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Suppressor T cells in rats with prolonged cardiac allograft survival after treatment with cyclosporine

DA rats treated with cyclosporine for 2 weeks after being grafted with an RT1-incompatible PVG heart graft did not reject the graft and developed a state of specific unresponsiveness to graft antigens. The cellular mechanisms maintaining this state of unresponsiveness were studied by testing the capacity of lymphocytes from these animals to effect or inhibit graft rejection in irradiated grafted hosts. Whole lymph node and spleen cell populations, and the T cell subpopulation separated from the latter, failed to restore the rejection of PVG hearts in irradiated DA recipients but restored third-party Wistar-Furth (W/F) rejection. Both whole spleen cells and the splenic T cell subpopulation had the capacity to suppress the ability of normal DA lymphocytes to cause graft rejection. Suppression was not dependent upon a state of chimerism in grafted cyclosporine -treated animals, and was not associated with any measurable alterations in the proportion of cytotoxic/suppressor T cells in lymphoid tissues. These studies show that the state of specific unresponsiveness that follows the treatment of heart grafted rats with cyclosporine is dependent, in part, upon active suppression that is induced or mediated by T lymphocytes. Many features of the immune reactivity of cyclosporine -treated grafted rats support the hypothesis that the mechanism of specific suppression in these animals is akin to that of enhancement, rather than to that of transplantation tolerance induced in neonatal rats.

Suppressor cells in transplantation tolerance. I. Analysis of the suppressor status of neonatally and adoptively tolerized rats

The lymphocytes from neonatally tolerant rats which adoptively transfer tolerance to sublethally irradiated recipients do so by specifically suppressing the regeneration of alloreactivity which normally occurs after irradiation. Although tolerant cells will only partially suppress normal alloreactive cells when the two are mixed in near equivalent numbers, experiments in which the interval between injection of tolerant and normal cells into irradiated recipients was gradually extended, indicated that total suppression of normally alloreactive cells was achieved after 8 weeks of prior residence of tolerant cells in the adoptive host. Further evidence that tolerant cells would only suppress if present in excess of normal cells was obtained by reducing the tolerant cell population in tolerant donor rats by whole body irradiation. These animals then lost their ability to suppress normal alloreactive cells administered to them. The immune status of adoptively tolerized animals did not mimic that of the donors of the tolerant cells. Even where full tolerance, as measured by skin graft survival, failure to synthesize alloantibodies, and capacity to further transfer skin graft tolerance to secondary recipients, was evident the lymphocytes of these animals showed considerable graft-versus-host (GVH) reactivity. The persistence of tolerance through repeated adoptive transfers was correlated with the persistence of donor (chimeric) cells and the indicator skin graft on adoptive recipients only amplified tolerance expression where the inocula of tolerant cells given was weakly suppressive. Finally, removal of the minor population of chimeric cells from tolerant inocula using cytotoxic alloantisera abolished the capacity to transfer tolerance. These results imply an active role for chimeric cells which is best understood as an immune response involving proliferation driven by the idiotypes of the alloreceptors on host cells.

The Cellular Basis of Transplantation Tolerance in the Rat

Since the seminal paper of Billingham et al. (1953) on acquired tolerance to antigens of the Major Histocompatibility Complex (MHC), it has become increasingly clear that the permanent acceptance of skin allografts can reflect a spectrum of underlying immunological mechanisms. These range from antibody mediated enhancement to complete tolerance. The latter can be unambiguously defined as complete specific non-reactivity of the lymphoid cells of tolerant donors in all assays (in vivo and in vitro) for alloimmune function. Although complete tolerance may be induced in both neonatal and adult animals by a variety of procedures, the injection of F, hybrid bone marrow cells into the circulation of newborn parental animals is the classical technique and may be the least complex to analyze. It was towards an understanding of the cellular mechanisms underlying tolerance induced in this way that the following studies were directed.

T Cell leukaemia in the rat: the pathophysiology

Summary A new transplantable lymphocytic leukaemia of the inbred Hooded Oxford strain of rat is described. Fewer than 10 cells will transfer disease to syngeneic recipients. Leukaemic cells bear the surface markers of thymus‐derived (T) cells and recirculate from blood to lymph. In contrast to the usual thymic lymphomas of rodents the pathophysiology of the disease‐bears a close resemblance to human acute lymphoblastic leukaemia.

T Cell subsets mediating lethal graft versus host disease: Demonstration that synergy between CD4+ and CD8+ T cells is the predominant mechanism in low responder rat strains

T cell subsets from rat strains that have been characterized as high and low responders to alloantigen were examined for their capacity to mediate lethal graft versus host disease (GVHD) across strain combinations incompatible for class I, class II, and non-MHC antigens. Inocula of 5 X 10(7) lymph node and spleen cells (LC) from low responder DA (RT1a) and high responder W/F (RT1u) strains caused lethal GVHD in (W/F X DA)F1 hybrids given 6 Gy whole body irradiation. W/F CD4+ (W3/25+) cells (2 X 10(7], equal to the number in 5 X 10(7) LC mediated lethal GVHD but 10(8) DA CD4+ cells were required to cause lethal GVHD. CD8+ (MRC OX8+) cells (5 X 10(7] from W/F rats alone caused lethal GVHD but those from DA rats could not. Mixtures of CD4+ and CD8+ DA T cells, equivalent to the number in 5 X 10(7) LC, did mediate lethal GVHD, demonstrating that synergy between the subsets was the predominant mechanism with DA cells. These results suggest that differences in alloreactivity between the strains tested may be due to alternate requirements for the alloactivation of T cell subsets; the high responder subsets being self-sufficient and the low responder subsets being dependent upon each other.

T cell leukaemia in the rat: stable marker chromosome in leukaemic cells

Summary The karyotype of a transplantable T cell leukaemia which arose originally in a PVG strain rat undergoing chronic internal β irradiation of the spleen was examined and a marker chromosome was found. Although the leukaemia progressively became more acute during 4 years of continuous passage the marker did not change. Cytogenetic analysis of normal rats given an acute exposure to external irradiation revealed, among other abnormalities, a marker of the same morphology; indicating that the original marker was probably radiation induced. This is the first description of a stable marker chromosome in an experimental animal leukaemia.