*Purpose: Paired immunoglobulin-like receptors (PIR) and CD47 are molecules expressed on host myeloid cells. They recognize donor polymorphic MHC and signal regulatory protein alpha (SIRPα), respectively, and are important for monocyte differentiation to DC after transplantation. PIR-A and CD47 are stimulatory while PIR-B is inhibitory. We investigated the roles of these innate allorecognition pathways in solid organ transplantation using mouse kidney and heart transplantation models.

*Methods: To study the MHC-PIR pathway, wild type (WT) Balb/c kidneys or hearts were transplanted into WT, PIR-A knock out (KO) or PIR-B KO B6 mice. WT or PIR-B KO recipients received heat allografts were treated or not with CTLA4-Ig or PIR-A3Fc fusion protein or mouse control IgG. To study the SIRPα-CD47 pathway, kidneys from NOD or NOD.B6sirpα (NOD mice carrying B6 SIRPα) or hearts from Balb/c mice were transplanted to WT or CD47 KO B6 mice. CD47 KO B6 kidneys were transplanted to Balb/c mice. CTLA4-Ig was used or not for heart recipients. T cells, macrophages, and monocyte derived dendritic cells (Mono-DC) infiltrating in the kidney or heart grafts and recipient serum DSA were determined by flow cytometry. Donor-specific IFNγ generating CD8+ T cells in grafts were detected by the mixed lymphocyte reaction (MLR). Graft function, survival, and histological changes were monitored and analyzed at time of harvest or determined time for timed studies.

*Results: In mouse kidney transplantation, PIR-B KO accelerated allograft rejection and this was prevented by PIR-A3Fc fusion protein, which blocks interaction between PIR-A and donor MHC. PIR-A KO attenuated chronic rejection. For SIRPα-CD47 pathway, we found reduced chronic rejection and DSA generation in absence of donor-recipient SIRPα mismatch or recipient CD47 expression. Conversely, transplanting CD47 KO allografts, which cannot deliver SIRPα inhibitory signal, accelerated acute rejection. In mouse heart transplantation, after preventing acute rejection with CTLA4-Ig, PIR-A3Fc fusion protein prolonged allograft survival beyond 100 d, PIR-B KO accelerated allograft rejection, but PIR-A KO did not significantly affect graft survival. For SIRPα-CD47 pathway, after CTLA4-Ig treatment, no difference in allograft survival was observed in CD47 KO recipient, but graft histology showed significantly reduced cell infiltration. Above effects conferred by manipulating these two allorecognition pathways were supported by flow data measuring kidney or heart allograft infiltration with CD8+ and donor-specific CD8+IFNγ+ T cells, macrophages, and Mono-DCs. Ongoing studies are addressing effect of conditionally depleting monocyte CD47 expression on graft survival and pathology.

*Conclusions: These findings provide new insights into preventing rejection by targeting novel innate allorecognition pathways.

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