distinct structural similarities exist between murine Ia and the hamster Ia-like molecules described here. In view of our previous immunochemical description of putative hamster class I homologues, the current identification of hamster class II homologues suggests that an adequate and contemporary description of the hamster major histocompatibility complex is possible and likely.

Induction of transplantation tolerance in rats by spleen allografts. III. The role of T suppressor cells in the induction of specific unresponsiveness.

Heterotopic (WAGxAGUS)F1 spleen allografts survive indefinitely when transplanted to normal AGUS recipients and induce long-term donor-specific unresponsiveness. In this report, we have examined the immune reactivity of spleen graft recipients soon after transplantation, in an attempt to define the immunological mechanisms responsible for the induction of donor-specific unresponsiveness. Unresponsiveness develops as early as one week after splenic transplantation. T cells obtained from the recipient lymph node and spleen exhibit reduced mixed lymphocyte reaction responses to donor (WAG) but respond normally to third-party (PVG) stimulators. In contrast, T cells obtained from the spleen graft are unresponsive to both donor and third-party stimulators. Donor specific T suppressor cells (Ta) appear in the recipients lymph node and spleen by one week posttransplantation-however, at this time antigen nonspecific suppressor cells predominate in the spleen graft. Only minimal cytotoxic T cell activity could be detected in the spleen graft, with the host spleen and lymph nodes being devoid of cytotoxic T lymphocytes. Sera obtained one or two weeks following splenic transplantation did not contain cytotoxic alloantibodies, and only a very weak response could be detected at one month. These data demonstrate that the unresponsiveness associated with the spontaneous acceptance of spleen allografts is correlated with the early induction of antigen specific Ta in recipient lymphoid tissue and the presence of nonspecific suppressor cells at the graft site.

Induction of transplantation tolerance in rats by spleen allografts. I. Evidence that rats tolerant of spleen allografts contain two phenotypically distinct T suppressor cells.

We have examined suppressor cell activity in transplantation tolerant (TT) rats bearing vascularized spleen allografts in several different donor-recipient combinations. More than 60% of WAG (RT-1u) and 65% of AGUS (RT-1l) spleen allografts were permanently accepted when transplanted to AGUS and PVG (RT-1c) rats, respectively. All (WAG X AGUS)F1 to AGUS and (AGUS X PVG)F1 to PVG spleen allografts survived indefinitely. Unseparated LNC, TDL, and whole T cell or W3/25+, OX8- T cell populations obtained from AGUS rats bearing (WAG X AGUS)F1 spleens exhibited reduced mixed lymphocyte reaction (MLR) responses to the spleen donor, and to some extent to BN(RT1n) third-party stimulators, but responded normally to PVG.A(RT1a) stimulators. Coculture experiments demonstrated that lymph node cells (LNC) and thoracic duct lymphocytes (TDL) of TT rats contain RT1 specific suppressor cells. Furthermore, T cells isolated from all donor-recipient combinations contained two phenotypically distinct suppressor cell populations: a radiosensitive W3/25+, OX8- (Th/i) and a relatively radioresistant W3/25-, OX8+ (Ts/c). These Ts may be responsible for the maintenance of TT.

The biochemical characterization of Syrian hamster cell-surface alloantigens: II. Immunochemical relationships between cell-surface alloantigens and class II MHC homologues

Immunochemical comparisons between hamster cell-surface p39/p29 alloantigens and putative MHC class I and class II products indicate that p39/p29 alloantigens are probable class II products. Both p39/p29 alloantigens and class II homologues have varying expression in hamster lymphoid tissues and are absent from fibroblasts. In addition, analysis by nonequilibrium pH gradient electrophoresis demonstrates similar, although nonidentical, alloantigen and class II homologous charge profiles. This observation could reflect multiple class II subregions within the hamster MHC. These data therefore suggest an immunochemical description of the hamster MHC which is compatible with MHC models proposed for other mammalian species.

Induction Of Transplantation Tolerance In Rats By Spleen Allografts Ii. Evidence That W3/25+ T Suppressor/inducer And 0x8+ T Suppressor/effector Cells Are Required To Mediate Specific Unresponsiveness

The results presented in this report demonstrate that T cells, isolated from AGUS rats bearing long-term (WAG X AGUS)F1 spleen allografts adoptively transferred to irradiated AGUS recipients could not mediate the rejection of WAG hearts but rejected PVG. A hearts in acute fashion. Further, unresponsive T cells were able to suppress the capacity of adoptively transferred (40 X 10(6) normal T cells to reject WAG but not PVG.A heart allografts. We also studied the role of W3/25+ and OX8+ T cells subsets in the maintenance of unresponsiveness. Isolated W3/25+ or OX8+ unresponsive T cells were not able to mediate acute rejection, but were less effective in prolonging WAG allograft survival than the unresponsive whole T cell population, suggesting that both W3/25+ Ts1 and OX8+ Ts2 subsets were required for effective suppression in vivo. When, however, unresponsive W3/25+ T cells were infused simultaneously with normal OX8+ T cells, they could produce indefinite survival of WAG heart allografts. These results indicate that the unresponsive state induced by (WAG X AGUS)F1 spleen allografts transplanted to AGUS rats is maintained by the interaction of W3/25+ T suppressor/inducer and OX8+ T suppressor/effector cells.