Lack of Role for CsA‐Sensitive or Fas Pathways in the Tolerization of CD4 T Cells Via BMT and Anti‐CD40L

Abstract

Anti-CD40L mAb plus bone marrow transplantation (BMT) and recipient CD8 T-cell depletion permits long-term mixed hematopoietic chimerism and systemic donor-specific tolerance to be achieved across full MHC barriers. Initial tolerance is characterized by peripheral deletion of donor-reactive CD4 cells. In regimens using costimulatory blockade without BMT to achieve allograft survival, cyclosporine inhibited graft survival, suggesting that the combination may not be clinically applicable. We assessed the role of cyclosporine-sensitive mechanisms and the mechanisms of T-cell apoptosis involved in the induction of early peripheral CD4 + T-cell tolerance by BMT with anti-CD40L. Neither a short course of cyclosporine (14 days) nor the absence of FAS-mediated activation-induced cell death (AICD) blocked the induction or maintenance of donor-specific tolerance. IL-2 production was not associated with tolerance induction, consistent with the lack of a role for Fas-mediated AICD. Mice in which passive T-cell death was impaired because of constitutive expression of a Bcl-x L transgene did not develop tolerance with this protocol. These data confirm that deletion of donor-reactive T cells is critical for the induction of mixed chimerism and tolerance. However, the mechanisms involved may differ from those involved in costimulatory blockade regimens that do not include BMT.

CD154 Blockade for Induction of Mixed Chimerism and Prolonged Renal Allograft Survival in Nonhuman Primates

“…Either activation-induced cell death (AICD) or passive cell death (PCD) could be responsible for the deletion of donor reactive peripheral CD4 + cells (27,28). However, the most recent murine studies using Fas-deficient mice further revealed that Fas-mediated AICD is not essential for marrow engraftment and donorspecific tolerance (29). Unlike murine studies that utilize V beta subunits on TCR or TCR transgenes to study clonal deletion of the donor reactive T cells, methods to examine such extrathymic deletion are not available in our monkey model.…”

Clonal Deletion Established via Invariant NKT Cell Activation and Costimulatory Blockade Requires In Vivo Expansion of Regulatory T Cells

“…It is believed that the initial deletion of donor-reactive T cells after BMT with costimulatory blockade occurs in the periphery, because an immediate reduction of donor-reactive Vb-TCR repertoire was shown in both euthymic and thymectomized recipients (16,17). It is thought that both activation-induced cell death (AICD) and passive cell death initially contribute to peripheral T cell deletion (31,32). Consistent with other reports, we observed the immediate reduction in the donorreactive Vb-TCR repertoire as well as a continuous decline of them (Figure 4).…”

A CD8 T cell–intrinsic role for the calcineurin-NFAT pathway for tolerance induction in vivo

“…We previously showed that CsA treatment does not interfere with CD4 tolerance in CD8-depleted recipients of allogeneic BMT with 3 Gy TBI/anti-CD154. 17 To evaluate the role of TCR-mediated signaling through the calcineurin pathway for CD8 tolerance, B6 mice were conditioned with 3 Gy TBI/anti-CD154 and received an MHC-mismatched B10.A BMT with or without a 2-week course of daily CsA ( Figure 1A). The initial rate of chimerism was similar in both groups.…”

“…Our previous studies in which we used anti-CD154 and allogeneic BMT have shown that CD4 tolerance can be readily achieved in the presence of calcineurin inhibition. 17 However, the possible role of a TCR-mediated signal through the calcineurin/NFAT pathway for CD8 allotolerance is unknown. In view of the aforementioned contradictory data, it was important to determine the role of this pathway in CD8 allotolerance induction.…”