Antibody mediated lymphocyte depletion is commonly used in clinical transplantation. However, memory T cells undermine the efficacy of lymphoablative induction therapies in sensitized transplant recipients. Using murine Thymoglobulin (mATG) in a mouse model of heterotopic heart transplantation, we reported that mATG treatment spares a population of memory CD4 T cells. The reconstitution of CD8 T cells leading to allograft rejection in mATG treated recipients requires help by the residual memory CD4 T cells delivered through B cells in a CD40/CD154 dependent manner. The goal of the current study was to devise a strategy to improve the efficacy of mATG treatment using approaches that limit CD4 T cell help yet do not induce overt immunosuppression. We tested how inhibiting CD4-B cell interactions during mATG depletion affects the survival of heart allografts using fully MHC-mismatched BALB/c (H-2^d) donors and B6 (H-2^b) recipients. Compared to mATG treatment alone (MST 17 d), significant graft prolongation was achieved by CD4 T cell depletion (MST 45 d), B cell depletion (MST 21 d), or by anti-CD154 mAb (MR1, 1 mg i.v. on d. -1; MST >150 d) in combination with mATG treatment. Next, B6 recipients were sensitized by BALB/c skin allografts 4 weeks prior to receiving BALB/c heart allografts. CD4 T cell depletion, MR1 treatment, or mATG alone did not extend the survival of heart allografts in these recipients (MST 3 d, 9 d, and 9.6 d, respectively). In contrast, combination of CD4 T cell depletion or MR1 treatment with mATG resulted in significant prolongation of graft survival (MST 45 d and 96 d, respectively). At the time of graft rejection, anti-donor T cells responses assessed by IFNɣ ELISPOT assay were at least five fold lower in the combination treatment groups compared to either monotherapy. To test the effects of combination treatments on T cell memory against donor-unrelated antigens, B6 mice were immunized with OVA/CFA 30 d before BALB/c heart transplantation and were treated with mATG, MR1 or mATG+MR1. Recall responses at d.30 posttransplant showed that mATG+MR1 treatment did not reduce the frequencies of OVA-specific IFNɣ-producing T cells compared to mATG monotherapy. Our results suggest that limiting helper functions of residual memory CD4 T cells increases the efficacy of ATG induction therapy and improves allograft outcome in sensitized transplant recipients without inhibiting memory T cell responses to third party antigens.

CITATION INFORMATION: Ayasoufi K, Gorbacheva V, Ran F, Valujskikh A. Limiting Helper Functions of CD4 T Cells Improves Efficacy of Induction Therapy without Compromising Responses to Third Party Antigens. Am J Transplant. 2016;16 (suppl 3).

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