Differential effects of pretreatment with ultraviolet-B modified or unmodified donor-specific leukocyte transfusions on intestinal and cardiac allograft survival in the rat.

Abstract

This study compares the effects of pretreatment with donor-specific leukocytes (DL) or UV-B irradiated donor-specific (UV-B DL) transfusion on day -7 relative to organ transplantation, in the induction of specific immunologic unresponsiveness to intestinal and cardiac allografts in the Lewis-to-ACI rat strain combination. Recipients of orthotopic small intestinal allografts, who were pretreated with UV-B DL survived for 7.2 +/- 3.6 days compared with 7.5 +/- 0.5 days in the control group. Pretreatment with unmodified DL induced hyperacute rejection of intestinal allografts, suggesting a sensitizing effect of DL in this model. In contrast, pretreatment with DL and UV-B DL transfusions significantly prolonged cardiac allograft survival with 25% (DL) and 50% (UV-B DL) of the grafts surviving indefinitely (greater than 120 days). To define the underlying mechanisms of the differential effects of DL and UV-B DL pretreatment on intestinal and cardiac allograft survival, we evaluated the ability of DL and UV-B DL transfusions to induce alloantibodies and donor-directed cytotoxic T lymphocytes (CTL). The finding that recipients of DL developed donor-specific cytotoxic alloantibodies and CTL may partially explain the accelerated rejection of intestinal allografts in such recipients while the disparity of the findings in cardiac and intestinal transplantation may be due to a higher affinity of the induced cytotoxic alloantibodies to antigens on the intestine than on the heart. Since UV-B DL pretreatment prevents the induction of cytotoxic alloantibodies and CTL, there is a significant difference in recipients transfused with DL as compared with UV-B DL. The proliferative response to donor alloantigens (MLR) of lymphocytes obtained from DL and UV-B DL pretreated animals was down-regulated as compared with the MLR response of lymphocytes obtained from unmodified animals. Subsequent coculture experiments demonstrated the appearance of suppressor cells following pretreatment with DL and UV-B DL. While DL and UV-B DL transfusions significantly increased cardiac allograft survival, there was no prolongation of intestinal allografts in our model despite the abrogation of the sensitizing effect of DL transfusions by prior UV-B irradiation. These differential effects on graft survival emphasize the importance of specific organ immunogenicity.