PREVENTION OF CYCLOSPORINE-INDUCED SYNGENEIC GRAFT-VERSUS-HOST DISEASE IN BONE-MARROW TRANSPLANTATION BY UV-B IRRADIATED BONE-MARROW CELLS

UV-B irradiation of allogeneic rat bone marrow cells (BMC) transplante d into lethally gamma-irradiated recipients prevents GVHD and induces stable complete hematopoietic chimerism. Cyclosporine (CsA), an effect ive immunosuppressive agent, causes an autoimmune syndrome termed syng eneic GVHD in syngeneic radiation chimeras following discontinuation o f CsA. To understand the in vivo interactions of CsA with UV-B modulat ed syngeneic bone marrow transplant (BMT), as this is essential before clinical use, we studied the effects of CsA therapy in recipients of UV-B irradiated donor BMT in the rat model. Lethally irradiated (10.5 Gy) Lewis recipients of naive or UV-B irradiated syngeneic BMT (admixt ure of 10(8) BMC and 5 x 10(6) spleen cells) were treated with CsA 12. 5 mg/kg/day) for 30 consecutive days after BMT. The results show that all irradiated Lewis recipients of syngeneic BMT modulated with 700 J/ m(2) UV-B were hematologically fully reconstituted in 25-35 days and s urvived their normal life span. In contrast, all lethally irradiated r ecipients of untreated BMT that received CsA for 30 days developed let hal acute syngeneic GVHD 7-12 days after CsA withdrawal, Of interest i s the finding that while higher doses of UV-B (500-700 J/m(2)) irradia tion of BMC prior to transplantation into CsA-treated animals prevente d hemopoietic reconstitution, lower doses (100-300 J/m(2)) allowed for hemopoietic recovery and, in addition, prevented the development of s yngeneic GVHD following the discontinuation of CsA. The development of syngeneic GVHD) was dependent on the presence of the thymus and did n ot occur in thymectomized recipients. Our data suggest that the use of UV-B at higher doses in addition to CsA recipient treatment is toxic to stem cells, whereas hemopoietic reconstitution occurs without the d evelopment of autoaggressive immune syndrome at lower W-B doses. This study suggests that caution should be exercised in clinical UV-B BMT t rials prior to using CsA therapy for the prevention or treatment of GV HD.