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Strategies to attenuate the indirect alloimmune response in encapsulated pancreatic islet transplantation

Award Number: F30DK136276
ORGANIZATION: NATIONAL INSTITUTE OF DIABETES & DIGESTIVE & KIDNEY DISEASES
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: FELLOWSHIP/SCHOLARSHIP/STUDENT LOANS

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Project Summary Type 1 diabetes (T1D) is an autoimmune condition that destroys the insulin-producing beta cells within the pancreatic islets of Langerhans. Although the treatment for T1D is aided with new technology like continuous glucose monitoring and automated insulin pumps, exogenous insulin administration is the core management strategy and T1D remains a life-changing and lifelong diagnosis. T1D can be cured by beta cell replacement through pancreatic islet transplantation, however the need for chronic systemic immunosuppression greatly limits the applicability of this procedure. Encapsulation of islets within selectively permeable hydrogels prior to transplantation may eliminate the need for chronic immunosuppression by blocking direct recipient cell and antibody contact with allogeneic islets. The Tomei lab has developed a unique encapsulation method, “conformal coating,” that addresses several considerations of traditional encapsulation methods. Altogether, islet encapsulation has been shown in animal models of T1D to be capable of restoring blood glucose regulation, however recipient innate and adaptive immune cells including macrophages and T cells still initiate a local inflammatory and pericapsular response and limit the long-term efficacy of encapsulated islet transplantation. Given the selective permeability of the hydrogel layer, soluble alloantigens shed by the transplanted islets are likely triggering an indirect allorecognition pathway, where recipient professional antigen-presenting cells scavenge and present alloantigens shed by transplanted islets to alloreactive T cells while simultaneously providing co-stimulatory signal activation. The overall goal of my project is to capitalize on this mechanism by blocking the co-stimulatory pathways required for T cell activation. I hypothesize that combining encapsulated islet transplantation with (1) localized and targeted nanoparticle delivery of biologic co-stimulatory blockers (cytotoxic T lymphocyte antigen 4 immunoglobulin) or (2) co-transplantation with immunomodulatory non- professional antigen presenting cells (that present antigen but do not provide adequate co-stimulation) will induce deletion/anergy of alloreactive T cells and promote tolerance to transplanted islets, thereby improving and prolonging their efficacy in restoring physiologic metabolic control.


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 = $52,694 )
2024	2024	UNIVERSITY OF MIAMI	1320 S DIXIE HWY STE 1200	CORAL GABLES	FL	33146	MIAMI-DADE	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	2	3/20/2024	NON-COMPETING CONTINUATION	$52,694
														Subtotal = $52,694

Issue Date FY: 2023 ( Subtotal = $52,694 )
2023	2023	UNIVERSITY OF MIAMI	1400 NW 10TH AVE	MIAMI	FL	33136	MIAMI-DADE	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	001	1	3/20/2023	NEW	$0
2023	2023	UNIVERSITY OF MIAMI	1400 NW 10TH AVE	MIAMI	FL	33136	MIAMI-DADE	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	1	3/20/2023	NEW	$52,694
														Subtotal = $52,694

Grand Total All Awards = $105,388

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Strategies to attenuate the indirect alloimmune response in encapsulated pancreatic islet transplantation

Award Number: F30DK136276

ORGANIZATION: NATIONAL INSTITUTE OF DIABETES & DIGESTIVE & KIDNEY DISEASES

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

AWARD ACTIVITY TYPE: FELLOWSHIP/SCHOLARSHIP/STUDENT LOANS

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