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Plasma-induced signatures as a measure disease heterogeneity and immunomodulation in T1D clinical trials

Award Number: R01DK121528
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/ABSTRACT A better understanding of Type 1 diabetes (T1D) pathogenesis has enabled development of immunomodulatory strategies aimed at inducing clinical remission. While much has been learned, the positive effects observed in these trials have generally been of limited duration and patient responses have been mixed. It has been suggested that this outcome has stemmed from an incomplete understanding of the complexity and heterogeneity of T1D pathogenesis. New measures of immune activity are needed to define patient heterogeneity and identify mechanisms that could enable selection of targeted, personalized therapies; monitor changes in the immune state associated with responses to treatment, and serve as surrogate outcomes to shorten the duration of clinical trials. To fill this gap we have employed an array-based bioassay, where subject serum/plasma is used to induce transcriptional responses in a well-controlled peripheral blood mononuclear cell population. We find that pre and new onset T1D plasma induces a disease-specific, partially interleukin (IL)-1 dependent signature relative to related and unrelated healthy controls. We have used this approach to study participants of the IL- 1 antagonism trials and the TrialNet CTLA4-Ig trial. Our analyses revealed that varying levels of the anticipated immunomodulation was achieved with these immunotherapies. Notably, plasma induced transcription defined T1D subgroups, where those with the highest inflammatory bias prior to treatment, experienced the greatest post-onset decline in stimulated C-peptide area under the curve and the greatest therapeutic response. Overall, our data support the hypothesis that heterogeneity in inflammatory and regulatory activity at clinical onset can be used to stratify T1D patients into subgroups that differ in disease progression rate and responsiveness to immune intervention. We propose the following Specific Aims: Aim 1: To test the hypothesis that plasma induced signatures measured at baseline define ROT1D subgroups that predict the rate of post-onset C-peptide decline and therapeutic responsiveness. Aim 2: To test the hypothesis that T1D subgroups defined by plasma induced transcription exhibit distinct immunological phenotypes.


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: 2023 ( Subtotal = $298,171 )
2023	2023	MEDICAL COLLEGE OF WISCONSIN, INC., THE	8701 WATERTOWN PLANK RD	MILWAUKEE	WI	53226	MILWAUKEE	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	4	1/13/2023	NON-COMPETING CONTINUATION	$298,171
														Subtotal = $298,171

Issue Date FY: 2022 ( Subtotal = $527,385 )
2022	2022	MEDICAL COLLEGE OF WISCONSIN, INC., THE	8701 WATERTOWN PLANK RD	MILWAUKEE	WI	53226	MILWAUKEE	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	001	3	3/24/2022	NON-COMPETING CONTINUATION	$52,738
2022	2022	MEDICAL COLLEGE OF WISCONSIN, INC., THE	8701 WATERTOWN PLANK RD	MILWAUKEE	WI	53226	MILWAUKEE	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	3	11/17/2021	NON-COMPETING CONTINUATION	$474,647
														Subtotal = $527,385

Issue Date FY: 2021 ( Subtotal = $520,498 )
2021	2021	MEDICAL COLLEGE OF WISCONSIN, INC., THE	8701 WATERTOWN PLANK RD	MILWAUKEE	WI	53226	MILWAUKEE	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	003	2	2/8/2021	NON-COMPETING CONTINUATION	$52,738
2021	2021	MEDICAL COLLEGE OF WISCONSIN, INC., THE	8701 WATERTOWN PLANK RD	MILWAUKEE	WI	53226	MILWAUKEE	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	002	2	12/24/2020	NON-COMPETING CONTINUATION	-$6,245
2021	2021	MEDICAL COLLEGE OF WISCONSIN, INC., THE	8701 WATERTOWN PLANK RD	MILWAUKEE	WI	53226	MILWAUKEE	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	2	12/17/2020	NON-COMPETING CONTINUATION	$480,892
2021	2020	MEDICAL COLLEGE OF WISCONSIN, INC., THE	8701 WATERTOWN PLANK RD	MILWAUKEE	WI	53226	MILWAUKEE	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	001	1	12/24/2020	NEW	-$6,887
														Subtotal = $520,498

Issue Date FY: 2020 ( Subtotal = $530,305 )
2020	2020	MEDICAL COLLEGE OF WISCONSIN, INC., THE	8701 WATERTOWN PLANK RD	MILWAUKEE	WI	53226	MILWAUKEE	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	1	2/20/2020	NEW	$530,305
														Subtotal = $530,305

Grand Total All Awards = $1,876,359

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Plasma-induced signatures as a measure disease heterogeneity and immunomodulation in T1D clinical trials

Award Number: R01DK121528

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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