Bone marrow augmentation in kidney transplantation: a large animal study

Specific immunomodulatory strategies are required to eliminate the need for lifelong dependence on debilitating immunosuppressants. One proposed strat egy is to simultaneously transplant the kidney and infuse donor-specific bo ne marrow cells. We prospectively studied the effect of unmodified donor-sp ecific bone marrow infusion (DSBMI) on rejection, infection, graft-versus-h ost disease (GvHD), and graft survival. We performed 57 kidney transplants in mixed lymphocyte culture (MLQ-reactive, outbred pigs. The groups of reci pient pigs differed according to the use of (1) indefinite versus shortterm tacrolimus-based immunosuppression. (2) DSBMI, and (3) recipient precondit ioning (RPC: whole body irradiation with 400 rads on day 0 and horse anti-p ig thymocyte globulin (ATG) on days -2, -1, and 0). In all, we studied eigh t groups: group 1, nonimmunosuppressed control pigs (n = 8); group 2, nonim munosuppressed DSBMI pigs (n = 7); group 3, nonimmunosuppressed RPC + DSBMI pigs (n = 5); group 4, tacrolimus (indefinite) pigs (n = 11); group 5, tac rolimus (10 days only) pigs (n = 5); group 6, DSBMI + tacrolimus (indefinit e) pigs (n = 8); group 7, DSBMI + tacrolimus (10 days only) pigs (n = 6); a nd group 8, RPC + DSBMI + tacrolimus (indefinite) pigs (n = 7). DSBMI alone (group 2) or in combination with RPC (group 3) did not prolong graft survi val, as compared with nonimmunosuppressed controls (group 1). In groups 1, 2, and 3, all but one pig died from rejection; in group 3 only, 45 % of the pigs died from concurrent infection or GvHD, indicating that RPC in combin ation with DSBMI aggravated the risk of generalized infection and GvHD. Pos t-transplant immunosuppression - irrespective of indefinite or shortterm ad ministration - was required for prolonged graft survival. With indefinite u se of immunosuppression, graft survival rates and death rates from rejectio n were not different for pigs with (group 6) versus without (group 4) DSBMI ; however, the death rate from infection was higher in group 6, suggesting that the bone marrow inoculum increased the risk of systemic infection. Wit h short-term use of immunosuppression, graft survival rates were higher and death rates from rejection lower for pigs with (group 7) versus without (g roup 5) DSBMI. But DSBMI and short-term immunosuppression (group 7) failed to prolong survival beyond that achieved with indefinite immunosuppression (groups 4 and 6). Although the combination of DSBMI and short-term immunosu ppression (group 7) reduced the risk of infection, it did not avert severe rejection. The addition of RPC to DSBMI and indefinite immunosuppression (g roup 8) significantly decreased graft survival, as compared with groups 4. 6, and 7. It also increased the incidence of death from rejection, GvHD. an d infection. or a combination thereof. Unmodified DSBMI did not prolong gra ft survival after kidney transplantation, nor did it decrease the incidence of rejection. But it aggravated the risk of GvHD and infection. Short-term immunosuppression with DSBMI reduced the incidence of death from infection or GvHD, but it resulted in a higher incidence of death from rejection (as compared with indefinite use of immunosuppression). RPC, combined with DSB MI and indefinite immunosuppression, increased the death rate from rejectio n, GvHD, infection. or a combination thereof. In this large animal study, t he effect of unmodified DSBMI has been disappointing. The search continues for the optimal way to successfully perform bone marrow augmentation in sol id organ transplants.