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[3327] IMMUNOGENETIC REQUIREMENTS FOR LYMPHOHEMATOPOIETIC GRAFT-VERSUS-HOST-REACTIONS IN MURINE MIXED CHIMERAS.
Yong-Mi Kim, Markus Y. Mapara, Megan Sykes Transplantation Biology Research Center, Massachussetts General Hospital/Harvard Medical School, Boston, MA, USA
Delayed donor leukocyte infusion (DLI) leads to conversion of mixed chimerism to full chimerism in a fully MHC-mismatched murine strain combination without causing GvHD. Such graft-versus-host-reactions confined to the lymphohematopoietic system (LGvHR) can lead to graft-versus-leukemia (GvL) effects. Although clinical bone marrow transplantation (BMT) has been associated with improved long-term survival in recent years, many patients need alternative donors because they lack a matched sibling or unrelated donor. Partially mismatched relatives could be alternative donors if GvHD could be avoided. We therefore compared the capacity to achieve LGvHR without GvHD in the presence of various histoincompatibilities. Mixed chimerism was induced by a cyclophosphamide (CTX)-based non-myeloablative conditioning regimen (anti-CD4 and anti-CD8 mAbs GK1.5 and 2.43 on day —5, CTX 200 mg/kg on day —1, 7 Gy thymic irradiation and BMT on day 0) followed by DLI (4x107 donor spleen cells) administered on day +35. Donor chimerism was followed by FACS analysis for 23-24 wks post BMT. Initial donor engraftment of class I (B6.C-H2Bm1/KhEg -> C57BL/6) and class II mismatched (B6.C-H2Bm12/KhEg -> B6Ly5.2) BMT was achieved. With the non-myeloablative regimen, chimerism was enhanced after administration of DLI in both groups. Statistically significant chimerism enhancement increased with time in the class I mismatched combination and was transient in the class II mismatched combination. In contrast, in the multiple minor antigen mismatched strain combination (C3H.SW -> C57BL/6), DLI did not lead to a significant increase in donor chimerism. No GvHD was observed in any DLI recipient. In a further effort to convert mixed to full chimerism, we presensitized donors of a second DLI in each strain combination with a host-type skin graft. Presensitized DLI was administered between day +175 and day +210 post-BMT. By 2-1/2 wks post-DLI, chimerism in the class I-mismatched strain combination was further moderately enhanced after second DLI administration, whereas chimerism in the class II-mismatched and multiple minor antigen strain combination was strongly increased, with statistical significance already attained (p<0.05). Further follow-up will reveal if full chimerism conversion occurs. Our result suggests that donor engraftment can be achieved across various histoincompatibility settings in this nonmyeloablative murine BMT model. DLI and presensitized DLI lead to an increase in chimerism. If transplantation across histoincompatibility barriers could be performed safely and effectively, DLI, with its GvL effects, would be available to a greater proportion of patients. In pursuit of this goal, the potential GvL effect of the LGvHR is being explored in the setting of each genetic disparity.
Keywords: Donor lymphocyte infusion (DLI); Graft-vs-leukemia activity |
