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C F Barker

Publications and source records attributed to C F Barker.

At least 73 records · Page 4Linked to original sources
PubMed1993

Allograft rejection by T cell receptor transgenic mice.

We have used a line of T cell receptor (TcR) transgenic mice, in which a significant portion of CD8+ T cells expresses a TcR that is specific for the minor histocompatibility antigen H-Y presented by the H-2Db Class I molecule, to examine the immune response to H-Y-incompatible skin or pancreatic islet allografts. Our results indicate that, in contrast to the conclusions of previous reports, pancreatic islet endocrine cells are invulnerable or only weakly vulnerable to an H-Y-directed immune response. An even more unexpected finding was that unlike normal female mice of the C57BL/6 background which consistently reject male skin within a few weeks, TcR transgene+ littermates reject male skin only infrequently. Our results are consistent with the conclusion that the inability of H-Y TcR females to reject male skin is due to a deficiency of cells with male-specific helper activity. Long-term acceptance of male grafts by H-Y TcR females leads to a state of T cell hyporesponsiveness to male skin grafts. In addition, T cells harvested from long-term skin acceptors were hyporesponsive to in vitro stimulation by a clonotype-specific monoclonal antibody. Transgenic mice with TcRs having antigenic specificity for defined transplantation antigens provide a unique model for study of the allograft response.

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PubMed1993

Examination of the mechanisms responsible for tolerance induction after intrathymic inoculation of allogeneic bone marrow.

OBJECTIVE: This study examined the immunologic mechanism(s) responsible for the induction of transplantation tolerance in rats pretreated with intrathymic inoculation of donor strain bone marrow. SUMMARY BACKGROUND DATA: Induction of unresponsiveness may involve deletion and/or inactivation of donor-reactive T-cell precursors maturing in a thymus harboring donor alloantigen or generation of regulatory/suppressor cells. It was reasoned that, if unresponsiveness is caused by deletion of alloreactive clones, the presence of additional thymic tissue devoid of donor alloantigen permits normal maturation of T-cells and, thus, prevents induction of tolerance. However, if unresponsiveness were primarily mediated by regulatory/suppressor cells, the presence of noninoculated thymic tissue should not affect the induction of tolerance. METHODS: Three strategies were used to define the cellular basis of cardiac and islet allograft survival in WF recipients of intrathymic LEW donor bone marrow as follows: (1) inoculation of bone marrow either into the native thymus and/or into an ectopic thymus, (2) limiting dilution analyses of the frequency of precursor cytotoxic T-lymphocytes (CTLp), and (3) adoptive transfer to syngeneic secondary hosts. RESULTS: Inoculation of bone marrow into only one lobe of the native thymus and/or into an ectopic thymus did not promote consistent survival of subsequent LEW cardiac allografts. Tolerant hosts displayed significant reductions in CTLp frequencies against donor alloantigens. Adoptive transfer of spleen cells from tolerant WF hosts harboring long-standing cardiac allografts led to permanent survival of LEW cardiac allografts in all secondary recipients. However, transfer of spleen cells from WF animals that received intrathymic LEW bone marrow (but no cardiac allograft) did not promote survival of LEW cardiac allografts in naive secondary hosts. CONCLUSIONS: These results indicate that the unresponsive state after intrathymic inoculation of bone marrow cells is primarily mediated by deletion and/or inactivation of donor-specific T-cell precursors maturing in a chimeric thymus. The demonstration by adoptive transfer studies of putative regulatory/suppressor cells suggested an important role for the persistence of donor alloantigen (supplied by a vascularized allograft) in the maintenance of the unresponsive state.

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PubMed1993

Islet allograft, islet xenograft, and skin allograft survival in CD8+ T lymphocyte-deficient mice.

Despite extensive study, the immunologic mechanisms mediating allograft rejection have not been completely defined. In the current study, we evaluated the T cell subsets important in islet allograft, skin allograft, and islet xenograft rejection using a genetically engineered line of mice deficient in beta 2-microglobulin expression. Because these mice lack cell surface MHC class I expression, they are deficient in T cells of the CD8 subset (class I-restricted cytotoxic T cells). Pancreatic islet allografts transplanted to CD8+ T cell-deficient recipients showed prolonged survival compared with controls. No prolongation was observed in the survival of pancreatic islet xenografts or in the survival of skin allografts transplanted to the CD8+ T cell--deficient hosts. We conclude that CD8+ T cells play a prominent role in islet allograft, but not islet xenograft or skin allograft, rejection in mice.

