Retroviral Transfer of Donor MHC Class I or MHC Class II Genes into Recipient Bone Marrow Cells Can Induce Operational Tolerance to Alloantigens In Vivo

Abstract

Infusion of allogeneic, donor bone marrow (BM) can induce specific immunological unresponsiveness in vivo resulting in long-term acceptance of subsequent fully allogeneic, donor-type solid organ grafts, but this may be associated with graft-versus-host disease. We hypothesize that transfer of donor MHC gene(s) to recipient-type BM or hematopoietic stem cells would enable delivery of donor alloantigens to the recipient without the risk of graft-versus-host disease. This strategy could also potentially take advantage of linked suppression to induce specific unresponsiveness to additional alloantigens expressed by the solid organ graft. We found that infusion of 5 × 10⁶ CBA (H-2^k ) recipient mouse BM cells transduced with a recombinant replication-defective retrovirus encoding either a single donor MHC class I or class II gene (H-2K^b or H-2IA^b ) in combination with anti-CD4 monoclonal antibody resulted in long-term survival of C57BL/10 (H-2^b ) but not third-party NZW (H-2^z ) heart grafts. BM cells (3 × 10³) enriched for hematopoietic stem cells by sorting for c-Kit⁺, lineage-negative cells, were able to induce long-term allograft survival in 50% of recipients after transduction with the vector encoding a single donor MHC class I gene. These results have important implications for future strategies to enhance clinical allograft survival by delivery of donor alloantigens.