Abstract
Abstract In a completely MHC-mismatched model of bone marrow transplantation [C57BL/6 (H-2b) donors into BALB/c (H-2d) hosts], we have developed a technique of non-myeloablative host conditioning using fractionated total lymphoid irradiation (TLI) and and anti-thymocyte serum (ATS) that prevents lethal graft-versus-host disease (GVHD). We have previously reported that this GVHD prevention is dependent on the secretion of IL-4 and on host regulatory NKT cells. In the current study, we assessed the graft-versus-tumor (GVT) effect of BMT to determine whether the GVT effect remains intact in this non-myeloablative conditioning model. Male BALB/c mice were given fractionated TLI (17 doses of 240 cGy each), 3 doses of ATS, and subsequently received intravenous infusion of 50 x 106 bone marrow and 60x 106 splenocytes from C57BL/6 donors, with and without the BCL1 B-cell lymphoma. Animals were observed for minimum of 100 days, and underwent autopsy at death to assess for sub-clinical evidence of GVHD or tumor infiltration. TLI/ATS-conditioned mice achieved a high percentage of donor chimerism, in the range of 50–100% in all lineages. TLI/ATS-conditioned hosts uniformly survived without signs of GVHD beyond day +100. By contrast, hosts conditioned with a single dose of 800cGy total body irradiation (TBI) died of acute GVHD (severe diarrhea, hunched back, weight loss) by day +21. When TBI/ATS or TBI-treated mice receive bone marrow, splenocytes, and BCL1 lymphoma, all hosts died with signs of acute GVHD by day +28. TLI/ATS-conditioned hosts receiving marrow, splenocytes and tumor cells showed no evidence of disease progression by day +100 and either cleared tumor idiotype completely or had persistence of low-intensity staining for tumor idiotype (tumor dormancy). TLI/ATS-conditioned hosts given BCL1 tumor cells without allogeneic BMT all succumbed to tumor. TLI/ATS hosts receiving bone marrow plus BCL1 without splenocytes all died by day +108 with high circulating BCL1 tumor burden and no clinical evidence of GVHD. The data indicate that peripheral donor T cells are necessary to maintain a robust graft-versus-tumor effect after TLI/ATS conditioning, and that complete donor chimerism is not a requirement for tumor eradication. In conclusion, using the TLI/ATS non-myeloablative conditioning regimen, it is possible to maintain a clinically significant graft-versus-tumor effect without inducing GVHD despite a high dose of infused donor peripheral T cells.