Innate allorecognition and KIR/LILR/HLA associations in kidney transplantation

Innate allorecognition and KIR/LILR/HLA associations in kidney transplantation Kidney transplantation is a life-saving treatment for patients with end-stage renal disease. Despite significant improvements in short-term renal allograft survival, long-term graft survival remains suboptimal due to chronic rejection. We hypothesize that innate allorecognition - the sensing of human leukocyte antigen (HLA) in the graft by killer Ig-like receptors (KIR) and leukocyte Ig-like receptors (LILR) on recipient NK cells and monocytes – is a key driver of chronic rejection. We propose to test the hypothesis by investigating associations between HLA/KIR/LILR genetic variations and clinicopathological allograft outcomes in 2,000 donor/recipient kidney transplant pairs derived from curated North American (Pittsburgh and San Francisco) and French (Paris and Lyon) patient cohorts that are ethnically diverse. We will perform high coverage short-read and HiFi long-read genomic DNA sequencing to obtain high resolution HLA and KIR/LILR typing, respectively. The related KIR and LILR gene families reside adjacent to each other in a region on chromosome 19 that spans <1Mbp. Low coverage whole genome sequencing will also be performed to infer genomic ancestry, donor/recipient relatedness, and polymorphisms that influence allograft outcomes. Finally, NK cell and monocyte analysis in blood and allografts will be conducted on a subset of patients to gain mechanistic insights. The work will be executed by a multidisciplinary team that includes experts from transplant nephrology, immunology, tissue typing, pathology, and biostatistics & bioinformatics. The uniqueness of the proposal derives from the high quality, long-term, clinicopathological data available for the cohorts; serially banked bio- samples; accurate assembly of the KIR/LILR region through HiFi long-read sequencing; concurrently available whole genome data; and the innovative scope of the proposal, which extends the concept of allorecognition beyond T, B, and NK cells to monocytes. Information gained could be readily implemented in the clinic to improve donor/recipient matching or patient risk stratification and to provide genetic underpinnings for therapeutic targeting of innate immune pathways in transplantation.