Breaking of CD8+ T cell tolerance by in vivo ligation of CD40 results in inhibition of chronic graft‐vs‐host disease (GVHD) and complete donor cell engraftment without inducing acute GVHD

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In the DBA/2□ unirradiated (C57BL/6 × DBA/2)F1 model of systemic lupus erythematosus‐like chronic graft‐vs‐host disease (cGVHD), donor CD4+ T cells play a critical role in breaking host B cell tolerance, while donor CD8+ T cells are removed after transfer into the host and the remaining cells fall into anergy. Previously we have demonstrated that in vivo ligation of GITR, a costimulatory receptor, can activate donor CD8+ T cells, which subsequently result in converting the disease pattern from cGVHD to an acute form (aGVHD). In this study, we investigated the effect of an agonistic mAb against CD40 on cGVHD. Treatment of anti‐CD40 mAb inhibited the production of anti‐DNA IgG1 autoantibody and the development of glomerulonephritis, typical symptoms of cGVHD. The inhibition of cGVHD occurred because anti‐CD40 mAb prevented donor CD8+ T cell anergy such that subsequently activated donor CD8+ T cells deleted host cells including host CD4+ T cells and host B cells involved in autoantibody production. In addition, functionally active donor CD8+ T cells induced full engraftment of donor cells and exhibited an increased graft‐vs‐leukemia (GVL) effect. However, induction of aGVHD by donor CD8+ T cells seemed to be not so apparent. Further CTL analysis indicated that there were lower levels of donor CTL activity against host cells in mice that received anti‐CD40 mAb, compared with mice that received anti‐ GITR mAb. Taken together, our results suggest that a different intensity of donor CTL activity is required for removal of host hematopoietic cells including leukemia vs induction of aGVHD. Therefore, it is possible to segregate a GVL effect from GVHD by modulate the cytotoxic activity of donor CD8+ T cells