RECIPIENT PRECONDITIONING AND DONOR-SPECIFIC BONE-MARROW INFUSION IN A PIG MODEL OF TOTAL BOWEL TRANSPLANTATION

Background. In an outbred pig model of total bowel transplantation, we previously showed that simultaneous donor-specific bone marrow infusi on (DSBMI), rather than promoting engraftment, sensitizes recipients a nd causes rejection; it also aggravates the risk of generalized graft- versus-host disease (GVHD) and infection, and tends to reduce recipien t and graft survival. Small and large animal models of bone marrow-ind uced transplant tolerance suggest that some form of recipient precondi tioning (RPC) may facilitate engraftment of co-transplanted bone marro w cells and fully expose their tolerogenic potential. Methods. In a pr eclinical model, we prospectively studied the effect of RPC on simulta neous DSBMI and total(i.e., small and large) bowel transplantation. RP C consisted of whole body irradiation with 400 R (day 0); some recipie nts additionally received horse anti-pig antithymocyte globulin (days -2, -1, and 0). We studied six groups of outbred pigs, all of which un derwent at least a total bowel transplant: group 1, nonimmunosuppresse d control pigs (n=5); group 2, nonimmunosuppressed DSBMI pigs (n=13); group 3, tacrolimus pigs (n=7); group 4, DSBMI+tacrolimus pigs (n=15); group 5, RPC+nonimmunosuppressed DSBMI pigs (n=11); and group 6, RPCDSBMI+tacrolimus pigs (n=14). Results. RPC did not prolong overall sur vival at 7, 14, 21, and 28 days after transplant. Survival rates were 100%, 100%, 86%, and 71% in group 3; 71%, 43%, 29%, and 29% in group 6 ; 55%, 9%, 0%, and 0% in group 5; and 60%, 0%, 0%, and 0% in Group 1. Moreover, RPC (groups 5 and 6) increased the incidence of death from r ejection, GVHD, and infection when compared with group 3. Survival was significantly higher for RPC+DSBMI+tacrolimus pigs (group 6), compare d with RPC+nonimmunosuppressed DSBMI pigs (group 5). Survival greater than 28 days was noted only in pigs that received tacrolimus after tra nsplant: 71% in group 3 versus 29% in group 6. With both RPC and DSBMI (groups 5 and 6), rejection, GVHD, and infection were not mutually ex clusive events. In groups 5 and 6, at autopsy, the incidence of reject ion and GVHD was 17%; rejection and infection, 17%; and GVHD and infec tion, 45%. A combination of all three immunologic events was noted in 14%. Conclusions. RPC, combined with DSBMI, and with or without posttr ansplant immunosuppression, does not prolong survival after total bowe l transplantation. Rather, it increases the incidence of death from re jection, GVHD, infection, or a combination of these three immunologic events. According to this preclinical study, RPC and unmodified DSBMI do not improve patient and graft outcome after total bowel transplanta tion and need to be refined before being applied clinically.