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Chronic Antibody-Mediated Rejection of Kidney Allografts

Award Number: R01AI167939
ORGANIZATION: NATIONAL INSTITUTE OF ALLERGY & INFECTIOUS DISEASES
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 02/01/2022
PERIOD OF PERFORMANCE END DATE: 01/31/2027

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Chronic Antibody-Mediated Rejection of Kidney Allografts - ABSTRACT Antibody-mediated mechanisms leading to acute and chronic renal allograft injury and loss remain poorly understood. Investigation into these mechanisms is hampered by the lack of appropriate animal models to study the development of allograft injury as the donor-specific antibody (DSA) response is initiated and progresses. We have developed a novel model of antibody-mediated rejection (ABMR) of kidney allografts in CCR5-/- recipients where DSA elicited in response to complete MHC-mismatched renal allografts are >50-fold higher than the titers elicited in wild-type recipients. The allografts are acutely rejected by the DSA in CCR5-/- recipients between days 17 and 22 with features that are virtually identical to those during acute ABMR of clinical kidney grafts, including identical histopathology and gene expression signatures indicating NK cell activation. We have recently demonstrated NK cell activation within the kidney allografts that is required for acute ABMR. In the absence of NK cell activation, however, the high DSA titers induced in CCR5-/- kidney allograft recipients are incapable of mediating acute ABMR but slowly induce development of tubular fibrosis and chronic glomerular injury that leads to eventual graft failure similar to that observed during late failure of clinical kidney transplants. Our preliminary results further indicate marked changes in the phenotype and functional transcriptome of graft infiltrating monocytes and macrophages during chronic vs. acute ABMR. Development of the chronic ABMR is also accompanied by the appearance of antibodies to several autoantigens that is not observed during acute AMR. These results suggest the generation of altered myeloid cells and autoantibodies as key mechanisms underlying the development of this chronic pathology and have led us to hypothesize that DSA binding to kidney allograft endothelium in the absence of NK cell activation stimulates production of myeloid cell recruitment and differentiation factors that skew their function to promote autoantibody production and development of chronic antibody-mediated graft injury. This hypothesis will be tested in three specific aims. In Specific Aim 1 we will test mechanisms of DSA-induced kidney allograft endothelial production of factors directing myeloid cell recruitment and function during development of chronic ABMR. In Specific Aim 2 we will test the role and functions of graft infiltrating myeloid cells that promote development of antibody-mediated allograft injury. In Specific Aim 3 we will test the production and role of auto-antibodies in the development of chronic ABMR. The proposed experiments will utilize novel and clinically relevant models of kidney allograft chronic ABMR to directly identify the inflammatory components and their mechanisms mediating chronic injury of the kidney grafts late after transplant. We anticipate that our studies will continue to reveal novel mechanisms critical to the development of kidney graft chronic ABMR and to identify new therapeutic targets to inhibit or attenuate this pathology and improve kidney graft function and survival.


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 = $626,971 )
2025	2025	CLEVELAND CLINIC LERNER COLLEGE OF MEDICINE OF CASE WESTERN RESERVE UNIVERSITY	9500 EUCLID AVE.	CLEVELAND	OH	44195	CUYAHOGA	USA	Allergy and Infectious Diseases Research	000	4	3/11/2025	NON-COMPETING CONTINUATION	$626,971
														Subtotal = $626,971

Issue Date FY: 2024 ( Subtotal = $646,362 )
2024	2024	CLEVELAND CLINIC LERNER COLLEGE OF MEDICINE OF CASE WESTERN RESERVE UNIVERSITY	9500 EUCLID AVE.	CLEVELAND	OH	44195	CUYAHOGA	USA	Allergy and Infectious Diseases Research	001	3	6/7/2024	NON-COMPETING CONTINUATION	$64,636
2024	2024	CLEVELAND CLINIC LERNER COLLEGE OF MEDICINE OF CASE WESTERN RESERVE UNIVERSITY	9500 EUCLID AVE.	CLEVELAND	OH	44195	CUYAHOGA	USA	Allergy and Infectious Diseases Research	000	3	1/17/2024	NON-COMPETING CONTINUATION	$581,726
														Subtotal = $646,362

Issue Date FY: 2023 ( Subtotal = $646,362 )
2023	2023	CLEVELAND CLINIC LERNER COLLEGE OF MEDICINE/CWRU	9500 EUCLID AVE	CLEVELAND	OH	44195	CUYAHOGA	USA	Allergy and Infectious Diseases Research	000	2	1/12/2023	NON-COMPETING CONTINUATION	$646,362
														Subtotal = $646,362

Issue Date FY: 2022 ( Subtotal = $646,362 )
2022	2022	CLEVELAND CLINIC LERNER COLLEGE OF MEDICINE/CWRU	9500 EUCLID AVE	CLEVELAND	OH	44195	CUYAHOGA	USA	Allergy and Infectious Diseases Research	000	1	1/28/2022	NEW	$646,362
														Subtotal = $646,362

Grand Total All Awards = $2,566,057

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Chronic Antibody-Mediated Rejection of Kidney Allografts

Award Number: R01AI167939

ORGANIZATION: NATIONAL INSTITUTE OF ALLERGY & INFECTIOUS DISEASES

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

PERIOD OF PERFORMANCE START DATE: 02/01/2022

PERIOD OF PERFORMANCE END DATE: 01/31/2027

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