758] DONOR LYMPHOCYTE INFUSIONS (DLI) CAN INDUCE ALLORESPONSES IN GRAFT-VERSUS-HOST (GVH) AND HOST-VERSUS-GRAFT (HVG) DIRECTION.
Markus Y. Mapara, Yong-Mi Kim, Megan Sykes Transplantation Biology Research Center, Massachusetts General Hospital/Harvard Medical School, Boston, MA, USA
We tested the effects of donor lymphocytes on mixed hematopoietic chimerism established using a cyclophosphamide-containing non-myeloablative conditioning regimen consisting of administration of CD4 and CD8 cell-depleting mAb's on day -5, 200mg/kg cyclophosphamide day -1, 7 Gy thymic irradiation day 0 and bone marrow transplantation on day 0 (fully MHC-mismatched B10.A (H2a) C57BL/6 (H2b) strain combination). Mixed chimeras received donor lymphocyte consisting of 3 x 107 B10.A spleen cells infusions either on day +21 or on day +35. Administration of DLI on day 35 resulted in conversion of mixed chimerism to full donor chimerism without development of graft-versus-host-disease (GVHD), indicating a GVH reaction limited to the lymphohematopoietic system. In contrast, administration of DLI on day +21 led to a precipitous decline in donor chimerism, leading eventually to complete loss of chimerism. Immunohistochemical staining of recipient thymus showed the presence of donor MHC class II+ cells at day +21 along with partial deletion of donor-reactive host cells as assessed by the presence of Mtv-8 and Mtv-9 endogenous superantigen-reactive Vb11+ and Vb5+ thymocytes. Mixed lymphocyte reaction assays performed at day + 21 demonstrated tolerance to the donor, with intact anti-third-party responses. Serum analysis at day 21 post-BMT showed the presence of high levels of circulating anti-CD4 and anti-CD8 mAbs, suggesting that donor T cells within the DLI inoculum were more susceptible to antibody-dependent elimination than residual donor-reactive host T cells. When DLI were given at day 21 to TCR-b gene-deficient BMT recipients, hematopoietic chimerism was maintained, demonstrating that loss of chimerism in wild-type recipients was mediated by host T cells. Anti-donor CTL responses were detectable in long-term recipients of day 21 DLI which had rejected their bone marrow grafts. In conclusion, we have been able to demonstrate completely diverging effects of DLI administered to mixed chimeras, depending on the timing of DLI administration. Thus, DLI can mediate GVH reactions without causing GVHD or can trigger HVG reactions if administered at a time when donor-host specific tolerance is still evolving.
Keywords: Graft-vs-host disease; Donor lymphocyte infusion (DLI) |
