Our focus for years in graft-vs-host disease (GVHD) has been on stopping Teffector (Teff) activation and expansion. We now believe that successful GVHD prevention can never be achieved unless we coordinate and control the fundamental process of gut tissue repair. Tissue repair can be inherently inflammatory. We will test the hypothesis that anti-inflammatory innate lymphoid type 2 cells (ILC2) are capable of tissue repair without inflammation.
Aim 1 will focus on a novel exogenous peri-bone marrow transplant (BMT) (d-10 to +4) IL33 approach initiated prior to total body radiation (TBI)-induced inflammation that primes the environment to support ILC2s (aim 1A). We show that that preconditioning IL33 increases host ILC2s by >100-fold even in TBI treated mice. We test the hypothesis that pre-TBI IL33 given along with early post-BMT IL33 will support infused donor ILC2s (aim 1A). Since ILC2s express arginase-1 and amphiregulin (AREG), we will test the hypothesis that arginase-1 and AREG may cooperate to repair tissues while minimizing immune mediated inflammation (aim 1B). Because 50% of gut regulatory T cells (Tregs) are IL33R+ that can survive TBI, we will test the hypothesis that host Tregs work in concert with ILC2s to contribute to the tissue reparative and anti-GVHD effects of IL33 and infused donor ILC2s (aim 1B). To examine the direct gut reparative effects of IL33 and its immunoregulatory (ILC2s; Tregs) targets, small intestinal organoid cultures will be utilized to test the direct effects of cytokines/proteins that support (IL25) or are produced (IL13; AREG) by ILC2s and Tregs (aim 1B). In clinical studies, circulating donor ILC2 recovery was slow after allo-transplant and ILC recovery affected GVHD development. We show that host gut (lamina propria, LP) ILC2 in conditioned mice are markedly reduced and ILC2 fail to repopulate the LP for ?84 days in allo-BMT recipients.
Aim 2 will determine rate-limiting factors impeding rapid recovery of ILC2s and develop strategies to overcome this deficiency. We will test the hypothesis that donor ILC2 precursors receive inadequate signals due to TBI mediated tuft cell injury creating an IL25 deficiency state. Without IL25, we hypothesize that immature donor ILC2 differentiation and maturation, and infused donor ILC2 longevity is compromised. We will test the hypothesis that endogenous IL25 deficiency can be circumvented by exogenous IL25 administration and that donor ILC2 derived IL13 will promote tuft cell regeneration and IL25 production, reversing the IL25 deficiency state (aim 2A).
In aim 2 B, we will test the hypothesis that ILC2 generation from ILC2 precursors is not supported due to the presence of pro-inflammatory signals (IFNg, IL12/23; retinoic acid) up-regulated during GVHD, which then results in the loss of donor and host ILC2 anti-inflammatory effects (aim 2B). Using uniquely available mice, reagents and small intestinal organoid cultures, our expert team will collaborate to develop new therapies for clinical application and to contribute significantly to our understanding of ILC2 development and function in BMT, organ transplant, allergy and autoimmune diseases.
Our team of experts will develop novel approaches and gain biological insights into immune system control by IL33, ILC2s and Tregs. Our findings will have broad implications for the use of Tregs in controlling adverse immune responses by focusing on translational applications to harness the full power of ILC2s and Tregs for hematopoietic stem cell and solid transplantation as well as autoimmunity settings.
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