PREVENTION OF GRAFT-VERSUS-HOST DISEASE IN RAT SMALL-BOWEL TRANSPLANTATION BY RECIPIENT PRETREATMENT WITH UV-B-MODULATED BONE-MARROW CELLS

UV-B irradiation (700 J/m2) of bone marrow cell (BMC) before transplan tation into lethally irradiate (1050R) allogeneic rats prevents graft- versus-host disease (GVHD) and results in stable chimerism. This study examined whether UV-B modulation of BMT is useful in the subsequent i nduction of tolerance to small bowel transplant (SBT) and avoids the d anger of GVHD, which remains the major obstacle to successful SBT. Let hally irradiated Lewis recipients of UV-B irradiated (700 J/m2) BMT (1 0(8) BMC admixed with 5x10(6) splenic leukocytes) either from ACI or W istar-Furth (WF) rats developed stable chimerism without any evidence of GVHD for >360 days. Lewis recipients of UV-B ACI BMC expressed 95+/ -6% ACI lymphoid cells at 50 and 150 days after BMT using complement-d ependent cytotoxicity assay. Unmodified Lewis recipients of orthotopic ACI SBT rejected their grafts and died in 7-9 days, whereas Lewis chi meras accepted permanently (>200 days) bone marrow donor (ACI) SBT wit hout any evidence of GVHD when the SBT was performed at 60 or 150 days after BMT. In contrast, when SBT was performed, only 30 days after in duction of chimerism with UV-B ACI BMT, the recipients developed sever e GVHD and died between 17 and 21 days. The Lewis chimeras rejected th ird part (WF) SBT acutely and died in 7-9 days, thus demonstrating the specificity of the induction of tolerance in this model. That this im munologic unresponsiveness is not restricted by the recipient-donor ra t strain combination was shown by the permanent acceptance of WF SBT w ithout GVHD by Lewis/WF chimeric recipients. Furthermore, the Lewis ch imeras that were made diabetic with STZ 28 days after BMT permanently accepted (>300 days) BM donor-type (WF) and recipient-type (Lewis) isl et cells and became normoglycemic, thus indicating tolerance to both d onor and recipient Ags. The diabetic Lewis chimeras that became normog lycemic permanently accepted (>200 days) WF SBT without any evidence o f GVHD after donor-type SBT 110 days after WF islet transplantation. T he apparent lack of organ-specific unresponsiveness in this model conf irmed our previous observation with combined islet and heart transplan ts. In vitro MLR studies showed that the chimeric animals were specifi cally unreactive to donor- and recipient-type alloantigens. Our result s demonstrate that UV-B irradiation of BMT is a promising approach to the induction of tolerance to SBT.