ALTERED GENE-EXPRESSION OF CYTOKINE, ICAM-1, AND CLASS-II MOLECULES PRECEDES MOUSE INTESTINAL ALLOGRAFT-REJECTION

Rapid and severe rejection remains as a major obstacle to successful c linical intestinal transplantation (IT). The aggressive nature of reje ction in IT has been attributed to the increased massive immune stimul us provided by large numbers of resident lymphocytes, antigen presenta tion capacity of enterocytes, and graft damage mediated by luminal mic roflora. Early small bowel expression of proinflammatory cytokines, MH C class II, and adhesion molecules may also promote IT rejection, but the lack of a mouse model has hampered extensive studies of gene expre ssion in IT. Using a recently developed surgical model, we examined th e temporal pattern of gene expression in CB6F1 (H-2(b/d)) vascularized , heterotopic intestinal allografts transplanted into BALB/c (H-2(d)) mice. Although histological evidence of rejection was not present unti l day 7 in allografts, Northern blot analysis demonstrated increases i n TNF alpha gene transcripts as early as day 3, followed by the expres sion of IL-1 beta, intercellular adhesion molecule-1, and MHC class II by day 5. Using reverse-transcriptase polymerase chain reaction, IFN- gamma was detected in allografts by day 3 and persisted to day 10. In contrast, IL-2, IL-4, IL-5, and IL-6 mRNA transcripts peaked by day 5 and then decreased, suggesting that both Th1 and Th2 subsets are invol ved in the rejection of unmodified small bowel allografts. The early a nd progressive expression of TNF alpha and IL-1 beta as well as IFN-ga mma, intercellular adhesion molecule-1, and MHC class II in IT rejecti on may contribute to the difficulty in controlling IT rejection with p resent immunosuppression.