Thursday, November 21, 2024 11/21/2024

A mechanistic understanding of B cell and macrophage plasticity in lupus disease activity states

Award Number: U19AI144306
ORGANIZATION: NATIONAL INSTITUTE OF ALLERGY & INFECTIOUS DISEASES
OPDIV: NIH
AWARD CLASS: COOPERATIVE AGREEMENT
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)

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Project Summary/Abstract Systemic lupus erythematosus (SLE) is a devastating autoimmune disease in which autoantibodies to ubiquitous nuclear antigens cause inflammation and tissue damage in multiple organs. The treatment of SLE has improved considerably over the past 30 years, but these advances have relied on existing medications with insufficient efficacy and significant toxicities. Although several new therapeutics are now available, the new drugs are still only modestly effective. It is imperative, therefore, that advances in immunologic knowledge be applied to improve the treatment and quality of life of SLE patients by maintaining them in a remission state. Both B cell activation and myeloid cell activation can drive SLE onset and flare, leading to our focus on these two immune subsets and the period prior to flare in this proposal. Our Autoimmunity Center of Excellence proposal is centered on the hypothesis that an improved understanding of the mechanisms that regulate disease specific immune states that are perturbed during active disease or disease flare will form the basis for appropriate patient stratification and selection for clinical trials and will provide insights into new therapeutic targets. Autoantibody production is central to the pathogenesis of SLE but many questions remain about the origins of the plasma cells that produce them. It is clear that autoantibody production can precede disease onset by many years, and that flares of SLE are often associated with a new wave of plasma cell proliferation. The Principal Project (Dr. Betty Diamond) will address what B cell pathways are associated with the tolerance state during disease quiescence compared with active disease and healthy controls and whether B cell selection, activation or differentiation to plasmablasts are affected during active disease and remission. A crucial tool is a new fluorescent nuclear antigen preparation, developed by the Diamond group that can be used to identify and isolate autoreactive B cells that represent only a small fraction of the total B cell population. One B cell subset of particular interest in SLE is the non-classical ABC (age-associated B cell) subset that expands and produces autoantibodies and cytokines in response to innate stimuli and can activate T cells through antigen presenting functions. The Pilot Project (Dr. Sun Jung Kim) will address how ABCs take up and present antigen and what metabolic state is needed for their T cell activating function. This may suggest strategies to modulate their state to treat active disease or prevent flares. Activated monocytes are found in the blood of patients with SLE flares. The Collaborative Project (Dr. Anne Davidson) will study disease specific monocyte cell states by sampling blood and urine and define those cell states that are present in active disease or increase in frequency prior to disease flares. Our proposal is bolstered by close scientific interactions among the three lead investigators, by the availability of legacy samples from the previous ACE cycle, by collaborations with experts in next generation sequencing methods and data analysis and by a robust clinical infrastructure that will add clinical depth and ensure timely recruitment of patient cohorts that will be shared by all three studies.


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 = $794,260 )
2024	2024	THE FEINSTEIN INSTITUTES FOR MEDICAL RESEARCH	350 COMMUNITY DR	MANHASSET	NY	11030	NASSAU	USA	Allergy and Infectious Diseases Research	002	6	4/25/2024	COMPETING CONTINUATION	$668,635
2024	2024	THE FEINSTEIN INSTITUTES FOR MEDICAL RESEARCH	350 COMMUNITY DR	MANHASSET	NY	11030	NASSAU	USA	Allergy and Infectious Diseases Research	003	6	9/11/2024	COMPETING CONTINUATION	$125,625
2024	2021	FEINSTEIN INSTITUTES FOR MEDICAL RESEARCH, THE	350 COMMUNITY DR	MANHASSET	NY	11030	NASSAU	USA	Allergy and Infectious Diseases Research	000	3	12/28/2023	SUPPLEMENT FOR EXPANSION	$0
2024	2020	FEINSTEIN INSTITUTES FOR MEDICAL RESEARCH, THE	350 COMMUNITY DR	MANHASSET	NY	11030	NASSAU	USA	Allergy and Infectious Diseases Research	001	2	1/26/2024	SUPPLEMENT FOR EXPANSION	$0
														Subtotal = $794,260

