Induction of specific tolerance to small-bowel allografts

The induction of specific tolerance would greatly improve survival and functional state of organ transplant recipients. One approach that has recently received attention is the creation of mixed hematopoietic chimerism through the transplantation of allogeneic and syngeneic T-cell-depleted (TCD) bone marrows. In these studies we examined whether tolerance to highly immunogenic small-bowel transplants could be induced by mixed allogeneic chimerism. Tolerance induction depends on the sharing of antigens between bone marrow cells and small-bowel tissue.

Adult Lewis rats were lethally irradiated and reconstituted with a mixture of 50 x 10(6) TCD bone marrow cells. Thirty days after reconstitution, animals were tested for chimerism by fluorescence-activated cell sorter analysis. Chimeric animals then received ACI heterotopic small-bowel allografts and were assessed daily for rejection. Small-bowel allograft survival was compared to three control groups: (1) untreated Lewis recipients, (2) irradiated TCD syngeneically reconstituted Lewis recipients, and (3) Lewis bone marrow recipients that did not develop chimerism.

Median graft survival in control groups was 8 days. Graft survival in eight mixed chimeras ranged from more than 135 to more than 304 days (p < 0.0001), and no episode of rejection or graft-versus-host disease was observed. Mixed lymphocyte reactivity of chimeric lymphocytes confirmed in vivo observation of tolerance.

Bone marrow cells share tissue-specific antigens with small-bowel cells to permit induction of tolerance.