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PubMed1993

Prolonged survival of rat orthotopic liver allografts after intrathymic inoculation of donor-strain cells.

Permanent donor-specific tolerance to tissue or organ allografts can be readily achieved without immunosuppression by administration of donor lymphohematopoietic cells to neonatal rodents. In adult recipients, however, induction of transplantation tolerance by this strategy generally requires intensive cytoablative conditioning of the recipient. We have now demonstrated that intrathymic inoculation of donor bone marrow or hepatic cells in conjunction with a single dose of antilymphocyte serum is effective in prolonging survival of DA rat orthotopic liver allografts in LEW strain recipients, which ordinarily rapidly reject such transplants. The unresponsive state achieved is donor-specific, as evidenced by the failure of intrathymic inocula of third-party WF cells to promote survival of LEW recipients of orthotopic DA liver allografts. Moreover, intravenous administration of the donor cells fails to extend liver allograft survival, demonstrating that the inoculum must be present in the thymus to promote unresponsiveness. Established DA liver allografts induced a state of systemic tolerance in LEW hosts, allowing their subsequent acceptance of donor-strain skin allografts. We hypothesize that the unresponsive state achieved by intrathymic inoculation of donor cells may result from the deletion or functional inactivation of alloreactive clones in a thymus bearing donor alloantigens. In this regard, cells of the macrophage/dendritic lineage (descendants of the bone marrow inoculum or hepatic Kupffer cells) may play a critical role by promoting thymic microchimerism and exerting modulatory effect on T cell development.

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PubMed1993

Deletion of donor-reactive T lymphocytes in adult mice after intrathymic inoculation with lymphoid cells.

Clonal deletion of self antigen-reactive T lymphocytes is known to be a dominant mechanism of tolerance induction in the normal immune system. This report considers whether deletion of antigen-reactive T cells is also the immunologic basis for the recently described model of transplantation tolerance that follows intrathymic inoculation with allogeneic lymphoid cells. We found that the outcome of injecting Mlsa- hosts with lymphocytes from Mlsa+ donors was depletion of V beta 6+ T cells (which are known to be reactive with the Mlsa superantigen). The process was found to be specific in that a similar reduction was not seen in an irrelevant T cell population (V beta 8+) in IT injected hosts. Deletion was observed in this model only if immunosuppression with ALS or anti-CD4 accompanied intrathymic injection. When the inoculum of allogeneic lymphocytes was administered intravenously instead of intrathymically only minimal deletion was observed. The induction of transplantation tolerance by intrathymic injection of donor lymphoid cells may prove especially efficacious since it relies on deletion of only those T cells specifically reactive to donor antigens, a process analogous to tolerance induction to self antigens.

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PubMed1993

Promotion of rat cardiac allograft survival by intrathymic inoculation of donor splenocytes.

Donor-specific unresponsiveness to LEW heterotopic cardiac allografts was induced in WF rats following intrathymic inoculation of LEW splenocytes in conjunction with a single intraperitoneal dose of antilymphocyte serum. In contrast, LEW cardiac allografts were promptly rejected in WF recipients pretreated with an intravenous inoculation of donor splenocytes. Without transient immunosuppression with antilymphocyte serum neither intrathymic nor intravenous inoculation of splenocytes led to allograft survival. Substitution of antilymphocyte serum by a short course of cyclosporine did not permit allograft survival, suggesting that a T-cell-depleting regimen is crucial to tolerance induction by this protocol. The unresponsive state could be transferred to secondary syngeneic hosts by spleen cells from long-term recipients of intrathymic splenocytes and cardiac allografts but not by spleen cells from recipients of intrathymic splenocytes alone. This suggests that persistence of donor alloantigen from the graft is necessary for maintenance of the tolerant state. The unresponsive state after intrathymic inoculation of allogeneic splenocytes may be mediated through interaction of maturing host thymocytes with donor alloantigen.

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PubMed1992

Prevention of autoimmune diabetes in the BB rat by intrathymic islet transplantation at birth.

Spontaneous diabetes in the BioBreeding (BB) rat, like human type I diabetes, results from the destruction of pancreatic islets by autoreactive T lymphocytes recognizing beta cell-specific antigens. T cell tolerance is in part mediated by interactions of maturing thymocytes with antigens expressed in the thymic microenvironment; islets were therefore implanted into the thymus of neonatal diabetes-prone BB rats to determine whether exposure of T cell precursors to beta cell antigens could influence the development of diabetes. This treatment completely prevented diabetes and insulitis in the native pancreas. The effect may be the result of specific modulation of diabetogenic T cells maturing in an islet-bearing thymus.

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