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Engineering dendritic cells to target islet antigen to pro-tolerogenic subsets for prevention and treatment of Type 1 Diabetes

Award Number: R01DK132544
ORGANIZATION: NATIONAL INSTITUTE OF DIABETES & DIGESTIVE & KIDNEY DISEASES
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)

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Project Summary Although induction of antigen-specific tolerance by means of targeting such antigens to dendritic cells (DCs) has been reported in multiple pre-clinical studies, there are currently no effective approaches using DCs in the clinic to prevent or reverse autoimmunity. DCs have been proven to intrinsically possess the ability to restore and maintain immune tolerance, making them very attractive candidates for treatment of autoimmune diseases. However, only non-activated DCs (which inherently possess a tolerogenic/suppressive phenotype) can induce tolerance, whereas activated DCs can trigger immunity. Notably, there is no strategy able to deliver antigen uniquely to non-activated DCs. To overcome this limitation, the long-term goal of this proposal is to engineer DCs to guarantee presentation of islet-derived antigen solely by tolerogenic subsets to treat Type 1 Diabetes (T1D). The central hypothesis is that by ensuring that islet-derived antigen is presented exclusively by tolerogenic DCs, these DCs will lead to elimination of islet-specific auto-reactive T cells and induction of protective Tregs. The overarching goal of this proposal will be tested by pursuing the following two specific aims: (1) Engineering DCs to express islet-derived antigen using circuits that limit expression to pro-tolerogenic DCs and (2) Engineering DCs to artificially enforce a pro-tolerogenic irreversible phenotype while also driving expression of islet-derived antigen. For Aim 1, constructs containing a new promoter driving expression to tolerogenic DCs in combination with microRNA-based circuits that prevent antigen expression in response to inflammation will be tested for induction of tolerance. For Aim 2, a transcription factor that can enforce DCs into a highly pro- tolerogenic state will be used in a construct encoding islet-derived antigen to engineer DCs in T1D mouse models. This transcriptional regulator was identified in intra-tumor DCs, and its enforced activation was found to shape DCs into an immune suppressive state that could not be reverted even in response to strong inflammatory stimuli. The proposed research is innovative because it attempts for the first time to engineer DCs to ensure presentation of islet-derived antigen only by pro-tolerogenic cells. The significance of this proposal is that, if successful, it will have identified a strategy to safely engineer DCs for induction of tolerance and will provide a strong scientific framework for further investigations to engineer these critical orchestrators of the immune system. Ultimately, the knowledge derived from this work has the potential to lay the ground for innovative engineering-based therapies to stop autoimmunity in T1D, which constitutes an essential step to achieve a cure.


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 = $445,000 )
2024	2024	DANA-FARBER CANCER INSTITUTE, INC.	450 BROOKLINE AVE	BOSTON	MA	02215	SUFFOLK	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	3	3/19/2024	NON-COMPETING CONTINUATION	$445,000
														Subtotal = $445,000

Issue Date FY: 2023 ( Subtotal = $445,000 )
2023	2023	DANA-FARBER CANCER INSTITUTE, INC.	450 BROOKLINE AVE	BOSTON	MA	02115	SUFFOLK	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	2	3/20/2023	NON-COMPETING CONTINUATION	$445,000
														Subtotal = $445,000

Issue Date FY: 2022 ( Subtotal = $445,000 )
2022	2022	DANA-FARBER CANCER INSTITUTE, INC.	450 BROOKLINE AVE	BOSTON	MA	02115	SUFFOLK	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	1	3/22/2022	NEW	$445,000
														Subtotal = $445,000

Grand Total All Awards = $1,335,000

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Engineering dendritic cells to target islet antigen to pro-tolerogenic subsets for prevention and treatment of Type 1 Diabetes

Award Number: R01DK132544

ORGANIZATION: NATIONAL INSTITUTE OF DIABETES & DIGESTIVE & KIDNEY DISEASES

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

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