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.

Public Health Relevance

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.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Method to Extend Research in Time (MERIT) Award (R37)
Project #
5R37AI034495-26
Application #
9517698
Study Section
Cancer Immunopathology and Immunotherapy Study Section (CII)
Program Officer
Nabavi, Nasrin N
Project Start
1993-07-01
Project End
2022-06-30
Budget Start
2018-07-01
Budget End
2019-06-30
Support Year
26
Fiscal Year
2018
Total Cost
Indirect Cost
Name
University of Minnesota Twin Cities
Department
Pediatrics
Type
Schools of Medicine
DUNS #
555917996
City
Minneapolis
State
MN
Country
United States
Zip Code
55455
Li, Yue; Guan, Xiaoqun; Liu, Weiren et al. (2018) Helminth-Induced Production of TGF-? and Suppression of Graft-versus-Host Disease Is Dependent on IL-4 Production by Host Cells. J Immunol 201:2910-2922
Li, Yue; Liu, Weiren; Guan, Xiaqun et al. (2018) STAT6 and Furin Are Successive Triggers for the Production of TGF-? by T Cells. J Immunol 201:2612-2623
Rashidi, Armin; Shanley, Ryan; Holtan, Shernan G et al. (2018) Pretransplant Serum Citrulline Predicts Acute Graft-versus-Host Disease. Biol Blood Marrow Transplant 24:2190-2196
Blazar, Bruce R; MacDonald, Kelli P A; Hill, Geoffrey R (2018) Immune regulatory cell infusion for graft-versus-host disease prevention and therapy. Blood 131:2651-2660
Lu, Yunjie; Gao, Ji; Zhang, Shaopeng et al. (2018) miR-142-3p regulates autophagy by targeting ATG16L1 in thymic-derived regulatory T cell (tTreg). Cell Death Dis 9:290
Amin, Khalid; Yaqoob, Usman; Schultz, Brittney et al. (2018) Amphiregulin in intestinal acute graft-versus-host disease: a possible diagnostic and prognostic aid. Mod Pathol :
Hülsdünker, Jan; Ottmüller, Katja J; Neeff, Hannes P et al. (2018) Neutrophils provide cellular communication between ileum and mesenteric lymph nodes at graft-versus-host disease onset. Blood 131:1858-1869
Fuchs, Anke; Gliwi?ski, Mateusz; Grageda, Nathali et al. (2017) Minimum Information about T Regulatory Cells: A Step toward Reproducibility and Standardization. Front Immunol 8:1844
Kean, Leslie S; Turka, Laurence A; Blazar, Bruce R (2017) Advances in targeting co-inhibitory and co-stimulatory pathways in transplantation settings: the Yin to the Yang of cancer immunotherapy. Immunol Rev 276:192-212
Zeiser, Robert; Blazar, Bruce R (2017) Acute Graft-versus-Host Disease - Biologic Process, Prevention, and Therapy. N Engl J Med 377:2167-2179

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