# Development of novel PD1 agonist therapeutic strategies for multiple sclerosis > **NIH NIH R21** · BRIGHAM AND WOMEN'S HOSPITAL · 2024 · $218,220 ## Abstract Project Summary/Abstract Current multiple sclerosis (MS) therapeutic approaches are insufficient to maintain long-term immune homeostasis and effectively recalibrate T helper cell imbalances in patients. There remains an unmet clinical need for new strategies that restore and sustain immune tolerance in MS. PD1 signaling plays a critical role in the maintenance of immune tolerance . Altered PDL1/PD1 expression, and/or blockade of PD1 signaling, results in the breakdown of immune tolerance and predisposes mice and humans to the development of autoimmunity and tissue inflammation. For example, blockade of PD1 and its ligands can exacerbate EAE, a mouse model of MS. In fact, we recently found that Smad7, a major molecule implicated in autoimmunity, sustains intestinal and CNS inflammation in mice by limiting PD1 in T cells and PD1 ligands in DCs, thereby dampening PD1-induced Tregs. Given the critical role of PD1 signaling in limiting tissue inflammation and autoimmunity, PD1 could represent a therapeutic target of high clinical interest in MS. However, the impact of enhancing PD1 signaling for therapeutic benefit in EAE and MS has never been tested. For this proposal, we began exploring PD1 agonists in human T cells. We found agonizing PD1 via immunoglobulin fusion proteins PDL1-Fc or PDL2-Fc promotes de novo human Treg induction and limits Treg plasticity. Interestingly, we also found that agonizing PD1 within myeloid cells inhibits inflammatory cytokines that are known to promote Th1/17 development and destabilize Tregs in MS and EAE. Therefore, we will test our hypothesis that PD1 agonist monotherapy could effectively restore immune tolerance by directly enhancing Treg homeostasis while quenching effector T cell responses in EAE and MS. Based on our exciting preliminary finding that IL-2 directly induces PD1 in CD4+ T cells and that combining low-dose IL-2 with PD1 agonists synergistically boosts human Treg induction, we will also investigate if combining low-dose IL-2 with PDL1/2-Fc will synergistically boost MS patient Treg responses. Because IL-2 can still promote effector T cell responses, combining PD1 agonist with low-dose IL-2 may also restrain any undesired direct effect of low-dose IL-2 on boosting effector T cells. In addition, PD1 agonist might further complement low-dose IL-2 by targeting other important cell types unaffected by IL-2 (e.g. myeloid cells). In Aim 1, we will test the translational relevance of PD1 agonism monotherapy by treating MS patient immune cells in vitro, and by treating humanized PD1 knock- in mice with EAE in vivo. In Aim 2, we will test PDL1/2-Fc and low-dose IL-2 combination therapy by treating MS patient immune cells in vitro, and by treating humanized PD1/IL-2 receptor alpha (RA) double knock-in mice with EAE in vivo, including single-cell RNA sequencing of immune responses in treated mice. In summary, we will explore the efficacy of a never tested PD1 agonist/low-dose IL-2 combination therapy strategy in ... ## Key facts - **NIH application ID:** 10758559 - **Project number:** 5R21AI174047-02 - **Recipient organization:** BRIGHAM AND WOMEN'S HOSPITAL - **Principal Investigator:** Murugaiyan Gopal - **Activity code:** R21 (R01, R21, SBIR, etc.) - **Funding institute:** NIH - **Fiscal year:** 2024 - **Award amount:** $218,220 - **Award type:** 5 - **Project period:** 2023-01-01 → 2024-12-31 ## Primary source NIH RePORTER: https://reporter.nih.gov/project-details/10758559 ## Citation > US National Institutes of Health, RePORTER application 10758559, Development of novel PD1 agonist therapeutic strategies for multiple sclerosis (5R21AI174047-02). Retrieved via AI Analytics 2026-05-26 from https://api.ai-analytics.org/grant/nih/10758559. Licensed CC0. --- *[NIH grants dataset](/datasets/nih-grants) · CC0 1.0*