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Mechanisms of alloantibody production following renal transplantation

Award Number: R01AI160740
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: 02/22/2021
PERIOD OF PERFORMANCE END DATE: 01/31/2027

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Mechanisms of alloantibody production following renal transplantation - ABSTRACT Acute and chronic antibody-mediated rejection (AMR) is a serious threat to the survival and function of transplanted organs. The current options for AMR prevention and treatment are limited by the incomplete understanding of the mechanisms underlying donor specific alloantibody (DSA) generation and pathogenic functions. Whereas the production of high affinity isotype-switched DSA is typically associated with germinal center formation by follicular B cells, the contribution of marginal zone (MZ) B cells to anti-donor responses following transplantation has not been previously addressed. Our preliminary studies identify MZ B cells as important players in orchestrating DSA responses and warrant detailed investigation of this B cell subset with an ultimate objective of reducing humoral alloimmunity in transplant recipients. Prolonged cold ischemia storage (CIS) of donor allografts and ensuing ischemia/reperfusion injury (IRI) remain among leading risk factors for poor transplant outcome. Using a mouse model of kidney transplantation in which allografts are subjected to 6 h CIS, we found that posttransplant inflammation specifically augments generation of class II-reactive DSA that mediate allograft glomerular injury. These findings are highly relevant to clinical studies revealing correlations between longer cold ischemia time, anti-class II DSA and late AMR in renal transplant patients. However, the mechanisms by which posttransplant inflammation affects generation of pathogenic class II DSA and the very source of donor class II antigens for B cell activation are poorly defined. Based on our preliminary data, we hypothesize that IRI amplifies class II DSA production through the following steps: 1) IRI up-regulates MHC class II expression on donor endothelial cells (EC) and EC release of class II containing extracellular vesicles (EEVs); 2) spleen MZ B cells rapidly acquire circulating EEVs, produce early DSA and facilitate further DSA production by FO B cells; and, 3) in addition to donor alloantigens, MZ B cell activation is initiated and enhanced by DAMPs carried by graft-derived EVs as well as by systemic effects of IRI. Therefore, targeting MZ B cell trafficking, activation and functions will inhibit generation of pathogenic class II DSA and improve outcome of renal allografts subjected to prolonged CIS. We will test this hypothesis in three Specific Aims: Aim 1. To test whether ischemia/reperfusion injury (IRI) augments class II DSA by enhancing endothelial extracellular vesicles (EEV) generation. Aim 2. To test the role of MZ B cells in DSA production following renal transplantation. Aim 3. To investigate the contribution of MZ B cells in the generation of pathogenic class II DSA after prolonged cold ischemia storage of renal allografts. The proposed studies will fill several gaps in current knowledge of humoral alloimmune responses to vascularized organ transplants and identify potential targets of therapeutic intervention to inhibit antibody- mediated rejection.


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 = $0 )
2026	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	5	11/4/2025	NON-COMPETING CONTINUATION	$0
														Subtotal = $0

Issue Date FY: 2025 ( Subtotal = $578,905 )
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	5	3/5/2025	NON-COMPETING CONTINUATION	$578,905
														Subtotal = $578,905

Issue Date FY: 2024 ( Subtotal = $596,809 )
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	4	1/17/2024	NON-COMPETING CONTINUATION	$537,128
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	4	6/6/2024	NON-COMPETING CONTINUATION	$59,681
														Subtotal = $596,809

Issue Date FY: 2023 ( Subtotal = $596,809 )
2023	2023	CLEVELAND CLINIC LERNER COLLEGE OF MEDICINE/CWRU	9500 EUCLID AVE	CLEVELAND	OH	44195	CUYAHOGA	USA	Allergy and Infectious Diseases Research	000	3	1/9/2023	NON-COMPETING CONTINUATION	$596,809
														Subtotal = $596,809

Issue Date FY: 2022 ( Subtotal = $620,959 )
2022	2022	CLEVELAND CLINIC LERNER COLLEGE OF MEDICINE/CWRU	9500 EUCLID AVE	CLEVELAND	OH	44195	CUYAHOGA	USA	Allergy and Infectious Diseases Research	000	2	1/14/2022	NON-COMPETING CONTINUATION	$620,959
														Subtotal = $620,959

Issue Date FY: 2021 ( Subtotal = $620,959 )
2021	2021	CLEVELAND CLINIC LERNER COLLEGE OF MEDICINE/CWRU	9500 EUCLID AVE	CLEVELAND	OH	44195	CUYAHOGA	USA	Allergy and Infectious Diseases Research	000	1	2/22/2021	NEW	$620,959
														Subtotal = $620,959

Grand Total All Awards = $3,014,441

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Mechanisms of alloantibody production following renal transplantation

Award Number: R01AI160740

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: 02/22/2021

PERIOD OF PERFORMANCE END DATE: 01/31/2027

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