Issue Date FY: 2023 ( Subtotal = $639,114 )
2023	2023	FEINSTEIN INSTITUTES FOR MEDICAL RESEARCH, THE	350 COMMUNITY DR	MANHASSET	NY	11030	NASSAU	USA	Allergy and Infectious Diseases Research	001	5	7/3/2023	NON-COMPETING CONTINUATION	$326,632
2023	2023	FEINSTEIN INSTITUTES FOR MEDICAL RESEARCH, THE	350 COMMUNITY DR	MANHASSET	NY	11030	NASSAU	USA	Allergy and Infectious Diseases Research	000	5	6/2/2023	NON-COMPETING CONTINUATION	$312,482
														Subtotal = $639,114

Issue Date FY: 2022 ( Subtotal = $316,209 )
2022	2022	FEINSTEIN INSTITUTES FOR MEDICAL RESEARCH, THE	350 COMMUNITY DR	MANHASSET	NY	11030	NASSAU	USA	Allergy and Infectious Diseases Research	004	4	8/26/2022	NON-COMPETING CONTINUATION	$0
2022	2022	FEINSTEIN INSTITUTES FOR MEDICAL RESEARCH, THE	350 COMMUNITY DR	MANHASSET	NY	11030	NASSAU	USA	Allergy and Infectious Diseases Research	001	4	5/4/2022	NON-COMPETING CONTINUATION	$316,209
2022	2021	FEINSTEIN INSTITUTES FOR MEDICAL RESEARCH, THE	350 COMMUNITY DR	MANHASSET	NY	11030	NASSAU	USA	Allergy and Infectious Diseases Research	000	3	4/18/2022	SUPPLEMENT FOR EXPANSION	$0
2022	2021	FEINSTEIN INSTITUTES FOR MEDICAL RESEARCH, THE	350 COMMUNITY DR	MANHASSET	NY	11030	NASSAU	USA	Allergy and Infectious Diseases Research	003	3	5/20/2022	SUPPLEMENT FOR EXPANSION	$0
2022	2020	FEINSTEIN INSTITUTES FOR MEDICAL RESEARCH, THE	350 COMMUNITY DR	MANHASSET	NY	11030	NASSAU	USA	Allergy and Infectious Diseases Research	002	2	5/20/2022	SUPPLEMENT FOR EXPANSION	$0
														Subtotal = $316,209

Issue Date FY: 2021 ( Subtotal = $1,003,906 )
2021	2021	FEINSTEIN INSTITUTES FOR MEDICAL RESEARCH, THE	350 COMMUNITY DR	MANHASSET	NY	11030	NASSAU	USA	Allergy and Infectious Diseases Research	001	3	5/19/2021	SUPPLEMENT FOR EXPANSION	$684,079
2021	2021	FEINSTEIN INSTITUTES FOR MEDICAL RESEARCH, THE	350 COMMUNITY DR	MANHASSET	NY	11030	NASSAU	USA	Allergy and Infectious Diseases Research	000	3	4/23/2021	NON-COMPETING CONTINUATION	$319,827
														Subtotal = $1,003,906

Issue Date FY: 2020 ( Subtotal = $1,938,641 )
2020	2020	FEINSTEIN INSTITUTE FOR MEDICAL RESEARCH, THE	350 COMMUNITY DR	MANHASSET	NY	11030	NASSAU	USA	Allergy and Infectious Diseases Research	002	2	8/27/2020	SUPPLEMENT FOR EXPANSION	$1,491,907
2020	2020	FEINSTEIN INSTITUTE FOR MEDICAL RESEARCH, THE	350 COMMUNITY DR	MANHASSET	NY	11030	NASSAU	USA	Allergy and Infectious Diseases Research	001	2	5/6/2020	NON-COMPETING CONTINUATION	$446,734
2020	2019	FEINSTEIN INSTITUTE FOR MEDICAL RESEARCH, THE	350 COMMUNITY DR	MANHASSET	NY	11030	NASSAU	USA	Allergy and Infectious Diseases Research	000	1	11/7/2019	NEW	$0
														Subtotal = $1,938,641

Issue Date FY: 2019 ( Subtotal = $541,250 )
2019	2019	FEINSTEIN INSTITUTE FOR MEDICAL RESEARCH, THE	350 COMMUNITY DR	MANHASSET	NY	11030	NASSAU	USA	Allergy and Infectious Diseases Research	000	1	3/29/2019	NEW	$541,250
														Subtotal = $541,250

Grand Total All Awards = $5,233,380

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A mechanistic understanding of B cell and macrophage plasticity in lupus disease activity states

Award Number: U19AI144306

ORGANIZATION: NATIONAL INSTITUTE OF ALLERGY & INFECTIOUS DISEASES

OPDIV: NIH

AWARD CLASS: COOPERATIVE AGREEMENT

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

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