Antibody mediated lymphocyte depletion is used in clinical transplantation to improve graft function. While the presence of donor-reactive memory T cells is the primary rationale for the use of T cell depleting therapies, memory T cells are particularly resistant to such therapies. Our studies focus the effects of murine Thymoglobulin analog (mATG) in a mouse model of heterotopic cardiac transplantation. We have reported that following mATG treatment, the residual T cells were effector/memory CD4 T cells and graft survival is modestly extended as CD8 T cells rapidly recover and mediate rejection. CD4 T cell depletion with mAb or blocking CD40/CD154 in addition to mATG treatment impaired CD8 T cell recovery. The goal of the current study is to use our findings on the mechanisms of T cell reconstitution to improve the efficacy of ATG treatment in sensitized transplant recipients. We used two robust models of recipient sensitization. First, B6 (H2^b) recipients were sensitized by BALB/c (H2^d) skin transplantation and received BALB/c heart grafts 4 weeks later. Neither antiCD4 mAb treatment nor mATG alone prolonged heart allograft survival in skin-sensitized recipients (MST 3d, 9d n=3-6). In contrast, CD4 T cell depletion in combination with mATG resulted in significant prolongation of graft survival in these recipients (MST 45d, n=6). The graft prolongation was associated with low numbers of CD8 T cells and a fivefold reduction in the frequencies of donor-reactive IFNγ secreting spleen cells at the time of rejection in comparison control or mATG treated mice. Second, memory CD4 T cells were isolated from spleens of BALB/c skin-sensitized B6 mice and transferred into naïve B6 mice followed by heart allograft. Consistent with our previous results, blocking CD40/CD154 with anti-CD154 mAb MR1 (1 mg i.v. on d. -1) failed to prolong allograft survival in recipients containing donor-reactive memory CD4 T cells (MST 14 d, n=4). However, the addition of MR1 treatment to mATG depletion significantly prolonged graft survival compared to mATG alone (MST 31 vs. 10 d, n=4). Recipients with prolonged allograft survival had delayed CD8 T cell recovery and decreased anti-donor T cell responses at the time rejection compared to recipients treated only with mATG. Targeting helper functions of residual memory CD4 T cells increases the efficacy of pre-transplant ATG induction therapy and improves allograft outcome in sensitized transplant recipients.

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