DIFFERENCES IN THE CONTRIBUTION OF CD4-CELLS TO PROISLET AND ISLET ALLOGRAFT-REJECTION CORRELATE WITH CONSTITUTIVE CLASS-II MHC ALLOANTIGENEXPRESSION( T)

Allografts of BALB/c (H-2(d)) fetal proislets facilitated long-term (> 100 days) reversal of streptozotocin-induced diabetes in CBA/H (H-2(k) ) mice treated with a combination of anti-CD4 and anti-CDS mAbs. Anti- CDS monotherapy was partially effective in restoring normoglycemia but anti-CD4 mAb treatment of host animals failed to promote allograft fu nction. In contrast, allografts of BALB/c adult islets demonstrated in definite reversal of diabetes in recipient mice treated only with anti -CD8 mAb. Anti-CD4 monotherapy resulted in only transient restoration of normoglycemia. These findings clearly demonstrate (1) a critical ro le for CD8 T cells in the acute rejection of pancreatic islet tissue a llografts and (2) tissue-specific differences in the participation of CD4 T cells as primary effecters in the rejection reaction. Immunohist echemical studies showed that the capacity for CD4 T cells to initiate the rejection of proislet but not adult islet allografts correlates w ith the presence/absence, respectively, of graft parenchymal cells tha t constitutively express Class II MHC alloantigens. Proislet grafts, u nlike transplants of purified adult islets, contain heterogeneous tiss ue components including Class II MHC+ve duct epithelium. Thus, the par ticipation of CD8 and CD4 T cells as primary effecters of graft reject ion depends on which class or classes of MHC antigens are constitutive ly expressed on graft parenchymal cells and are available for recognit ion. Islet tissue in both rejecting proislet and islet allografts show ed de novo induction of Class II MHC alloantigens only after severe di sruption to islet architecture had been achieved by infiltrating monon uclear cells. Thus, at this stage of advanced allograft injury, CD4 T cells have the potential to act as secondary effecters, possibly by am plifying the inflammatory reaction and thus accelerating graft destruc tion. The capacity for antirejection mAb therapy to establish transpla nt tolerance was facilitated in the islet allograft model where it was necessary to target only the CD8 T cell subpopulation.