Innate allorecognition is a process by which myeloid cells, such as monocytes, distinguish syngeneic from allogeneic cells. Monocytes that recognize donor cells as non-self differentiate into monocyte-derived dendritic cells (mo-DCs) and contribute to allograft rejection. Initiation of this recognition process is mediated through binding of signal regulatory protein alpha (SIRPa) on graft cells to its receptor, CD47, on recipient monocytes. SIRPa is an immunoglobulin superfamily (IgSF) membrane protein with a highly polymorphic IgV domain that binds monomorphic CD47. SIRPa polymorphism modulates the SIRPa-CD47 binding affinity such that SIRPa mismatch between the donor and recipient is sufficient to trigger allorecognition. We have determined the degree of amino acid variability within each domain of mouse SIRPa derived from the sequences of 19 mouse strains available through Mouse Genome Informatics (MGI). Furthermore, we developed a phylogram representation of the polymorphism in SIRPa IgV domain, which shows a correlation between IgV polymorphism and the degree of innate alloresponse. These findings raised the possibility that SIRPa polymorphism influence transplant outcomes in humans. As a prelude to testing this hypothesis, we have used the 1000 Genomes Project to identify polymorphism in human SIRPa from the compilation of multiple data sets. From this data, we have derived 13 haplotypes that occur with >1% frequency across five different ethnic backgrounds, with 7 common haplotypes accounting for 88-90% of tested individuals depending on ethnicity, 2 of which account for 58-74% of individuals. We are currently using 3-D rendering to overlay each haplotype on the crystal structure of the SIRPa IgV domain bound to CD47 (from PDB) to predict if and which haplotypes could have effects on CD47 binding by altering polarity, hydrophobicity, or causing steric hindrance. Future studies will investigate associations between donor and recipient SIRPa polymorphism and graft outcomes.

CITATION INFORMATION: Friday A., Dai H., Williams A., Oberbarnscheidt M., Danska J., Lakkis F. Identification of Human SIRPa Diversity That Could Regulate Innate Allorecognition Am J Transplant. 2017;17 (suppl 3).

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