Wednesday, April 2, 2025 4/2/2025

Local regulation and deletion of T cells to induce tolerance and establish long-term survival of high-risk corneal transplants

Award Number: R01EY030283
ORGANIZATION: NATIONAL EYE INSTITUTE
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)

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Local regulation and deletion of T cells to induce tolerance and establish long-term survival of high-risk corneal transplants - Abstract: Immunological rejection is the most common cause of corneal allo-transplant failure particularly when the recipient has a high risk vascularized corneal bed. Because corneal transplantation (CT) is the most common solid organ transplant performed in the United States (>50,000 /annum), induction of immune tolerance is a critical and unmet medical need according to the NEI (https://www.nei.nih.gov/sites/default/files/2021-12/NEI- StrategicPlan-VisionForTheFuture_508_edit.pdf). The studies proposed in this application, represent a translational basic science immunology project, which will directly apply our provocative pre-clinical experimental findings targeting TNFRSF25 in vivo to manipulate the Treg compartment to induce long-term tolerance in recipients of high-risk CT. Notably, Treg expansion has shown promise in graft vs host disease (GVHD)and type 1diabetes, however when IL-2 treatment is stopped the diseases return. New approaches are needed to induce long-term tolerance to CT and other allografts. The overall objective of this proposal is to develop combinatorial treatment strategies based on deletion and immune regulation. Here we will apply the concept of post-CT cyclophosphamide (Cy) treatment successfully used as singular prophylaxis for GVHD, for the first time to a vascularized solid organ, CT. Our new data identified an extended low dose Cy protocol administered post-CT (PTCy) that markedly prolonged transplant survival. Proposed studies will exploit the survival of Tregs after PTCy administration with novel TL1A and IL-2 based fusion proteins (FP) to target, expand and activate CD4+FoxP3+ T cells in vivo via TNFRSF25 and CD25. Importantly, studies here will develop an approach restricting Treg expansion to the ophthalmic compartment thereby minimizing potential global immune dysregulation. Experiments will first identify the optimal treatment protocol to prolong CT survival examining a unique IL2/CD25 FP currently in clinical trials. Additionally, we will test another recently developed, novel IL2-10/CD25 FP to test the hypothesis that together with Treg expansion, IL-10 mediated suppression of antigen presentation which underlies corneal allograft survival will be down-regulated. T cell receptor transgenic anti-allograft specific T cells dependent on either direct or indirect antigen presentation will be examined in vivo in transplanted mice to directly monitor their regulation (Aim 1). Experiments will investigate mechanistic pathways through in vivo readouts, TNFRSF25 knock-out and chimeric animals and cutting-edge spatial biology analyses via CODEX technology (Aim 2). Lastly, epigenetic regulation using a new bromodomain inhibitor to block local cytokine production will be tested to complement the treatment strategy (Aim 3). Overall, the research plan is to systemically build a tolerance platform by combining 3 highly complementary strategies for the establishment of allograft tolerance to maintain permanent CT. Importantly, because human mAbs and FPs specific for TNFRSF25, IL-2R and IL- 10R have recently been developed, the long-term goal of our pre-clinical research program is to translate our strategies into patients undergoing CT who experience high rates of immune 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: 2025 ( Subtotal = $672,170 )
2025	2025	UNIVERSITY OF MIAMI	1320 S DIXIE HWY STE 1200	CORAL GABLES	FL	33146	MIAMI-DADE	USA	Vision Research	000	5	2/21/2025	COMPETING CONTINUATION	$672,170
														Subtotal = $672,170

Issue Date FY: 2023 ( Subtotal = $478,450 )
2023	2023	UNIVERSITY OF MIAMI	1400 NW 10TH AVE	MIAMI	FL	33136	MIAMI-DADE	USA	Vision Research	000	4	2/6/2023	NON-COMPETING CONTINUATION	$410,000
2023	2023	UNIVERSITY OF MIAMI	1400 NW 10TH AVE	MIAMI	FL	33136	MIAMI-DADE	USA	Vision Research	001	4	2/13/2023	SUPPLEMENT FOR EXPANSION	$68,450
														Subtotal = $478,450

Issue Date FY: 2022 ( Subtotal = $442,178 )
2022	2022	UNIVERSITY OF MIAMI	1600 NW 10 AVE	MIAMI	FL	33136	MIAMI-DADE	USA	Vision Research	000	3	2/22/2022	NON-COMPETING CONTINUATION	$397,393
2022	2022	UNIVERSITY OF MIAMI	1600 NW 10 AVE	MIAMI	FL	33136	MIAMI-DADE	USA	Vision Research	001	3	8/11/2022	SUPPLEMENT FOR EXPANSION	$44,785
														Subtotal = $442,178

Issue Date FY: 2021 ( Subtotal = $397,443 )
2021	2021	UNIVERSITY OF MIAMI	1600 NW 10 AVE	MIAMI	FL	33136	MIAMI-DADE	USA	Vision Research	000	2	3/15/2021	NON-COMPETING CONTINUATION	$397,443
														Subtotal = $397,443

Issue Date FY: 2020 ( Subtotal = $410,000 )
2020	2020	UNIVERSITY OF MIAMI	1600 NW 10 AVE	MIAMI	FL	33136	MIAMI-DADE	USA	Vision Research	000	1	3/26/2020	NEW	$410,000
														Subtotal = $410,000

Grand Total All Awards = $2,400,241

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Local regulation and deletion of T cells to induce tolerance and establish long-term survival of high-risk corneal transplants

Award Number: R01EY030283

ORGANIZATION: NATIONAL EYE INSTITUTE

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

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