Age-related factors in cyclosporine-induced syngeneic graft-versus-host disease: regulatory role of marrow-derived T lymphocytes

dary recipients resulted in the development ofsyngeneic GVHD (6, 10, 22) . These findings suggest that normal animals possess a radiation-sensitive component that regulates the activity of autoreactive cells, thus preventing the development of autoimmune GVHD. Adoptive transfer studies in our laboratory provided evidence that an irradiation-and cyclophosphamide-sensitive thymic-dependent system played a major role in the prevention of SGVHD (11, 12) . Furthermore, normal splenic T lymphocytes, when cotransferred with autoimmune effector cells, prevented the development ofsyngeneic GVHD in secondary recipients (12) . This regulatory effect of normal splenic T lymphocytes required collaboration between CD4+ and CD8+ T cell subsets, findings comparable with the results of the present studies. Of impor- 93 Fischer and Hess tance was the finding that the adoptive transfer of this host resistance mechanism was dose dependent, requiring twice the number of splenic T lymphocytes to SGVHD effector cells . In contrast, the present studies demonstrate that addition of small numbers ofT lymphocytes to the marrow graft at the initiation of the induction phase prevented the development of SGVHD. The mechanism whereby the T lymphocytes from mature animals inhibit the induction of SGVHD is unclear. One possibility is that the mature T lymphocytes contained in the marrow graft expand (despite the presence of CsA) to levels that are able to modify the action of the autoreactive cells produced during the 30-d course of CsA therapy. Recent evidence presented by Powrie and Mason (18) suggest that mature T cells can proliferate in a thymic-and antigen-independent environment (thymectomized hosts reconstituted with T cell-depleted marrow) . The present studies demonstrate that thymectomized rats, reconstituted with T cell-depleted marrow and infused with small numbers of T lymphocytes were resistant to the adoptive transfer of SGVHD with effector splenocytes after waiting 30 d to allow expansion of the normal T cells. However, administration of CsA during this 30-d period prevented the expansion of this host resistance mechanism, and SGVHD was successfully transferred, clearly indicating that CsA prevented the expansion of this host resistance mechanism such that a limited number of effector cells (3 x 10') were capable of establishing disease in these animals . Further, infusion of 3 x 107 normal T lymphocytes on the day of C&A withdrawal failed to prevent development of SGVHD. These data imply that the number of autoreactive cells generated during CsA therapy exceeded the capacity of the host resistance mechanism contained in 3 x 107 normal T lymphocytes . On the other hand, only a minimum number of normal T cells (5 x 106) were required to be added to the marrow inoculum and infused on the day of transplant, to prevent the development of SGVHD. Since CsA administration prevented the expansion of the host resistance mechanism, it would seem likely that the host resistance mechanism contained in the mature T lymphocyte population carried over with the marrow graft inactivates the autoreactive cells as they are generated during the course of CsA therapy. This hypothesis is also supported by the failure to adoptively transfer SGVHD from animals grafted with marrow plus mature T lymphocytes to irradiated secondary recipients in which the host resistance mechanism had been eliminated. If the failure to induce SGVHD in animals grafted with marrow plus T lymphocyt