VALIDITY OF PRIMARY AND SECONDARY SKIN AND ORGAN GRAFTS AS A TEST OF DONOR-SPECIFIC TOLERANCE (DST): CHALLENGING A GOLD STANDARD

Abstract

267 The traditional in vivo test for DST is re-transplantation of a second graft from the donor. Usually a donor skin graft (DSG) is the common standard. Recently, a variety of studies from our group and others have suggested wide spreads in the differences between skin and organ graft survivals in a host of DST models. In addition, immunobiological differences in rejection mechanisms of skin and organs such as kidney and heart have been documented. We tested primary and secondary donor grafts in a rat model of DST using pre-transplant donor spleen injections and ATG. Cardiac allografts (ACI→Lewis) were markedly prolonged to 73 ±14 days (ATG control = 26 ±4 days). Subsequent ACI cardiac grafts retransplanted in the abdomen, survived 63 ±16 days (p>0.10 with first cardiac grafts). In contrast, primary ACI skin grafts in recipients treated with a similar ATG-spleen extract tolerance induction protocol gave ACI skin graft survival of 42.3 ±2.6 days (p<0.01 with skin graft controls). Naïve ACI skin grafts transplanted to Lewis recipients harboring a tolerant skin graft were rejected in 9 ±2.4 days. Naïve ACI skin grafts transplanted to Lewis rat recipients harboring a ACI heart graft were rejected at 11.3 ±4 days (p>0.10 with grafts to naïve recipients). Finally, removal of the ACI hearts followed by skin grafts 2 weeks later did not change the skin graft survival (9.6 ±3.0 days). In contrast, third party skin and heart grafts were all rejected in 7-10 days (all skin graft rejections were biopsy-proven). Removal of the tolerant heart did not appear to affect the skin graft survival. Thus, there was an extraordinary spread between a DST challenge skin graft and organ graft survival. Similar disparities have been observed in 4 other models of tolerance including 1 xenogenic model. We conclude that the DST is a suboptimal and often invalid measure of donor-specific tolerance in both allogeneic and xenogenic DST models. This is probably due to a certain uniqueness of skin graft rejection mechanisms demonstrated in other studies. True DST should be validated by placement of a similar second donor organ and not a DST.