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Specificity, Phenotype and Function of Pancreatic CD8 T Cells in Human Type 1 Diabetes

Award Number: R01AI092453
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: 04/01/2024
PERIOD OF PERFORMANCE END DATE: 03/31/2029

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Specificity, Phenotype and Function of Pancreatic CD8 T Cells in Human Type 1 Diabetes - Title: Specificity, Phenotype and Function of Pancreatic CD8 T Cells in Human Type 1 Diabetes Project Summary Human type 1 diabetes (T1D) is characterized by the immune-mediated destruction of insulin-producing pan- creatic beta cells. CD8 T cells are the most common cell found in insulitis lesions and are the principal T cell type implicated in beta cell destruction. Insulin and its precursors have been identified as key autoantigens in humans and mice due to their local abundance. The previous funding cycles for this grant have enabled us to lead the field of human islet cell investigation in T1D. Using samples from the national pancreatic organ donor consortium (nPOD) we have detected, precisely quantified, and identified the exact location of autoreactive pre-proinsulin (PPI) specific CD8 lymphocytes within the pancreata of human donors. Studies performed within this project have already revealed significant and novel findings. We first identified auto-reactive CD8 T cells in the islets of patients with T1D using a specially designed method of tetramer staining. We found that their frequency is high and likely the most predominant autoreactive cell type (1), a finding which has been inde- pendently confirmed with other methods by Nakayama et al. (2). More recently (3) we defined the precise location of these cells within a pseudo-timeline of disease development and concluded that PPI cytotoxic T lymphocytes (CTL) are already present in healthy pancreata and appear to become 'attracted' to islets during the development of T1D. This seminal observation indicates that the islets appear to expose themselves to immune recognition, and thus become a key culprit in driving T1D development. A new key development of this grant is the Orion (Rarecyte) technology that allows for highly multiplexed studies in whole tissue sec- tions, combined with state-of-the-art analysis software. The study of the whole section and multiple targets simultaneously allows to define the islet/immune interface and the communication between PPI CTL and other immune cells more precisely and with a much reduced number of samples. The present proposal will define the precise location and function of these interactions, and corroborate these findings in highly innova- tive human islet microtissues and living donor pancreatic tissue slices using dynamic in vitro models. Finally, this proposal will decipher mechanistically how some aspects of the islet immune interface can be reset/restored by the action of GLP1 agonists, building on our recent work which has shown that this drug class can maintain beta cell function (glucose-induced insulin secretion) in vitro and in vivo during the devel- opment of T1D (4). Overall, our findings should give us an unprecedented and unique understanding of how and why T1D develops, and provide mechanistic information using our novel in vitro systems, thus ultimately aiding the development of new therapeutic options.


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 = $0 )
2025	2024	UNIVERSITY OF MIAMI	1320 S DIXIE HWY STE 1200	CORAL GABLES	FL	33146	MIAMI-DADE	USA	Allergy and Infectious Diseases Research	001	12	1/23/2025	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	$329,555
2025	2024	UNIVERSITY OF MIAMI	1320 S DIXIE HWY STE 1200	CORAL GABLES	FL	33146	MIAMI-DADE	USA	Allergy and Infectious Diseases Research	002	12	5/20/2025	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	$0
2025	2023	LA JOLLA INSTITUTE FOR IMMUNOLOGY	9420 ATHENA CIR	LA JOLLA	CA	92037	SAN DIEGO	USA	Allergy and Infectious Diseases Research	000	11	1/23/2025	COMPETING CONTINUATION	-$329,555
														Subtotal = $0

Issue Date FY: 2024 ( Subtotal = $460,500 )
2024	2024	UNIVERSITY OF MIAMI	1320 S DIXIE HWY STE 1200	CORAL GABLES	FL	33146	MIAMI-DADE	USA	Allergy and Infectious Diseases Research	001	12	3/18/2024	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	$460,500
2024	2023	LA JOLLA INSTITUTE FOR IMMUNOLOGY	9420 ATHENA CIR	LA JOLLA	CA	92037	SAN DIEGO	USA	Allergy and Infectious Diseases Research	000	11	3/15/2024	COMPETING CONTINUATION	$0
														Subtotal = $460,500

Issue Date FY: 2023 ( Subtotal = $549,000 )
2023	2023	LA JOLLA INSTITUTE FOR IMMUNOLOGY	9420 ATHENA CIR	LA JOLLA	CA	92037	SAN DIEGO	USA	Allergy and Infectious Diseases Research	001	11	4/10/2023	COMPETING CONTINUATION	$549,000
2023	2021	LA JOLLA INSTITUTE FOR IMMUNOLOGY	9420 ATHENA CIR	LA JOLLA	CA	92037	SAN DIEGO	USA	Allergy and Infectious Diseases Research	000	10	3/23/2023	NON-COMPETING CONTINUATION	$0
														Subtotal = $549,000

