HLA immunogenetics and kidney allograft outcomes

Active Project Grant Awarded Last action

Award ID
R01AI173095
Recipient
Awarding agency
Obligated
$7,796,665

Award facts

Assistance listing
93.855 Allergy and Infectious Diseases Research
Completion date 79% complete
Place of performance
Philadelphia, PA 19104, USA

Award details come from USAspending.gov.

Description

As the agency reported it.

Abstract
Kidney transplantation is the preferred treatment of patients with end-stage renal disease compared to dialysis in terms of patient survival, quality of life and cost. One of the most common causes of premature graft loss after kidney transplantation is alloimmune-mediated injury. HLA alloantigens represent a significant barrier to long-term allograft outcome. Kidney allograft failure is often caused by recipient immune recognition of foreign human leukocyte antigen (HLA) proteins of the donor organ. The HLA gene complex comprises multiple loci and has a high degree of genetic polymorphism. HLA amino acid (AA) polymorphisms strongly impact key structural and functional features of HLA molecules, including allorecognition by t cells and alloantibody. Previous studies have shown that mismatches (MMS) at HLA antigens are associated with worse outcomes, with the highest risk of graft failure (GF) particularly associated with HLA-DRB1 MMS. However, the relative impact of AA variation is unknown because organ allocation systems have not collected comprehensive molecular HLA typing data. Single-center studies using high resolution HLA typing to evaluate MMS at surface- exposed amino acids (termed "eplets") have shown that the number of MMS correlates with the presence of DE novo donor specific antibodies (dndsa) and GF. However, these studies involved relatively few subjects and were not representative of the ethnically diverse transplant population. In addition, these studies assumed monotonic risk increase, a GAP that we plan to address in this grant application. We will use HLA imputation methods that we have developed to unlock the capability to utilize the srtr database for association analysis of AA MM categories with graft failure. In addition, we will validate and further investigate AA MM associations using a large multi-center cohort of kidney transplants wherein high resolution HLA class i and class II typing is readily available. We will also evaluate associations of HLA AA MM assortments with risk of dndsa development. This project aims to answer several unresolved questions about HLA AA MMS and outcomes: (1) which HLA loci are most important to match? (2) on top of antigen-level mismatches, can amino acid level mismatches further stratify outcomes? (3) are some assortments of AA or AA motifs more important to match for than others? Our team has developed a machine learning feature engineering to discover and optimize AA MM groupings (bins) associated with GF and dndsa. Improved patient risk stratification may help identify which transplant recipients would benefit from less aggressive immunosuppressive regimens and by reducing the number of repeat transplants due to graft failure with a poorly matched donor. Our approach generalizes broadly to other organ transplantation and possibly to hematopoietic cell transplantation.

Transactions

Action Obligated Date
Amendment $731,553
Amendment $728,342
Amendment $728,342
Amendment $75,795
Amendment $75,795
Amendment $682,146
Amendment $682,146
Amendment $682,146
Amendment $852,600
Amendment $852,600
Amendment $852,600
Original award $852,600
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Subawards

Subrecipient Amount Awarded
The Administrators Of Tulane Educational Fund "Objective or Purpose: Perform immunogenetic association analysis and HLA bioinformatics support for solid organ transplant outcomes studies Tasks and… $148,400
Cedars-Sinai Medical Center The Urbanowicz lab, led by Dr. Ryan Urbanowicz at the Cedars-Sinai Medical Center will be primarily responsible for the adaptation, testing, evaluation and… $160,200
Arbor Research Collaborative For Health "Arbor Research Collaborative for Health (Arbor Research) will perform services (Services) as detailed in in this Statement of Work (SOW): Investigate… $127,900
The Administrators Of Tulane Educational Fund "Objective or Purpose: Perform immunogenetic association analysis and HLA bioinformatics support for solid organ transplant outcomes studies Tasks and… $148,250
Cedars-Sinai Medical Center The Urbanowicz lab, led by Dr. Ryan Urbanowicz at the Cedars-Sinai Medical Center will be primarily responsible for the adaptation, testing, evaluation and… $160,000
Arbor Research Collaborative For Health "Arbor Research Collaborative for Health (Arbor Research) will perform services (Services) as detailed in in this Statement of Work (SOW): Investigate… $125,338
Baylor Research Institute The goals are to test the hypothesis that DRB1 and DQB1 amino acid mismatches improve risk stratification after adjusting for ABDR antigen mismatches, with DRB1… $16,700
Duke University The current research proposal aims to investigate this risk stratification using a larger kidney transplant cohort from multiple transplant centers in the US.… $11,764
The Leland Stanford Junior University 1. Problem Statement The PI discovered that amino acid (AA) mismatches (MMs) at peptide-binding pockets of HLA-DRB1 molecule account for the significant… $12,417
The Johns Hopkins University The PI discovered that amino acid (AA) mismatches (MMs) at peptide-binding pockets of HLA-DRB1 molecule account for the significant incremental risk of kidney… $11,816
Arbor Research Collaborative For Health Arbor Research Collaborative for Health (Arbor Research) will perform services (Services) as detailed in in this Statement of Work (SOW): Investigate… $6,300
Cedars-Sinai Medical Center The Urbanowicz lab, led by Dr. Ryan Urbanowicz at the Cedars-Sinai Medical Center will be primarily responsible for the adaptation, testing, evaluation and… $11,000
The Administrators Of Tulane Educational Fund Objective or Purpose: Perform immunogenetic association analysis and HLA bioinformatics support for solid organ transplant outcomes studies Tasks and… $11,000
The Administrators Of Tulane Educational Fund $128,763
University Of Alabama At Birmingham This proposal includes a multicenter cohort where unambiguous amino acid mismatches are determined using high resolution HLA typing by Next Generation… $18,188
New York University The goals are to test the hypothesis that DRB1 and DQB1 amino acid mismatches improve risk stratification after adjusting for ABDR antigen mismatches, with DRB1… $13,355
Baylor Research Institute The goals are to test the hypothesis that DRB1 and DQB1 amino acid mismatches improve risk stratification after adjusting for ABDR antigen mismatches, with DRB1… $15,745
University Of North Carolina Hospitals At Chapel Hill 1. Problem Statement The PI discovered that amino acid (AA) mismatches (MMs) at peptide-binding pockets of HLADRB1 molecule account for the significant… $20,983
Cedars-Sinai Medical Center The Urbanowicz lab, led by Dr. Ryan Urbanowicz at the Cedars-Sinai Medical Center will be primarily responsible for the adaptation, testing, evaluation and… $143,827
Arbor Research Collaborative For Health Arbor Research Collaborative for Health (Arbor Research) will perform services (Services) as detailed in in this Statement of Work (SOW): Investigate… $111,863
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Quick answers

Who received award R01AI173095?

R01AI173095 was awarded to The Trustees Of The University Of Pennsylvania by National Institute of Allergy and Infectious Diseases (National Institutes of Health) on November 21, 2022.

How much is award R01AI173095 worth?

$7,796,665 has been obligated on R01AI173095.

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