Mediate Graft Rejection Research Articles

48] Structural analysis of murine class I major histocompatibility complex antigens

This chapter describes the murine major histocompatibility complex (MHC), or H-2 as a cluster of loci coding for proteins involved in the processes of cell-mediated immunity. On the basis of this evolutionary homology the MHC loci have been divided into classes. The chapter outlines the methods used to obtain structural information about the H-2 Class I antigens. It discusses that there are two groups of Class I genes. Class I genes located in the left-hand side of the MHC encode the cell-surface molecules that represent the “classical” transplantation antigens known to mediate graft rejection. These antigens are to be found on virtually all nucleated cells in the mouse. The Class I genes found to the right-hand portion of the MHC, known as the Qa and Tla region, encode cell surface antigens that are distributed in a tissue-specific fashion. The Class I genes to the left-end of the MHC are particularly notable for their extensive polymorphism, whereas those to the right-hand end are far less polymorphic. The chapter reviews that there are structural differences among the H-2 Class I antigens but they do have certain features in common. Currently, the classical transplantation antigens are the best characterized of the Class I antigens although structural data on antigens of the Qa and the Tla regions can be expected to accumulate in the near future.

In vitro activity and in vivo correlates of alloantigen-specific murine suppressor T cells induced by allogeneic pregnancy.

The fetus that results from allogeneic mating in an outbred population bears a variety of antigens against which the maternal immune system reacts, but the type of immunity that is elicited by pregnancy does not mediate graft rejection. Previous studies have demonstrated the presence of nonspecific non-thymus derived suppressor cells in the lymph nodes draining the uterus (DLN) and in the uterine decidua during first allogeneic pregnancy. These suppressor cells appear to be small lymphoid cells that inhibit the generation of cytotoxic T cells (CTL) against paternal alloantigens. We now report that after a single allogeneic pregnancy, C3H and A strain mice develop paternal alloantigen-specific suppressor T cells (Thy-1.2+, Lyt-1-2+) that are distributed systemically in peripheral lymph nodes and spleen. These suppressor cells appear to act directly on CTL generation because the frequency of CTL precursors and the ability to produce T helper cells in response to paternal alloantigens remains unchanged after allogeneic pregnancy. Suppressor T cell activity could be detected both in vitro and in vivo, and the presence of suppression in vivo was associated with increased uterine weight 5 days after inoculation of allogeneic paternal tumor cells into the uterus of pseudopregnant mice. Nevertheless, both subcutaneous and intrauterine tumor inocula regressed in these mice with suppressor T cells. The possible role of suppressor T cells in contrast to non-T suppressor cells in successful reproduction and allopregnancy-induced tolerance is discussed.

Active suppression of host-versus-graft reaction in pregnant mice. V. Kinetics, specificity, and in vivo activity of non-T suppressor cells localized to the genital tract of mice during first pregnancy.

ABSTRACT: The fetus resulting from allogeneic mating in an outbred population such as man represents an antigenic graft against which the mother mounts an immune response. However, the type of immunity elicited by the “fetal allograft” does not appear to mediate graft rejection. This observation suggests that suppression of those types of immune responses that cause graft rejection may account for fetal survival. Allografts placed experimentally within the uterus appear to enjoy prolonged survival compared to grafts at other sites, and this latter finding suggests that localized suppression of graft rejection may exist within the uterus at the maternal‐fetal interface. Previous studies have shown that suppressor cells which develop in the lymph nodes draining the uterus (DLN, paraaortic and renal lymph nodes draining the uterus) of allogeneically mated C3H and CBA strain mice are small lymphoid cells that sediment at 3 mm/h in unit gravity; arise early during first pregnancy, reaching maximum activity near the time of implantation (“grafting”); selectively inhibit the generation of cytotoxic T cells (cytotoxic T lymphocyte—CTL—or killer T cells) in vitro and in vivo; and are absent in the DLN of CBA mice which spontaneously resorb their litters. Furthermore, this suppressor cell population appears to be concentrated within the uterine decidua, and both DLN and decidual suppressor cells are under hormonal control. We now report that initial onset of suppression in decidua occurs more rapidly than in DLN after mating. The suppressor cell population in both DLN and decidua is resistant to destruction by anti‐T serum plus complement and anti‐Ly sera plus complement, and preliminary studies show that suppressor cell activity is associated with a population of granulated small lymphocytes. A soluble suppressor activity can be obtained from the decidual lymphoid population similar to that obtained in studies of the DLN suppressor cell. Small numbers of suppressor cells can prevent the infiltration of sponge matrix allografts by cytotoxic T cells in vivo. Thus, a non‐T suppressor cell population may accumulate within the uterus and protect the fetal allograft from cell‐mediated immune rejection.