Issue Date FY: 2021 ( Subtotal = $450,000 )
2021	2021	LA JOLLA INSTITUTE FOR IMMUNOLOGY	9420 ATHENA CIR	LA JOLLA	CA	92037	SAN DIEGO	USA	Allergy and Infectious Diseases Research	000	10	11/17/2020	NON-COMPETING CONTINUATION	$450,000
														Subtotal = $450,000

Issue Date FY: 2020 ( Subtotal = $450,000 )
2020	2020	LA JOLLA INSTITUTE FOR ALLERGY AND IMMUNOLOGY	9420 ATHENA CIR	LA JOLLA	CA	92037	SAN DIEGO	USA	Allergy and Infectious Diseases Research	000	9	11/22/2019	NON-COMPETING CONTINUATION	$450,000
														Subtotal = $450,000

Issue Date FY: 2019 ( Subtotal = $450,000 )
2019	2019	LA JOLLA INSTITUTE FOR ALLERGY AND IMMUNOLOGY	9420 ATHENA CIR	LA JOLLA	CA	92037	SAN DIEGO	USA	Allergy and Infectious Diseases Research	000	8	11/22/2018	NON-COMPETING CONTINUATION	$450,000
														Subtotal = $450,000

Issue Date FY: 2018 ( Subtotal = $450,000 )
2018	2018	LA JOLLA INSTITUTE FOR ALLERGY AND IMMUNOLOGY	9420 ATHENA CIR	LA JOLLA	CA	92037	SAN DIEGO	USA	Allergy and Infectious Diseases Research	000	7	11/20/2017	NON-COMPETING CONTINUATION	$450,000
														Subtotal = $450,000

Issue Date FY: 2017 ( Subtotal = $450,000 )
2017	2017	LA JOLLA INSTITUTE FOR ALLERGY AND IMMUNOLOGY	9420 ATHENA CIR	LA JOLLA	CA	92037	SAN DIEGO	USA	Allergy and Infectious Diseases Research	001	6	12/14/2016	COMPETING CONTINUATION	$450,000
2017	2015	LA JOLLA INSTITUTE FOR ALLERGY AND IMMUNOLOGY	9420 ATHENA CIR	LA JOLLA	CA	92037	SAN DIEGO	USA	Allergy and Infectious Diseases Research	002	5	4/13/2017	NON-COMPETING CONTINUATION	$0
2017	2015	LA JOLLA INSTITUTE FOR ALLERGY AND IMMUNOLOGY	9420 ATHENA CIR	LA JOLLA	CA	92037	SAN DIEGO	USA	Allergy and Infectious Diseases Research	000	5	12/8/2016	NON-COMPETING CONTINUATION	$0
														Subtotal = $450,000

Issue Date FY: 2015 ( Subtotal = $401,400 )
2015	2015	LA JOLLA INSTITUTE FOR ALLERGY & IMMUNOLOGY	10355 SCIENCE CENTER DRIVE	SAN DIEGO	CA	92121	SAN DIEGO	USA	Allergy and Infectious Diseases Research	000	5	4/15/2015	NON-COMPETING CONTINUATION	$401,400
														Subtotal = $401,400

Issue Date FY: 2014 ( Subtotal = $401,400 )
2014	2014	LA JOLLA INSTITUTE FOR ALLERGY & IMMUNOLOGY	10355 SCIENCE CENTER DRIVE	SAN DIEGO	CA	92121	SAN DIEGO	USA	Allergy and Infectious Diseases Research	000	4	3/27/2014	NON-COMPETING CONTINUATION	$401,400
														Subtotal = $401,400

Issue Date FY: 2013 ( Subtotal = $377,316 )
2013	2013	LA JOLLA INSTITUTE FOR ALLERGY & IMMUNOLOGY	10355 SCIENCE CENTER DRIVE	SAN DIEGO	CA	92121	SAN DIEGO	USA	Allergy and Infectious Diseases Research	000	3	4/24/2013	NON-COMPETING CONTINUATION	$377,316
														Subtotal = $377,316

Issue Date FY: 2012 ( Subtotal = $401,400 )
2012	2012	LA JOLLA INSTITUTE FOR ALLERGY & IMMUNOLOGY	10355 SCIENCE CENTER DRIVE	SAN DIEGO	CA	92121	SAN DIEGO	USA	Allergy and Infectious Diseases Research	000	2	3/30/2012	NON-COMPETING CONTINUATION	$401,400
														Subtotal = $401,400

Issue Date FY: 2011 ( Subtotal = $401,400 )
2011	2011	LA JOLLA INSTITUTE FOR ALLERGY & IMMUNOLOGY	10355 SCIENCE CENTER DRIVE	SAN DIEGO	CA	92121	SAN DIEGO	USA	Allergy and Infectious Diseases Research	000	1	5/2/2011	NEW	$401,400
														Subtotal = $401,400

Grand Total All Awards = $5,242,416

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Specificity, Phenotype and Function of Pancreatic CD8 T Cells in Human Type 1 Diabetes

Award Number: R01AI092453

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: 04/01/2024

PERIOD OF PERFORMANCE END DATE: 03/31/2029

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