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)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Project (R01)
Project #
5R01AI034495-21
Application #
8471036
Study Section
Cancer Immunopathology and Immunotherapy Study Section (CII)
Program Officer
Nabavi, Nasrin N
Project Start
1993-07-01
Project End
2017-06-30
Budget Start
2013-07-01
Budget End
2014-06-30
Support Year
21
Fiscal Year
2013
Total Cost
$361,942
Indirect Cost
$119,398
Name
University of Minnesota Twin Cities
Department
Pediatrics
Type
Schools of Medicine
DUNS #
555917996
City
Minneapolis
State
MN
Country
United States
Zip Code
55455
Kaliyaperumal, Saravanan; Watkins, Benjamin; Sharma, Prachi et al. (2014) CD8-predominant T-cell CNS infiltration accompanies GVHD in primates and is improved with immunoprophylaxis. Blood 123:1967-9
Rogosheske, J R; Fargen, A D; DeFor, T E et al. (2014) Higher therapeutic CsA levels early post transplantation reduce risk of acute GVHD and improves survival. Bone Marrow Transplant 49:122-5
Lin, Kaifeng Lisa; Fulton, LeShara M; Berginski, Matthew et al. (2014) Intravital imaging of donor allogeneic effector and regulatory T cells with host dendritic cells during GVHD. Blood 123:1604-14
MacDonald, Kelli P A; Le Texier, Laetitia; Zhang, Ping et al. (2014) Modification of T cell responses by stem cell mobilization requires direct signaling of the T cell by G-CSF and IL-10. J Immunol 192:3180-9
Ganguly, Sudipto; Ross, Duncan B; Panoskaltsis-Mortari, Angela et al. (2014) Donor CD4+ Foxp3+ regulatory T cells are necessary for posttransplantation cyclophosphamide-mediated protection against GVHD in mice. Blood 124:2131-41
Jacobson, Caron A; Sun, Lixian; Kim, Haesook T et al. (2014) Post-transplantation B cell activating factor and B cell recovery before onset of chronic graft-versus-host disease. Biol Blood Marrow Transplant 20:668-75
Sawitzki, Birgit; Brunstein, Claudio; Meisel, Christian et al. (2014) Prevention of graft-versus-host disease by adoptive T regulatory therapy is associated with active repression of peripheral blood Toll-like receptor 5 mRNA expression. Biol Blood Marrow Transplant 20:173-82
Dubovsky, Jason A; Flynn, Ryan; Du, Jing et al. (2014) Ibrutinib treatment ameliorates murine chronic graft-versus-host disease. J Clin Invest 124:4867-76
Karras, Nicole A; Weeres, Matthew; Sessions, Wendy et al. (2013) A randomized trial of one versus two doses of influenza vaccine after allogeneic transplantation. Biol Blood Marrow Transplant 19:109-16
Saha, Asim; Aoyama, Kazutoshi; Taylor, Patricia A et al. (2013) Host programmed death ligand 1 is dominant over programmed death ligand 2 expression in regulating graft-versus-host disease lethality. Blood 122:3062-73

Showing the most recent 10 out of 133 publications