CD18 Separates GVHD and GVL effect (50.9)

Abstract

Abstract Graft-versus-host disease (GVHD) remains a major cause of morbidity and mortality in allogeneic hematopoietic stem cell transplantation. Migration of donor-derived T cells into GVHD target organs plays an essential role in the development of GVHD. β2 integrins, a group of heterodimeric molecules including CD11a/CD18 (LFA-1), CD11b/CD18 (Mac-1), CD11c/CD18 and CD11d/CD18, are of critical importance for leukocyte extravasation through vascular endothelia and for T cell activation. We asked whether CD18-deficient T cells would induce less GVHD while sparing graft-versus-leukemia (GVL) effect. In murine allogeneic BMT models, we found that recipients of CD18−/− donor T cells had significantly less GVHD morbidity and mortality compared with recipients of WT donor T cells. A cell-dose titration experiment indicated that the ability of CD18−/− T cells had more than 4-fold reduction compared to that of WT T cells in the induction of GVHD. Analysis of alloreactive showed that CD18−/− and WT T cells had comparable activation, expansion and cytokine production in vivo. Reduced GVHD was associated with a significant decrease in donor-T cell infiltration of recipient intestine and with an overall decrease in pathologic scores in intestine and liver. Finally, we found that in vivo GVL effect of CD18−/− donor T cells was largely preserved, because mortality of the recipients transplanted with CD18−/− T cells plus tumor cells was greatly delayed or prevented. Our data suggest that strategies to target β2 intergrin have clinical potential to alleviate or prevent GVHD while sparing GVL activity.