Graft-versus-host disease (GVHD) is a substantial cause of mortality. We hypothesize that conditioning injury creates a pro-inflammatory environment that recruits Teffector cells (Teffs) to the gut, essential for GVHD. Our studies point to the vitamin A metabolite, all-trans-retinoic acid (RA), as a key component of acute GVHD lethality. We have identified critical vitamin A metabolizing enzymes that lead to RA production as markedly up-regulated in the gut and uncovered a fundamental insight that donor T cells sense excessively high RA levels early post-transplant. We show that donor T cells expressing a dominant-negative RAR-alpha (dnRAR?) transgene have markedly impaired GVHD lethality, providing the previously unrecognized cause-and-effect evidence for RA signaling in acute GVHD. Our goal is to determine the best drug approach to block RA production and response. RA signaling occurs via distinct RAR isoforms (?, ?, ?). Because dnRAR? can sequester its dimeric RXR partners, these data do not prove that targeting RAR? alone was responsible for the striking benefits of GVHD inhibition. This is critical since we now show that RAR? and ? have distinct functions on in vitro RA induced T cell gut homing receptor expression. Although the RA pathway is highly druggable, no one knows the appropriate RA pathway target. We will solve this dilemma, which will result in the testing of a new class of drugs to restore RAR signaling to homeostatic levels. RA also has anti-inflammatory properties by acting on immune suppressive Tregulatory cells (Tregs). We need to minimize Treg impact. We have shown RA promotes Treg generation, stability and gut homing. An efficient way to expose Tregs to RA in vitro prior to infusion, "imprinting" Tregs to acquire these desirable properties before transfer. This would favor Tregs over Teffs even in the presence of drugs that inhibit RA production or signaling in vivo. If positive, we have 2 clinical GVHD trials using ex vivo expanded natural and inducible Tregs that could immediately benefit from this strategy. We will test the hypotheses that:
Aim 1. High in vivo levels of key vitamin A metabolizing enzymes and RA augment GVHD, whereas in vitro RA exposure augments Treg mediated GVHD suppression regardless of RA signaling in vivo. Hypotheses. We will test the hypothesis that deletion of vitamin A metabolizing enzymes in lineage-specific cell types reduces GVHD, providing insights as to how RA production in situ causes GVHD (1A). We will test the hypothesis that in vitro RA increases Treg generation, stability and gut homing, leading to reduced gut injury and GVHD that can occur in the absence of in vivo RA signaling (1B);
Aim 2. RAR isoforms differentially regulate GVHD in vivo. Hypothesis. We will test the hypotheses that RAR isoforms are differentially expressed and have unique functions in donor Teffs, donor Tregs and antigen-presenting cells (2A) and dnRAR? T cells have reduced Teff differentiation, homing and survival (2B). Lastly, we will determine whether our preferred GVHD approach(es) affect graft-versus-leukemia (GVL) responses. When done, we will have developed new therapies to prevent GVHD and maintain GVL.

Public Health Relevance

Guided by our target identification and mechanistic studies, our team will gain new insights into the retinoic acid pathway in graft-vs-host disease (GVHD) and develop new drug-based therapies to prevent GVHD and maintain anti-leukemia effects, which can be rapidly moved into the clinic, as we propose for in vitro RA exposure and our Treg trials. Our findings have broad implications for autoimmunity, organ transplant, tumor immunity and regulatory T cell applications.

Agency
National Institute of Health (NIH)
Type
Research Project (R01)
Project #
5R01AI034495-22
Application #
8688871
Study Section
Cancer Immunopathology and Immunotherapy Study Section (CII)
Program Officer
Nabavi, Nasrin N
Project Start
Project End
Budget Start
Budget End
Support Year
22
Fiscal Year
2014
Total Cost
Indirect Cost
Name
University of Minnesota Twin Cities
Department
Pediatrics
Type
Schools of Medicine
DUNS #
City
Minneapolis
State
MN
Country
United States
Zip Code
55455
Borges, Christopher M; Reichenbach, Dawn K; Kim, Beom Seok et al. (2016) Regulatory T cell expressed MyD88 is critical for prolongation of allograft survival. Transpl Int 29:930-40
Schönle, Anne; Hartl, Frederike A; Mentzel, Jan et al. (2016) Caveolin-1 regulates TCR signal strength and regulatory T-cell differentiation into alloreactive T cells. Blood 127:1930-9
Zeiser, Robert; Blazar, Bruce R (2016) Preclinical models of acute and chronic graft-versus-host disease: how predictive are they for a successful clinical translation? Blood 127:3117-26
Lu, Yunjie; Hippen, Keli L; Lemire, Amanda L et al. (2016) miR-146b antagomir-treated human Tregs acquire increased GVHD inhibitory potency. Blood 128:1424-35
Li, Wei; Liu, Liangyi; Gomez, Aurelie et al. (2016) Proteomics analysis reveals a Th17-prone cell population in presymptomatic graft-versus-host disease. JCI Insight 1:
Matta, B M; Reichenbach, D K; Blazar, B R et al. (2016) Alarmins and Their Receptors as Modulators and Indicators of Alloimmune Responses. Am J Transplant :
Mochizuki, Kazuhiro; Meng, Lijun; Mochizuki, Izumi et al. (2016) Programming of donor T cells using allogeneic δ-like ligand 4-positive dendritic cells to reduce GVHD in mice. Blood 127:3270-80
Sarhan, Dhifaf; Cichocki, Frank; Zhang, Bin et al. (2016) Adaptive NK Cells with Low TIGIT Expression Are Inherently Resistant to Myeloid-Derived Suppressor Cells. Cancer Res 76:5696-5706
Saha, Asim; O'Connor, Roddy S; Thangavelu, Govindarajan et al. (2016) Programmed death ligand-1 expression on donor T cells drives graft-versus-host disease lethality. J Clin Invest 126:2642-60
Matta, Benjamin M; Reichenbach, Dawn K; Zhang, Xiaoli et al. (2016) Peri-alloHCT IL-33 administration expands recipient T-regulatory cells that protect mice against acute GVHD. Blood 128:427-39

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