Syngeneic hematopoietic stem cell transplantation with post-transplantation cyclophosphamide to induce immune tolerance of allogenic skin graft survival in rat

Abstract In haploidentical hematopoietic stem cell transplantation (HSCT), the addition of post-transplantation cyclophosphamide (Cy) can help to induce immunotolerance between the donor and haploidentical immune system, preventing graft-versus-host disease between the haploidentical immune system and organs/ tissues of the recipient. We hypothesized that the situation could be reversed and replicated during the transplantation of allogenic tissue and syngeneic (autologous model) HSCT with post-HSCT Cy. We hypothesized that conditioning (pre-HSCT Cy) causes immunoablation of the recipient, and post-HSCT Cy deletes allo-reactive clones from transplanted HSC thus enabling immunotolerance to simultaneously transplanted tissue (organ). To test this hypothesis, we developed a model of autologous HSCT (syngeneic HSCT) with simultaneous transplantation of allogenic tissue in rat. The study rats received: first immunoablation, then allogenic skin graft and syngeneic HSCT, and later post-transplantation Cy. The administration of Cy before and after syngeneic HSCT with simultaneous transplantation of skin graft prolonged skin graft survival from 3 to 12 days and changed the pattern of rejection. The addition of Cy post-HSCT resulted in a statistically significant increase in TNFα secretion before rejection compared to acute rejection without Cy post-HSCT. The sole administration of Cy before and after syngeneic HSCT with simultaneous organ transplantation is not sufficient to achieve full tolerance to allogenic tissue. However, with changes to conditioning or additional immunosuppression, this goal could be achieved.