EXPRESSION OF AN ALLOGENEIC MHC DRB TRANSGENE, THROUGH RETROVIRAL TRANSDUCTION OF BONE-MARROW, INDUCES SPECIFIC REDUCTION OF ALLOREACTIVITY

Background.: Transfer of MHC class II genes, through allogeneic bone m arrow (BM) transplantation, induced long-lasting acceptance of renal a llografts in miniature swine. To adapt this approach to the clinic, we have now examined whether somatic transfer of allogeneic class II DR genes, into otherwise autologous bone marrow cells (BMC), can provide the matching required for inducing immune tolerance. Methods. Autologo us BMC were transduced ex vivo with recombinant retroviruses for allog eneic DRB followed by BM transplantation, The recipients were then cha llenged with kidney allografts solely matched to the DRB transgene. Re sults. Five miniature swine received autologous BMC conditioned with g rowth factors and transduced with recombinant retrovirus vectors conta ining allogeneic (n=4) or syngeneic (n=1) class II DRB genes and a dru g-resistance marker. Expression of retrovirus-derived products in BM-d erived cells was demonstrated by the detection of drug-resistant colon y-forming progenitors and the presence of DRB retrovirus transcripts i n peripheral cells. Analysis of selective mixed lymphocyte reaction re sponses to DR or DQ antigens indicated decreased reactivity toward the transduced DR gene product. Among all of the animals receiving fully mismatched kidney allografts, but with DRB matched to the transduced D RB, the one with the highest gene transduction rate showed stable allo graft function and essentially normal renal histology for 2.5 years. A control animal, which received a syngeneic DRB gene, rejected its kid ney allograft in 120 days after an earlier rejection crisis. Conclusio ns. These studies demonstrate that allogeneic MHC gene transfer into B M provides a new strategy for inducing tolerance across MHC barriers.