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Characterization of a LILRB3 SNP cluster in kidney transplant recipients associated with post-transplant renal failure

Award Number: R01DK149129
ORGANIZATION: NATIONAL INSTITUTE OF DIABETES & DIGESTIVE & KIDNEY DISEASES
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 08/15/2026
PERIOD OF PERFORMANCE END DATE: 05/31/2031

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Characterization of a LILRB3 SNP cluster in kidney transplant recipients associated with post-transplant renal failure - Kidney transplant recipients in certain population face a high risk of graft failure, regardless of HLA mismatches, socioeconomic factors or other co-morbidities [1-3]. Genetic factors may be one cause contributing to the poorer graft survival observed in kidney transplant recipients[3], but the discovery of such factors is still limited. Recently, we reported a cluster of four consecutive SNPs in the LILRB3 gene (called LILRB3-4SNPs) associated with post-transplant renal failure or declined kidney function by analyzing RNA sequencing data of pretransplant whole blood from kidney transplant recipients in a multi-center transplant cohort (GoCAR) and validated in three external transplant cohorts[4]. These SNPs encode missense mutations of EP to PS at amino acids 617-618 between two ITIM motifs that binds SHP-1 and SHP-2 phosphatases for downstream signaling[5]. Furthermore, these SNPs are also associated with the severity or complications of immune-related diseases in EHR-linked biobanks. In addition, the pretransplant peripheral blood from the recipients with LILRB3-4SNPs exhibited overexpression of genes in B/T cell activation/differentiation and IL17 signaling pathways and down- regulation of genes involved in erythrocyte/myeloid cell differentiation, iron ion homeostasis and oxidative phosphorylation. The down regulation of ferroptosis negative regulators was also specifically detected in monocytes in PBMC and post-transplant kidneys. Last, the in vitro overexpression of the variant allele of LILRB3- 4SNPs is linked to an augmented immune response and an increase in ferroptosis-associated cell death within the THP-1 cell line (a human macrophage cell line). Our new data indicated that the same missense mutation in mouse Pirb gene (the human LILRB3 ortholog) enhanced inflammation and ferroptosis in mouse PBMC and LPS-treated bone marrow derived monocytes (BMDM) and increased macrophage infiltration and kidney damage in Ischemia Reperfusion Injury (IRI) mouse model, which confirmed the causal association of LILRB4- 4SNPs with inflammation. Based on these preliminary data, we hypothesize the LILRB3 EP->PS mutation attenuates the binding of LILRB3 to SHP-1 and/or SHP-2, reducing downstream phosphatase activity, resulting in enhanced NF𝜅B dependent inflammation, JAK/STAT activation, and subsequent ferroptosis, predominantly by graft infiltrating monocyte/macrophages. The ensuing inflammatory cell death directly promotes interstitial fibrosis and amplifies graft-reactive cellular and humoral alloimmunity together accelerating graft failure despite standard immunosuppression We will test our hypothesis by 1) To prospectively investigate the relationship between LILRB3-4SNPs and transplant outcomes in transplant cohorts; 2) To assess the molecular mechanisms linking LILRB-4SNPs to monocyte/macrophage ferroptosis; 3) To assess the impact of recipient LILRB3-4SNPs variants on graft reactive adaptive immunity and intragraft inflammation. If successful, we will define a clinically relevant risk allele that contributes to the poorer outcomes of this subpopulation and discern underlying mechanisms. As ferroptosis is specifically targetable using novel therapeutics, the findings could have readily translatable potential.


Issue Date FY	Funding FY	Legal Entity Name	Legal Entity Address	Legal Entity City	Legal Entity State	Legal Entity Zip Code	Legal Entity COUNTY	Legal Entity COUNTRY	Assistance Listing	Award Code	Budget Year	Action Date	Action Type	Action Amount

Issue Date FY: 2026 ( Subtotal = $910,670 )
2026	2026	ICAHN SCHOOL OF MEDICINE AT MOUNT SINAI	1 GUSTAVE L LEVY PL	NEW YORK	NY	10029	NEW YORK	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	1	8/11/2026	NEW	$910,670
														Subtotal = $910,670

Grand Total All Awards = $910,670

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Characterization of a LILRB3 SNP cluster in kidney transplant recipients associated with post-transplant renal failure

Award Number: R01DK149129

ORGANIZATION: NATIONAL INSTITUTE OF DIABETES & DIGESTIVE & KIDNEY DISEASES

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)

PERIOD OF PERFORMANCE START DATE: 08/15/2026

PERIOD OF PERFORMANCE END DATE: 05/31/2031

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