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A novel immunomodulatory approach to overcome innate and adaptiveimmune barriers to islet transplantation

Award Number: R01AI121281
ORGANIZATION: NATIONAL INSTITUTE OF ALLERGY & INFECTIOUS DISEASES
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)

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PROJECT SUMMARY Type I diabetes is a chronic autoimmune that affects 3 million children and adults in the US with healthcare costs exceeding $14.9 billion annually. Currently, there is no cure for type 1 diabetes, representing a critical unmet medical need. Transplantation of allogeneic islets is a reliable method of achieving durable glucose homeostasis and preventing the devastating complications of type 1 diabetes. However, there are four major barriers to allogeneic islet transplantation; i) ineffective engraftment, ii) rejection, iii) adverse effects of immunosuppression used to control rejection, and iv) shortage of cadaveric donor islets. Therefore, there is a significant need for strategies that overcome these limitations of islet transplantation for a broader clinical practice. This R01 application aims to develop an innovative and highly translational immunomodulatory protocol to overcome the limitations of islet transplantation for sustained long-term graft survival in the absence of chronic use of immunosuppression. Infusion of islets into the liver via portal vein, the only route of transplantation in clinical use, instantly exposes the graft to blood and initiates an immediate blood-mediated inflammatory reaction (IBMIR). IBMIR is mediated by thrombotic and inflammatory reactions and is responsible for the destruction of 50-80% islets immediate post-transplantation. The remaining islets are then subject to rejection by the slower, but potent adaptive immune responses. Significant early islet loss requires transplantation from 2-3 donors per recipients, which further contribute to the shortage of cadaveric donors. The goal of this proposal is to develop powerful, yet focused therapies to simultaneously target the immediate inflammatory reactions and adaptive immune response to prevent early and late graft loss. This will be accomplished by generating novel recombinant proteins with robust inhibitory functions on prothrombotic, proinflammatory, and adaptive immune reactions. These proteins will be engineered on pancreatic islets before transplantation for localized modulation of thrombotic and inflammatory responses to enhance engraftment and achieve indefinite graft survival without the chronic use of debilitating immunosuppression that is currently standard. This concept will be tested in three different allogeneic islet transplantation settings for efficacy and mechanisms; chemically diabetic BALB/c-to-C57BL/6 mice, spontaneously diabetic C57BL/6-to-NOD mice, and human islets into humanized mice. These models will generate critical data relevant to the human setting. Furthermore, proof-of-efficacy and the elucidation of the immune mechanisms regulating effective outcomes will expedite further refinement of this immunomodulatory concept and its eventual translation to nonhuman primates as a prelude to clinical trials for the treatment of type 1 diabetes.


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 = $342,267 )
2024	2024	UNIVERSITY OF MISSOURI SYSTEM	121 UNIVERSITY HALL	COLUMBIA	MO	65211	BOONE	USA	Allergy and Infectious Diseases Research	000	6	10/26/2023	NON-COMPETING CONTINUATION	$342,267
														Subtotal = $342,267

Issue Date FY: 2023 ( Subtotal = $394,300 )
2023	2023	UNIVERSITY OF MISSOURI SYSTEM	316 UNIVERSITY HALL	COLUMBIA	MO	65211	BOONE	USA	Allergy and Infectious Diseases Research	000	5	11/3/2022	NON-COMPETING CONTINUATION	$394,300
														Subtotal = $394,300

Issue Date FY: 2022 ( Subtotal = $0 )
2022	2021	UNIVERSITY OF MISSOURI SYSTEM	316 UNIVERSITY HALL	COLUMBIA	MO	65211	BOONE	USA	Allergy and Infectious Diseases Research	000	4	11/17/2021	NON-COMPETING CONTINUATION	$0
														Subtotal = $0

Issue Date FY: 2021 ( Subtotal = $373,065 )
2021	2021	UNIVERSITY OF MISSOURI SYSTEM	316 UNIVERSITY HALL	COLUMBIA	MO	65211	BOONE	USA	Allergy and Infectious Diseases Research	000	4	10/19/2020	NON-COMPETING CONTINUATION	$373,065
2021	2020	UNIVERSITY OF MISSOURI SYSTEM	316 UNIVERSITY HALL	COLUMBIA	MO	65211	BOONE	USA	Allergy and Infectious Diseases Research	002	3	6/5/2021	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	$232,784
2021	2019	UNIVERSITY OF LOUISVILLE	2301 S 3RD ST	LOUISVILLE	KY	40208	JEFFERSON	USA	Allergy and Infectious Diseases Research	001	1	6/5/2021	NEW	-$232,784
														Subtotal = $373,065

Issue Date FY: 2020 ( Subtotal = $372,323 )
2020	2020	UNIVERSITY OF LOUISVILLE	2301 S 3RD ST	LOUISVILLE	KY	40208	JEFFERSON	USA	Allergy and Infectious Diseases Research	001	2	8/10/2020	NON-COMPETING CONTINUATION	-$385,000
2020	2020	UNIVERSITY OF MISSOURI SYSTEM	316 UNIVERSITY HALL	COLUMBIA	MO	65211	BOONE	USA	Allergy and Infectious Diseases Research	002	3	8/10/2020	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	$372,323
2020	2020	UNIVERSITY OF LOUISVILLE	2301 S 3RD ST	LOUISVILLE	KY	40208	JEFFERSON	USA	Allergy and Infectious Diseases Research	000	2	11/6/2019	NON-COMPETING CONTINUATION	$385,000
														Subtotal = $372,323

Issue Date FY: 2019 ( Subtotal = $376,360 )
2019	2019	UNIVERSITY OF LOUISVILLE	2301 S 3RD ST	LOUISVILLE	KY	40208	JEFFERSON	USA	Allergy and Infectious Diseases Research	000	1	11/5/2018	NEW	$376,360
														Subtotal = $376,360

Grand Total All Awards = $1,858,315

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A novel immunomodulatory approach to overcome innate and adaptiveimmune barriers to islet transplantation

Award Number: R01AI121281

ORGANIZATION: NATIONAL INSTITUTE OF ALLERGY & INFECTIOUS DISEASES

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

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