Active suppression of host-vs-graft reaction in pregnant mice. IV. Local suppressor cells in decidua and uterine blood

The mammalian fetus bears a wide variety of antigens against which the maternal immune system can respond. Although some of these antigens are transplantation antigens, the type of immune response mounted by the mother seems incapable of mediating graft rejection. We have previously demonstrated suppressor cells in the lymph nodes draining the uterus (DLN) that regulate the immune response in allogeneically pregnant C3H/HeJ and CBA/J mice. The suppressor cells were shown to be small lymphocytes (sedimenting at 3 mm/h at unit gravity) resistant to anti-T cell serum + complement that elaborated a soluble suppressor activity and selectively inhibited the generation of cytotoxic T lymphocytes (CTL) reactive with paternal alloantigens. Suppression could be induced in the DLN by syngeneic pregnancy or pseudopregnancy, and behaved as an anatomically localized activity during pregnancy. We now report that during first allogeneic pregnancy, the most potent suppressor cell activity is found in lymphocytes in uterine venous blood and in decidual lymphocytes. This suppressor cell population also sediments at 3 mm/h and is associated with production of a soluble suppressor factor. Substantial suppressor cell activity can also be obtained from the deciduomata of pseudopregnant mice. Local suppressor cell activity within the uterus may play an important role in ensuring the immunological success of the fetal allograft.

Cells mediating graft rejection in the mouse. I. Lyt-1 cells mediate skin graft rejection.

The Ly phenotype of cells mediating skin graft rejection was determined using monoclonal anti-Lyt-1.1 and Lyt-2.1 antibodies in CBA mice that received CBA lymphoid cells from mice sensitized to C57BL/6; i.e., alloantigenic differences arising from the H-2 and non-H-2 loci. It was clear that graft rejection was due wholly to the presence of Lyt-1 cells in the inoculum and that Lyt-123 or Lyt-23 cells had no effect. Furthermore, no synergism was noted between Lyt-1 and Lyt-2 cells. In this model, both the cytotoxic T cell and cytotoxic lymphocyte precursors were shown to be Lyt-123 and these could be depleted from sensitized Lyt-1 populations that mediated graft rejection. Thus cytotoxic T cells are not responsible for skin graft rejection, but rather, this is mediated by an Lyt-1 cell. Whether this T cell is distinct from other Lyt-1 cells (T helper, T cells mediating delayed hypersensitivity) is not clear at present, but other evidence, and traditional concepts, link graft rejection and delayed type hypersensitivity as being different manifestations of the same mechanism.

Immunity to human haematopoietic stem cells.

Graft rejection is an important problem in human bone marrow transplantation, with a 25–60% incidence in grafts between HLA–identical siblings1–6. In mice, two models of rejection of bone marrow grafts have been described: T-lymphocyte-mediated immunity and hybrid resistance (for reviews see refs 7, 8). The first model involves the recognition of foreign histo-compatibility (H–2) antigens by selected subsets of T lymphocytes. These antigen-reactive cells undergo clonal expansion and differentiate into cytotoxic effector cells which mediate graft rejection. In the hybrid resistance model, mononuclear cells, probably identical to natural killer (NK) cells, react against haematopoietic histocompatibility antigens on parental marrow cells9. Cells involved in hybrid resistance exhibit ‘spontaneous’ cytotoxicity to disparate haematopoietic cells and, in contrast to T-lymphocyte-mediated immunity, do not require a sensitisation phase before differentiating into cytotoxic effector cells. The mechanism of graft rejection following bone marrow transplantation in man is unknown. In transplants between HLA-identical siblings the target antigens of graft rejection are not HLA or antigens closely linked to the major histocompatibility complex (MHC). To study the problem of graft rejection in man we developed and describe here an in vitro model to detect immunity to haematopoietic stem cells committed to granulocyte–macrophage differentiation (CFU-C; colony-forming unit culture). We found that human peripheral blood and bone marrow but not thymus contain a population of cells which are cytotoxic to haematopoietic stem cells following in vitro sensitisation. The effector cell population is not a conventional T or B lymphocyte, monocyte–macrophage or NK cell.