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Overcoming humoral rejection after xenotransplantation in sensitized nonhuman primate recipients

Award Number: R01AI175411
ORGANIZATION: NATIONAL INSTITUTE OF ALLERGY & INFECTIOUS DISEASES
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)

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Overcoming humoral rejection after xenotransplantation in sensitized nonhuman primate recipients - Abstract Xenotransplantation has long been proposed as a therapeutic strategy to address the ongoing organ shortage in transplantation. In recent years, pig-to-primate xenotransplantation outcomes have dramatically improved following advances in the genetic engineering of pig donors and utilization of costimulation blockade-based immunosuppression, such that translation to the clinic appears within reach. Highly allosensitized patients, those who have developed anti-donor antibody as a response to foreign HLA exposure, are potential first candidates for xenotransplantation given their reduced chances of undergoing allotransplantation. However, the impact of allosensitization in the setting of xenotransplantation has not yet been fully elucidated in pig-to- primate models. Our preliminary data suggest that allosensitization promotes antibody-mediated rejection (AMR) following kidney xenotransplantation and leads to early graft failure. Use of donor kidneys from highly engineered pigs prolong xenograft survival yet do not fully alleviate AMR development. Additional therapeutic strategies are thus needed to dampen the post-transplant humoral response following xenotransplantation in sensitized recipients. This project aims to evaluate novel desensitization and immunosuppression strategies to control the post-transplant humoral response and foster long-term xenograft survival in sensitized recipients. Our overarching hypothesis is that both conditioning the host immune response ahead of xenotransplantation through desensitization and continuous targeting of B cells, plasma cells, or complements following transplantation, are necessary to control the post-transplant humoral response and alter the repopulating xenoreactive immune repertoire to favor long-term graft acceptance. To explore this, we propose 3 specific aims: Specific aim 1: We will define the effects of desensitization (costimulation blockade and proteasome inhibitor) pre-transplant in rhesus monkeys undergoing kidney xenotransplantation. Specific aim 2: We will define the impact of adjuvant therapies targeting downstream elements of the humoral response following xenotransplantation. Specific aim 3: We will identify the functional phenotype of xeno-specific T and B cell repertoires required to establish long-term AMR-free xenograft survival while preserving anti-viral/vaccinal response. These advances will ultimately position us to conduct a first-in-human xenokidney transplantation in sensitized patients testing this optimized immunosuppressive regimen. Our proposal involves many academic and industry collaborations that are ongoing as attested by letters of support. The impact of this proposal has broad implications that may benefit U.S. citizens affected by end stage renal failure or by immune-mediated illnesses or infections.


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: 2025 ( Subtotal = $762,292 )
2025	2025	DUKE UNIVERSITY	2200 W MAIN ST	DURHAM	NC	27705	DURHAM	USA	Allergy and Infectious Diseases Research	000	3	2/12/2025	NON-COMPETING CONTINUATION	$762,292
														Subtotal = $762,292

Issue Date FY: 2024 ( Subtotal = $797,199 )
2024	2024	DUKE UNIVERSITY	2200 W MAIN ST	DURHAM	NC	27705	DURHAM	USA	Allergy and Infectious Diseases Research	001	2	5/23/2024	NON-COMPETING CONTINUATION	$79,720
2024	2024	DUKE UNIVERSITY	2200 W MAIN ST	DURHAM	NC	27705	DURHAM	USA	Allergy and Infectious Diseases Research	000	2	1/9/2024	NON-COMPETING CONTINUATION	$717,479
														Subtotal = $797,199

Issue Date FY: 2023 ( Subtotal = $818,532 )
2023	2023	DUKE UNIVERSITY	2200 W MAIN ST	DURHAM	NC	27705	DURHAM	USA	Allergy and Infectious Diseases Research	000	1	2/6/2023	NEW	$818,532
														Subtotal = $818,532

Grand Total All Awards = $2,378,023

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Overcoming humoral rejection after xenotransplantation in sensitized nonhuman primate recipients

Award Number: R01AI175411

ORGANIZATION: NATIONAL INSTITUTE OF ALLERGY & INFECTIOUS DISEASES

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

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