*Purpose: Allograft rejection is initiated by host immune system distinguishing between self and allogeneic non-self (allorecognition). Paired immunoglobulin-like receptor (PIR) and CD47 are molecules expressed on host myeloid cells that sense donor polymorphic MHC and signal regulatory protein alpha (SIRPα) molecules, respectively, during innate allorecognition after transplantation. PIR-A and CD47 are stimulatory while PIR-B is inhibitory. We here investigated the unknown role of these two innate allorecognition pathways (MHC-PIR-A/B and SIRPα-CD47) in solid organ transplantation using a mouse renal transplantation model.

*Methods: To study the MHC-PIR pathway, wild type (WT) Balb/c kidneys were transplanted into WT, PIR-A knock out (KO) or PIR-B KO B6 mice. T cells, macrophages, and monocyte derived dendritic cells (Mono-DC) infiltrating in the grafts were determined by flow cytometry. Donor-specific IFNγ generating CD8+ T cells in grafts were detected by the mixed lymphocyte reaction (MLR). To study the SIRPα-CD47 pathway, kidneys from NOD mice were transplanted to WT or CD47 KO B6 mice (CD47 WT and CD47 KO groups). Graft function, survival, and histological changes were monitored and analyzed at time of harvest.

*Results: PIR-B KO mice (n=6) quickly rejected renal allografts with mean graft survival time 13.2±3.2 days and elevated serum creatinine (SCr) at 1.3±0.7 mg/dl at graft harvest time (10-17 days). Graft histology showed severe diffuse lymphocytic infiltration with tubulitis and interstitial inflammation typical of cell mediated acute rejection. All PIR-A KO (n=5) and WT (n=4) recipients survived beyond 130 days with normal graft function (SCr < 0.2 mg/dl). At postoperative day 131-146, grafts were harvested and histological examination showed focal nodular lymphocyte infiltration in WT recipients, which were significantly attenuated in PIR-A KO recipients. Flow analysis of graft cells demonstrated significantly lower CD8+ T cell, macrophage, and Mono-DC in PIR-A KO than WT group (p=0.02, <0.0001, and =0.02, respectively). MLR showed decreased donor-specific CD8+IFNγ+ T cells in grafts from PIR A KO compared to WT mice (p=0.004). For SIRPα-CD47 pathway, we found that all recipients survived >150 days in both WT and CD47 KO groups (n=4/per group). At postoperative day 159-171, graft function in both groups was stable (SCr<0.3 mg/dl); however, graft histological changes demonstrated typical chronic rejection features of interstitial inflammation and fibrosis in WT recipients but not CD47 KO recipients. In fact, grafts in the latter group had near-pristine histology. Ongoing studies are addressing effect of these pathways on alloantibody production and effect of anti-CD47 antibodies on graft survival and pathology.

*Conclusions: The MHC-PIR-A/B and SIRPα-CD47 innate allorecognition pathways play key roles in kidney allograft rejection. PIR-B receptor inhibits acute rejection, while PIR-A and CD47 molecules potentiate chronic rejection. The findings in this study provide new insights into preventing kidney allograft rejection by targeting novel allorecognition pathways.

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