| Popis: |
The limiting factor to the broad use of bone marrow transplantation (BMT) to cure hematopoietic malignancy is graft verses host disease (GVHD). GVHD is caused by mature T cells present in the bone marrow graft that recognize and destroy host epithelial tissue. Mature T cells facilitate several beneficial effects including elimination of residual malignant cells, the so-called graft-vs-leukemia (GVL) effect. The goal of this work was to develop a strategy for attenuating GVHD pathology mediated by donor T cells without compromising beneficial GVL effects. During GVHD, integrins present on the surface of T cells dictate T cell localization and accumulation patterns. CD103 is an integrin that is upregulated on CD8 T cells during GVHD. Given that the only known ligand of CD103 is the epithelial-specific molecule E-cadherin, we postulated that CD103 expression is required for destruction of the gut epithelium during GVHD, but is not required for effective clearance of a blood malignancy. To test this overall hypothesis, we first characterized CD103 expression and its role in promoting GVHD pathology in the host gut in both an MHC-disparate and a clinically relevant MHC-matched GVHD model. We then assessed the capacity of donor T cells on the CD103-deficient background to mediate GVL effects. Our studies showed that CD103 expression was required for optimal accumulation of CD8 T cells in the gut epithelium. Co-depletion ofiiiCD4 and CD103 expressing cells completely prevented mortality following MHC-disparate BMT. Interestingly, CD103 depletion exacerbated GVHD pathology following MHC-matched GVHD induction. Adoptive transfer studies showed that T cells from CD103-deficient donors cleared malignant B cells as effectively as those from wild-type donors. Our data show a conflicting role for CD103 following BMT, however, our data suggest that CD103 expression on CD8 T cells promotes intestinal pathology, but is not required for host defense against hematopoietic malignancy. Together, these data suggest that CD103 blockade may have the potential to prevent gut GVHD pathology without compromising GVL effects. |
