Experimental short-term immunosuppression after bowel transplantation and donor-specific bone marrow infusion

Hypothesis: We previously showed in a large animal pig model that unmodifie d donor-specific bone marrow infusion (DSBMI) did not facilitate total bowe l engraftment; in contrast, it increased the risks of rejection, infection, and graft-vs-host disease (GVHD) posttransplant. We hypothesize that conti nuous immunosuppression, in combination with DSBMI, might contribute to-or even trigger-these unwarranted immune responses by both host and graft; the refore, discontinuing immunosuppression might decrease these risks and prol ong survival. Methods: Six groups of outbred, mixed lymphocyte culture-reactive pigs unde rwent a total (small and large) bowel transplant: group 1, nonimmunosuppres sed control pigs(n=5); group 2, nonimmunosuppressed DSBMI pigs (n=6); group 3, tacrolimus (indefinite) pigs (n=7); group 4, tacrolimus (indefinite) pl us DSBMI pigs (n=7); group 5, tacrolimus (10 days only) pigs (n=5); and gro up 6, tacrolimus (10 days only) plus DSBMI pigs (n=6). Results: The combination of short-term immunosuppression and DSBMI (group 6 ) significantly prolonged survival, compared with short-term immunosuppress ion only (group 5) or DSBMI only (group 2). Shortterm immunosuppression and DSBMI (group 6) did not prolong overall survival, compared with indefinite immunosuppression with (group 4) or without (group 3) DSBMI: survival rate s at 7, 14, and 28 days posttransplant were 100%, 100%, and 67% in group 6; 100%, 100%, and 71% in group 3, and 100%, 67%, and 47% in group 4 (P=.14). Short-term immunosuppression and DSBMI (group 6) increased the incidence o f rejection, infection, and GVHD, compared with indefinite immunosuppressio n without (but not with) DSBMI. Conclusions: Short-term immunosuppression and DSBMI did not prolong surviva l and did not reduce the incidence of death from rejection, infection, or G VHD, compared with indefinite immunosuppression without DSBMI. But short-te rm immunosuppression and DSBMI resulted in a lower incidence of death from infection and GVHD, compared with indefinite immunosuppression and DSBMI. W hen immunosuppression was discontinued 10 days posttransplant, the effect o f DSBMI was insufficient to avert death from rejection. Clinical Relevance: The clinical results of bowel transplantation trail tho se of other solid organ transplants. It reduced the rates of infection and GVHD. Our study shows that systemically infused donor-specific bone marrow with short-term or indefinite immunosuppression does not improve outcome af ter bowel transplantation. It seems necessary to modify the time, dosing, r outing, and/or composition of donor-specific bone marrow before it can be s uccessfully used in clinical bowel transplantation.