Costimulation blockade (CoB) is a promising strategy for more targeted/less toxic transplant immunosuppression which has led to the first improvement in long-term outcomes for transplant patients in over 30 years. Increased rates of acute rejection have tempered enthusiasm for wider adoption of CoB. Type 1 interferons (IFN) induce an antiviral state in host tissues and augment the adaptive immune response. We investigated the role of Type 1 IFN in costimulation independent rejection. In a stringent model of fully MHC-mismatched skin transplantation from Balb/C (H2^d) donors to C57BL/6 (H2^b) recipients, untreated mice rejected rapidly (MST=11 days). CoB treatment (250 ug CTLA4-Ig [BMS, Princeton NJ) + 250 ug Anti-CD40L (MR1, BioXCell, Lebanon NH) given by IP injection day 0, 2, 4, 6) improved survival but resulted in CoB-inedependent rejection (MST=23 d ). CoB+aIFNAR1 (200 ug (MAR15A3, BioXCell) given day 0, 2, 4, 6) abrogated CoB-Independent rejection and significantly prolonged survival (MST>60d). We next asked if this survival benefit was dependent on intragraft activity of IFNAR utilizing IFNAR^-/- mice as recipients of Balb/C (IFNAR^+/+) grafts. IFNAR1-/- mice treated with CoB and WT mice treated with CoB+aIFNAR1 demonstrated similar graft survival benefit (MST>60d). At day 10 post-transplant, both adjuvant aIFNAR1 blockade, and genetic deletion of IFNAR in recipient mice resulted in a significant reduction in the frequency of activated CD8+CD44+ and CD4+CD44+ T cells. These data suggest that IFNAR1 signaling augments the alloimmune response and supports costimulation independent rejection.

CITATION INFORMATION: Mathews D., Ghosh A., Dong Y., Polireddy K., Stephenson A., Breeden C., Liu Y., Adams A. Recipient IFNAR1 Signaling Supports Costimulation Independent Rejection by Promoting T Cell Activation Am J Transplant. 2017;17 (suppl 3).

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