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Promoting and Visualizing Immune Regulation in Transplantation

Award Number: U01AI170074
ORGANIZATION: NATIONAL INSTITUTE OF ALLERGY & INFECTIOUS DISEASES
OPDIV: NIH
AWARD CLASS: COOPERATIVE AGREEMENT
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 06/13/2022
PERIOD OF PERFORMANCE END DATE: 03/31/2027

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Promoting and Visualizing Immune Regulation in Transplantation - PROJECT SUMMARY Two main issues currently plague the field of transplantation in humans: (i) poor control of chronic rejection by current immunosuppressive drugs; and (ii) low success of tolerance induction. At the center of these issues is innate immune memory stemming from both innate allorecognition and trained immunity, which generate a state of chronic inflammation. Unfortunately, innate immune memory is not specifically targeted by current immunosuppressive drugs. In addition, commonly used immunosuppressive regimens hinder the much-needed immune regulation processes required for tolerance by impeding CD4+ Foxp3+ regulatory T cells (Treg) homeostasis and suppressor function. Thus, a key deficit in the field is a lack of available therapeutics that both target innate immune memory and promote immune regulation. In this regard, our data demonstrate that innate cells are central to Treg suppressor function within allografts, highlighting the robust relationship between innate cells and Treg. Therefore, we hypothesize that inhibition of innate immune memory promotes a long-lasting regulatory environment by enhancing both myeloid regulatory cells (MRCs) and Treg suppressor functions, which protects allograft from rejection. We will test this in the following AIMs: This project will investigate whether inhibition of innate immune memory promotes MRC (AIM 1) and Treg (AIM 2) regulatory functions in the setting of transplantation. We will use both genetic approaches and novel nanotherapeutics to specifically inhibit innate allorecognition and trained immunity in transplanted mice, and the promotion of MRCs and Treg, as well as their immune regulatory functions, will be assessed. These experiments will enhance our knowledge on the role of innate immune memory in immune regulatory functions, which remains largely unexplored. Importantly, the visualization of MRC and Treg suppressor function using multi-photon intravital microscopy and the use of novel nanotherapeutics targeting innate immune memory are central in testing these hypotheses. These AIMs will be accomplished through the collaborative efforts of an interdisciplinary group of experts in the fields of in nanotherapeutics, intravital microscopy, innate allorecognition trained immunity, and transplant immunobiology. Therefore, this grant application is dually responsive to this RFA (Emerging Science and Technology in Transplantation (U01)) as it will both use intravital imaging and targeted therapeutic delivery. Overall, new knowledge generated from this grant will: 1) identify molecular targets to inhibit innate immune memory and promote immune regulatory function; and 2) visualize – at the cellular level, in the living host, and in real time – MRCs and Treg immune regulation in the setting of transplantation.


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 = $394,733 )
2026	2026	UNIVERSITY OF PITTSBURGH - OF THE COMMONWEALTH SYSTEM OF HIGHER EDUCATION	4200 FIFTH AVENUE	PITTSBURGH	PA	15260	ALLEGHENY	USA	Allergy and Infectious Diseases Research	000	5	4/1/2026	NON-COMPETING CONTINUATION	$394,733
														Subtotal = $394,733

Issue Date FY: 2025 ( Subtotal = $394,733 )
2025	2025	UNIVERSITY OF PITTSBURGH - OF THE COMMONWEALTH SYSTEM OF HIGHER EDUCATION	4200 FIFTH AVENUE	PITTSBURGH	PA	15260	ALLEGHENY	USA	Allergy and Infectious Diseases Research	000	4	3/20/2025	NON-COMPETING CONTINUATION	$394,733
														Subtotal = $394,733

Issue Date FY: 2024 ( Subtotal = $394,733 )
2024	2024	UNIVERSITY OF PITTSBURGH - OF THE COMMONWEALTH SYSTEM OF HIGHER EDUCATION	4200 FIFTH AVENUE	PITTSBURGH	PA	15260	ALLEGHENY	USA	Allergy and Infectious Diseases Research	000	3	3/20/2024	NON-COMPETING CONTINUATION	$394,733
														Subtotal = $394,733

Issue Date FY: 2023 ( Subtotal = $394,733 )
2023	2023	UNIVERSITY OF PITTSBURGH - OF THE COMMONWEALTH SYSTEM OF HIGHER EDUCATION	4200 FIFTH AVENUE	PITTSBURGH	PA	15260	ALLEGHENY	USA	Allergy and Infectious Diseases Research	000	2	3/7/2023	NON-COMPETING CONTINUATION	$394,733
														Subtotal = $394,733

Issue Date FY: 2022 ( Subtotal = $409,028 )
2022	2022	UNIVERSITY OF PITTSBURGH, THE	4200 5TH AVE	PITTSBURGH	PA	15260	ALLEGHENY	USA	Allergy and Infectious Diseases Research	000	1	6/13/2022	NEW	$409,028
														Subtotal = $409,028

Grand Total All Awards = $1,987,960

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Promoting and Visualizing Immune Regulation in Transplantation

Award Number: U01AI170074

ORGANIZATION: NATIONAL INSTITUTE OF ALLERGY & INFECTIOUS DISEASES

OPDIV: NIH

AWARD CLASS: COOPERATIVE AGREEMENT

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

PERIOD OF PERFORMANCE START DATE: 06/13/2022

PERIOD OF PERFORMANCE END DATE: 03/31/2027

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