Inflammatory bowel diseases (IBDs), including Crohn’s disease (CD) and ulcerative colitis (UC), affect more than
10 million people worldwide with steadily growing prevalence. Unfortunately, current IBD therapeutic approaches
fail to maintain long-term homeostatic immune tolerance. Thus, there remains an unmet clinical need for new
strategies that sustain immune tolerance in IBD. Rationale: Treatment with regulatory T cells (Tregs) is an
attractive strategy to promote immune tolerance in IBD. Among the Treg expansion therapies under
development, low-dose interleukin-2 (IL-2) is exciting because it preferentially targets Tregs with high-affinity
receptor IL-2RA, and it has shown some efficacy in patients with IBD and other diseases. However, IL-2 has a
narrow therapeutic window given that it also expands inflammatory T cells and myeloid cells. Other IL-2
limitations are that its therapeutic effect is restricted to expanding Tregs, and it does not limit Treg instability.
Therefore, identifying factors that synergistically boost Tregs while preventing any undesired action of low-dose
IL-2 on expanding inflammation is of high clinical significance. 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.
Preliminary findings: For this proposal, we began exploring PD1 agonism in human T cells. We found agonizing
PD1 via recombinant human PDL1-Fc and PDL2-Fc promotes de novo human Treg induction and limits Treg
plasticity. 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
combination of low-dose IL-2 with PD1 agonist synergistically promotes human Tregs. Hypothesis: 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. Furthermore, we will investigate if combining low-
dose IL-2, which induces PD1 on T cells, with PDL1/2-Fc will synergistically boost Treg cells while restraining
undesired IL-2-induced inflammation to better treat IBD.
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 immune cells in vitro.
In Aim 2, we will test the translational relevance of PD1 agonist monotherapy and combination therapy with low-
dose IL-2 by
treating translationally relevant humanized models of colitis. In summary, we will explore the
efficacy of a never tested PD1 agonist/low-dose IL-2 combination therapy in IBD.