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.
