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Defining the induction and maintenance of myelin-specific tolerance in T cells and B cells using local lymph node depots

Award Number: R01AI169686
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: 02/01/2022
PERIOD OF PERFORMANCE END DATE: 01/31/2027

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Defining the induction and maintenance of myelin-specific tolerance in T cells and B cells using local lymph node depots - PROJECT SUMMARY: During autoimmunity, the body incorrectly identifies “self” molecules as foreign. In multiple sclerosis (MS) attack of myelin in the central nervous system (CNS) leads to neurodegeneration. Existing therapies for MS range from immunosuppressants to newer monoclonal antibodies, but even the latter do not distinguish between healthy and self-reactive cells displaying the antibody target. Thus, while beneficial, existing therapies are not curative, cause immunocompromising side effects, and require life-long compliance. These limitations have motivated efforts to control autoimmunity with vaccine-like specificity, leaving the rest of the immune system intact. One such antigen-specific tolerance strategy being studied pre-clinically and in human trials is co-delivery of myelin peptide and tolerizing immune signals to promote populations, such as regulatory T cells (TREG) that combat MS. The polarization of T cells into inflammatory T cells (e.g., TH17) or TREG is localized to lymph nodes (LNs), tissues that coordinate immunity. New studies also reveal TREG can adopt memory functions to maintain tolerance. Further, in appropriate tissue niches, inflammatory TH17 cells can transdifferentiate to TREG. Likewise, B cells are relevant to MS in several ways, including producing pathogenic myelin-specific antibodies, and as therapeutic targets able to adopt regulatory function. LNs play key roles in these processes, directing dynamic stromal organization to promote and regulate cell interaction and modulatory cues that control T and B cell polarization between (auto)inflammatory and tolerance functions. From a therapeutic view, controlling this niche is challenging using conventional delivery technologies (e.g., systemic injections/infusions), and even biomaterial approaches such as targeted nanoparticles face difficulty establishing durable tissue environments after injection. However, the ability to understand and control the integration of signals in the LN microenvironment could enable potent, myelin-specific immunotherapies that avoid immunosuppression. We propose tackling this goal using a platform that combines direct intra-LN (i.LN.) injection with controlled release biomaterial depots. We have shown diffusion-restricted polymer depots that are too large to drain from LNs after injection concentrate and retain depot-loaded cargo in LNs. Using depots loaded with myelin peptide and rapamycin - an immunoregulatory drug, we have shown a single treatment at the peak of disease in a pre-clinical model of MS reverses paralysis for over 90 days. Efficacy is not achieved with i.LN. injection of soluble cargo, or during injection of depots via traditional routes. We will use this interdisciplinary immune engineering approach to understand how local controlled release promotes a tolerogenic stromal LN environment and how these effects induce and maintain long-lasting tolerizing function against myelin in T and B cells. The aims are 1) Define the robustness of efficacy and the underpinning therapeutic effects on neuroinflammation, 2) Show the durability of tolerance is antigen-dependent and driven by TREG maintenance & plasticity, 3) Show i.LN. depots disrupt germinal centers, reduce auto-antibodies, & induce tolerogenic B cells.


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: 2026 ( Subtotal = $554,697 )
2026	2026	UNIVERSITY OF MARYLAND, COLLEGE PARK	3112 LEE BUILDING	COLLEGE PARK	MD	20742	PRINCE GEORGES	USA	Allergy and Infectious Diseases Research	000	5	1/23/2026	NON-COMPETING CONTINUATION	$554,697
														Subtotal = $554,697

Issue Date FY: 2025 ( Subtotal = $538,057 )
2025	2025	UNIVERSITY OF MARYLAND, COLLEGE PARK	3112 LEE BUILDING	COLLEGE PARK	MD	20742	PRINCE GEORGES	USA	Allergy and Infectious Diseases Research	000	4	1/21/2025	NON-COMPETING CONTINUATION	$538,057
														Subtotal = $538,057

Issue Date FY: 2024 ( Subtotal = $554,697 )
2024	2024	UNIVERSITY OF MARYLAND, COLLEGE PARK	3112 LEE BUILDING	COLLEGE PARK	MD	20742	PRINCE GEORGES	USA	Allergy and Infectious Diseases Research	000	3	1/23/2024	NON-COMPETING CONTINUATION	$499,228
2024	2024	UNIVERSITY OF MARYLAND, COLLEGE PARK	3112 LEE BUILDING	COLLEGE PARK	MD	20742	PRINCE GEORGES	USA	Allergy and Infectious Diseases Research	001	3	5/24/2024	NON-COMPETING CONTINUATION	$55,469
														Subtotal = $554,697

Issue Date FY: 2023 ( Subtotal = $554,697 )
2023	2023	UNIVERSITY OF MARYLAND, COLLEGE PARK	3112 LEE BLDG 7809 REGENTS DR	COLLEGE PARK	MD	20742	PRINCE GEORGES	USA	Allergy and Infectious Diseases Research	000	2	1/12/2023	NON-COMPETING CONTINUATION	$554,697
														Subtotal = $554,697

Issue Date FY: 2022 ( Subtotal = $568,324 )
2022	2022	UNIVERSITY OF MARYLAND, COLLEGE PARK	3112 LEE BLDG 7809 REGENTS DR	COLLEGE PARK	MD	20742	PRINCE GEORGES	USA	Allergy and Infectious Diseases Research	000	1	1/27/2022	NEW	$568,324
														Subtotal = $568,324

Grand Total All Awards = $2,770,472

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Defining the induction and maintenance of myelin-specific tolerance in T cells and B cells using local lymph node depots

Award Number: R01AI169686

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: 02/01/2022

PERIOD OF PERFORMANCE END DATE: 01/31/2027

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