Development of novel PD1 agonist therapeutic strategies for inflammatory bowel disease - Project Summary/Abstract Current inflammatory bowel disease (IBD) 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 sustain immune tolerance in IBD. The programmed death 1 (PD1) pathway has emerged as a critical inhibitory signal which controls T cell responses and maintains immune homeostasis. Altered PD1 signaling can predispose mice and humans to autoimmunity. For example, PD1 blockade can cause colitis in mice and humans. Recently, we identified that Smad7, a major molecule implicated in IBD, sustains intestinal inflammation in mice by limiting PD1 signaling, thereby dampening PD1-induced Tregs. Given the critical role of PD1 in limiting tissue inflammation, PD1 represents a therapeutic target of high clinical interest. We found that enhancing PD1 signaling via recombinant human PDL1-Fc or PDL2-Fc (PD1 agonist) promotes de novo human Treg induction and stability. Interestingly, we also found that agonizing PD1 in myeloid cells inhibits inflammatory cytokines that are known to promote Th1 and Th17 development and destabilize Tregs during IBD. In our effort to identify factors that upregulate PD1, we found that IL-2 directly induces PD1 on human T cells. Excitingly, we found that a combination of low-dose IL-2 with PD1 agonist synergistically promotes human Tregs. Based on these findings, we will test our hypothesis that PD1 agonist monotherapy could effectively restore immune tolerance by directly enhancing Treg homeostasis while quenching inflammatory T cell and myeloid cell responses. We also hypothesize that combining low-dose IL-2, which induces PD1 on T cells, with PDL1/2-Fc will synergistically boost Treg responses to better treat IBD. Because IL-2 can expand inflammatory T cell and myeloid cell responses, combining PD1 agonist with low-dose IL-2 may also restrain this undesired IL-2-induced inflammation. This is particularly exciting, since low-dose IL-2 for Treg induction has shown some efficacy in currently advancing clinical trials in IBD and other contexts, and strategies to improve low-dose IL 2 therapy are being actively pursued. In Aim 1, we will test the translational relevance of PD1 agonist monotherapy and combination therapy with low-dose IL-2 by treating IBD patient T cells in vitro and T helper cell-specific PD1- deficient (KO) mice with colitis. In Aim 2, we will test the translational relevance of PD1 agonist monotherapy and combination therapy with low-dose IL-2 by treating IBD patient myeloid cells in vitro and myeloid cell-specific PD1-deficient (KO) mice with colitis. In Aim 3, we will test the translational relevance of PD1 agonist monotherapy and combination therapy with low-dose IL-2 by treating translationally relevant humanized mice with colitis. In summary, we will explore the efficacy of a never tested PD1 agonist/low-dose IL-2 combination therapy strategy in IBD to address unanswered questions around how PD1 agonism promotes human immune tolerance, the translational potential of PD1 agonist therapeutic strategies, and how to implement them in IBD.
