ANTIBODY-MEDIATED TARGETING OF CD45 ISOFORMS - A NOVEL IMMUNOTHERAPEUTIC STRATEGY

CD45 is a family of transmembrane protein tyrosine phosphatases exclus ively expressed by hematopoietic cells and critically involved in the regulation of T cell activation signals, We now demonstrate that three 100-mu g doses of antiCD45RB mAb MB23G2 can induce long-term engraftm ent of islets into major histcompatibility complex-disparate chemicall y diabetic mice, Long-term graft survivors (>120 days) were tolerant t o new islet allografts from the original donor strain, MB23G2 induced a temporary decrease in number circulating leukocytes but had no effec t on leukocyte number in other lymphoid compartments, Histologic exami nation of allografts from treated and untreated recipients revealed a similar peri-islet infiltration on day 6, Eleven days after transplant , the peri islet infiltrate in treated animals persisted, but in marke d contrast to untreated control animals, there was no insulitis and is let integrity was preserved, The peri-islet infiltrate from treated an imals showed a mild increase in CD4 cells, a decrease in CD8 cells, an d decreased intensity of CD45RB expression, Treatment of naive animals with anti-CD45RB (MB23G2) resulted in a shift in CD45 isoform express ion on T cells with a loss of higher molecular weight isoforms and inc reased expression of lower molecular weight (CD45R0) isoform, This shi ft in CD45 isoform expression from CD45RBH(Hi) to CD45RB(Lo) was assoc iated with an increase in the intragraft expression of transcripts for interleukin (IL) 4 and IL-10, consistent with the expected activity o f this distinct immunoregulatory T cell subset, Antibody-mediated targ eting of CD45 may induce tolerance through novel mechanisms and have d irect applicability to clinical transplantation in humans.