Donor CD8 cells prevent allogeneic marrow graft rejection in mice: potential implications for marrow transplantation in humans

doi:10.1084/jem.178.2.703

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Donor CD8 cells prevent allogeneic marrow graft rejection in mice: potential implications for marrow transplantation in humans

PJ Martin
Division of Clinical Research, Fred Hutchinson Cancer Research Center, Seattle, Washington 98104.

Numerous experimental models have demonstrated that graft-vs.-host disease (GVHD) does not occur in irradiation chimeras when the graft does not contain mature, immunocompetent T lymphocytes, but clinical studies have shown that T cell depletion of donor marrow can be associated with a greatly increased risk of graft failure. We have developed a model where engraftment of (C57BL/6J x C3H/HeJ)F1 (B6C3) marrow in 800-cGy-irradiated (BALB/cJ x C57BL/6J)F1 (CB6) recipients depends on the presence of donor T cells in the graft. Recipients transplanted with 5.0 x 10(6) marrow cells depleted of T lymphocytes showed host lymphoid and myeloid reconstitution, whereas recipients transplanted with the same marrow plus 2.5 x 10(5) purified donor T cells showed donor reconstitution. Adding as few as 0.5 x 10(5) CD8- enriched donor T cells to marrow grafts containing 5.0 x 10(6) T cell- depleted donor cells was sufficient to enable donor reconstitution, while surviving recipients transplanted with the same marrow and 0.5- 2.5 x 10(5) CD4-enriched donor cells showed only host reconstitution. To address the question of whether donor CD4 cells could facilitate engraftment under conditions where GVHD would not represent a limiting factor, engraftment of bm1 marrow was tested in major histocompatibility complex (MHC) class I-disparate B6.Ly5a recipients. Results indicated that the donor CD8-enriched population was at least fivefold more active than the CD4-enriched population for facilitating allogeneic marrow engraftment in this strain combination. Thus, the lymphokines and MHC class II-specific cytotoxic T cells generated by CD4 cells were relatively ineffective for enhancing engraftment, possibly reflecting the fact that the host T cells that contain effectors responsible for causing rejection do not express MHC class II antigens. The ability of donor CD8 cells to facilitate engraftment could reflect the activity of a cytokine uniquely elaborated after recognition of an MHC class I disparity. More likely, the graft- enhancing effect of donor CD8 cells may result from the generation of MHC class I-specific or class I-restricted cytotoxic T cells that recognize the host CD4 and CD8 cells responsible for causing rejection. The possibility remains that other mechanisms such as veto inactivation of host T cells by donor CD8 cells may also contribute to the graft- enhancing effect.
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