Abstract 4018

CD26 is a 110-kDa multifunctional membrane-bound glycoprotein with dipeptidyl peptidase IV (DPPIV) enzyme activity present on a wide variety of cells, and is critical in T cell biology, as a marker of T cell activation. The role of CD26 in immune regulation has been extensively characterized, with our recent findings elucidating its linkage with signaling pathways and structures involved in T cell activation as well as antigen presenting cell (APC)-T cell interaction. CD26 in human T cells has a costimulatory function and is upregulated after activation. On the other hand, in murine lymphocytes, CD26 is expressed in CD4-CD8- thymocytes and its expression level is not changed by various stimulation procedures. Moreover, murine T cells are not observed to be activated via CD26. Therefore, for the analysis of CD26-mediated immuneregulation leading to clinical applications, it is necessary to use a pathological model system caused by human T cells but not murine T cells. For this purpose, we used a xenogeneic graft-versus-host disease (x-GVHD) murine model, which is generated by transplantation of human T cells into NOG-Scid mice (hu-PBL-NOG). In this model mouse, x-GVHD is developed by manifesting rough hair, loss of weight and motility, since transplanted human T cells become effector cells in murine organs. By examining the cytotoxic functions of human CD8+ T cells after CD26-mediated costimulation in vitro, we have shown that CD26-mediated costimulation induced vigorous secretion of inflammatory cytokines, TNF-a, IFN-g and soluble Fas Ligand, and strongly enhanced the expression of Granzyme B. These results suggested that cytotoxic function in human CD8+ T cells activated via CD26-mediated costimulation has a key role in developing x-GVHD. In the present study, we showed that CD26 blockade by humanized anti-CD26 monoclonal antibody (huCD26mAb) reduced development of x-GVHD, and that this effect of CD26 blockade was exerted by suppression of cytotoxic activity of human CD8+ T cells in vivo. Moreover, huCD26mAb showed as same effect on suppression of x-GVHD as clinically available drug, abatacept (CTLA4-Ig), a blockade of CD28-mediated costimulation. While increased dose of CTLA4-Ig showed more suppressive effect on x-GVHD but sustained suppression of engraftment of transplanted human T cells, the same dose of huCD26mAb showed no delay in engraftment. We performed a further analysis of peripheral human lymphocytes in hu-PBL-NOG after administration of huCD26mAb or CTLA4-Ig. Although CD26 expression on both human CD4+ T cells and CD8+ T cells was markedly increased in control mice with human IgG administration as compared with those before transplantation, the engraftment of human CD26+ T cells was completely inhibited in huCD26mAb administered hu-PBL-NOG. As a result of analysis of human T cells engrafted in spleen of NOG-Scid mice transplanted with carboxyfluorescein diacetate succinimidyl ester (CFSE)-labeled human lymphocytes, huCD26mAb administration preferentially suppressed the priming of human CD8+ T cells rather than CD4+ T cells, while CTLA4-Ig strongly suppressed the cell division of both human CD4+ T cells and CD8+ T cells. Our data strongly suggested that CD26-mediated costimulatory activation in human CD8+ T cells was deeply involved in the pathogenesis of x-GVHD, and blocking the CD26-mediated costimulation resulted in prophylaxis and treatment of x-GVHD. Taken together, our results support the notion that CD26 blockade by huCD26mAb may become a promising therapeutic strategy for GVHD and other refractory immune-mediated disorders.

Disclosures:

No relevant conflicts of interest to declare.

Author notes

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Asterisk with author names denotes non-ASH members.