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Development of a Regulatory T Cell Mimetic for Tolerance Induction in Skin Transplantation

Award Number: R21AI139828
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: 02/06/2019
PERIOD OF PERFORMANCE END DATE: 01/31/2023

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Development of a Regulatory T Cell Mimetic for Tolerance Induction in Skin Transplantation - Each year in the United States there are close to 30,000 hospitalizations in specialized burn centers. Many of these patients benefit from human skin allografts as temporary wound closure to promote rapid healing. Skin allografts, being highly immunogenic, begin to lose viability shortly after transplantation and are completely rejected by cytotoxic T cells within two weeks. Extending skin allograft survival is an unmet medical need because it will prolong the duration in which burn victims are protected from dehydration and infection. Regulatory T cells (Treg) have the potential to prolong the viability of skin allografts, but adoptive cell therapy of Treg is not feasible in urgent care settings. Systemic infusion of the principal Treg inhibitory molecules, namely TGF-, IL-10, and CTLA-4 (TIC), is complicated by off-target toxicities and the different pharmacokinetics of the agents. To address this need, we seek to develop a versatile platform on which TIC are optimized spatiotemporally for prolonging the survival of skin allografts. In this project we propose to deliver TIC simultaneously and locally into skin allografts established on full-MHC mismatched mice. The Treg mimicking strategy entails formulating TIC into an injectable by intermixing with novel bioaffinity amphiphilic peptides, generating a gel in which Fc-fusion proteins can be loaded. The multivalent, multifunctional (“multiplexing”) system will enforce a powerful multi-pronged immunosuppression at the transplant site by cross-linking TGF- and IL-10 receptors, as well as B7 molecules on target leukocytes. Three specific aims will be carried out to delineate the cellular and molecular mechanisms of the strategy. The first task is to optimize the dose combination of TIC with respect to raising Treg to Th1 ratio in an allogeneic skin explant T cell co-culture system. In the second task, we will validate the biocompatibility of the materials system. In the third task, we will evaluate the capacity of muxTIC to steer T cells toward suppressive phenotypes in vivo. The public health impact centers on leveraging an enabling technology by which burn care can be improved. Given the in vivo transplant model at hand and the biomaterials tools we have developed, our team is uniquely poised to advance the novel strategy. The materials platform is versatile; Fc-fusion proteins or antibodies targeting other pathways can be displayed, thereby increasing the scope of the modulation. The broader impact is that the data generated will set the stage for testing multiplexed Treg factors in vascularized composite allografts (VCA) transplantation in which the skin is a primary driver of immune 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: 2024 ( Subtotal = $0 )
2024	2020	DUQUESNE UNIVERSITY OF THE HOLY SPIRIT	600 FORBES AVENUE	PITTSBURGH	PA	15282	ALLEGHENY	USA	Allergy and Infectious Diseases Research	000	2	1/5/2024	NON-COMPETING CONTINUATION	$0
														Subtotal = $0

Issue Date FY: 2023 ( Subtotal = -$657 )
2023	2020	DUQUESNE UNIVERSITY OF THE HOLY SPIRIT	600 FORBES AVENUE	PITTSBURGH	PA	15282	ALLEGHENY	USA	Allergy and Infectious Diseases Research	000	2	10/21/2022	SUPPLEMENT FOR EXPANSION	-$657
														Subtotal = -$657

Issue Date FY: 2022 ( Subtotal = $0 )
2022	2020	DUQUESNE UNIVERSITY OF THE HOLY SPIRIT	600 FORBES AVE	PITTSBURGH	PA	15282	ALLEGHENY	USA	Allergy and Infectious Diseases Research	000	2	12/17/2021	NON-COMPETING CONTINUATION	$0
														Subtotal = $0

Issue Date FY: 2021 ( Subtotal = $0 )
2021	2020	DUQUESNE UNIVERSITY OF THE HOLY SPIRIT	600 FORBES AVE STE 205	PITTSBURGH	PA	15219	ALLEGHENY	USA	Allergy and Infectious Diseases Research	000	2	12/2/2020	SUPPLEMENT FOR EXPANSION	$0
														Subtotal = $0

Issue Date FY: 2020 ( Subtotal = $190,741 )
2020	2020	DUQUESNE UNIVERSITY OF THE HOLY SPIRIT	600 FORBES AVE STE 205	PITTSBURGH	PA	15219	ALLEGHENY	USA	Allergy and Infectious Diseases Research	001	2	7/2/2020	SUPPLEMENT FOR EXPANSION	$47,784
2020	2020	DUQUESNE UNIVERSITY OF THE HOLY SPIRIT	600 FORBES AVE STE 205	PITTSBURGH	PA	15219	ALLEGHENY	USA	Allergy and Infectious Diseases Research	000	2	1/23/2020	NON-COMPETING CONTINUATION	$142,957
														Subtotal = $190,741

Issue Date FY: 2019 ( Subtotal = $186,863 )
2019	2019	DUQUESNE UNIVERSITY OF THE HOLY SPIRIT	600 FORBES AVE STE 205	PITTSBURGH	PA	15219	ALLEGHENY	USA	Allergy and Infectious Diseases Research	000	1	2/6/2019	NEW	$186,863
														Subtotal = $186,863

Grand Total All Awards = $376,947

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Development of a Regulatory T Cell Mimetic for Tolerance Induction in Skin Transplantation

Award Number: R21AI139828

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: 02/06/2019

PERIOD OF PERFORMANCE END DATE: 01/31/2023

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