PREVENTION OF GRAFT-VERSUS-HOST DISEASE AND THE INDUCTION OF TRANSPLANT TOLERANCE BY LOW-DOSE UV-B IRRADIATION OF BM CELLS COMBINED WITH CYCLOSPORINE IMMUNOSUPPRESSION

GVHD is prevented and stable chimerism is induced in the rat EMT model by 700 J/m(2) but not 100-500 J/m(2) W-B irradiation of allogeneic BM cells. Paradoxically, CsA which prevents GVHD in clinical BMT causes an aggressive autoimmune disease termed syngeneic GVHD in irradiated s yngeneic BMT recipients after its withdrawal. Recently, we have shown that while 500-700 J/m(2) UV-E irradiation of syngeneic BM cells combi ned with a 30-day course of CsA recipient immunosuppression impairs he mopoiesis due to lack of hemopoietic factors, a low dose of 100-300 J/ m(2) W-B is effective in preventing CsA-induced autoimmune disease wit hout endangering BM engraftment. This study extends these findings to the P-to-F-1 hybrid and fully allogeneic rat BMT models and examines t he effectiveness of low-dose W-B irradiation of BM cells combined with a short course of CsA treatment in the prevention of GVHD and inducti on of transplant tolerance. Lethally gamma-irradiated (10.5 Gy) LBNF(1 ) recipients of naive or W-B irradiated (100-700 J/m(2)) BMT were trea ted with CsA (12.5 mg/kg/day) for 30 consecutive days after BMT. All l ethally irradiated LENF(1) that did not receive BMT died in <16 days, while animals transplanted with W-B (700 J/m(2)) BMT survived >1 year without GVHD. In contrast, all recipients of naive BMT died of lethal GVHD in <50 days. Similarly, all recipients of naive BMT that received a 30-day course of CsA therapy developed severe GVHD with 60% mortali ty after cessation of CsA therapy. CsA-treated recipients of BMT irrad iated with 700 J/m(2) died between 12 and 25 days from failure of hemo poiesis. In contrast, CsA-treated recipients of 100-200 J/m(2) W-B irr adiated BMT showed full BM engraftment without GVHD after cessation of CsA and survived >1 year. These results were reproducible in the full y allogeneic UV-B BMT model. To test for donor-specific tolerance, the animals challenged 100 days after BMT with cardiac allografts accepte d permanently (>100 days) Lewis but not BN (non-BMT parental donor) ca rdiac allografts. Our results confirm that 700 J/m(2) W-B irradiation of BM cells combined with CsA recipient immunosuppression impairs the recovery capacity of stem cells while the use of lower W-B (100-200 J/ m(2)) is effective in preventing CsA-induced autoimmune disease withou t endangering BM engraftment and leads to induction of transplant tole rance.