In our first-in-human phase I studies, ex vivo expanded regulatory T cell (Tregs) transfer reduced but did not eliminate graft-versus-host disease (GVHD). Tregs were not designed to function alone but to cooperate with supporting innate immune cells to function. We hypothesized that myeloid-derived suppressor cells (MDSCs), were the missing cell type required for optimal Treg suppression. Amongst their suppressive mechanisms MDSCs locally deplete essential amino acids placing highly proliferative GVHD-causing T cells under metabolic stress. We showed that IL-13 cultured MDSCs upregulate arginase I, causing in vivo depletion of the essential amino acid, L-arginine. MDSCs cultured with IFNg upregulate indoleamine 2,3-dioxygenase (IDO), which both can augment Treg function and deplete the essential amino acid tryptophan. Due to the relative resistance of Tregs vs Teffectors to amino acid starvation, Tregs would be favored over Teffector cells. We have uncovered that neither MDSC subset alone is completely effective in preventing GVHD. We now attribute these findings to the new observation that MDSCs lose their suppressive capacity upon activation of the inflammasome; a molecular machine that activates proinflammatory cytokine proteolytic processing. Since MDSCs are immature myeloid cells, we propose progression of GVHD injury drives MDSCs into differentiated myeloid cells that lose their suppressor potency. We hypothesize Tregs will promote MDSC suppression by inhibiting inflammasome activation and proinflammatory cytokine driven MDSC differentiation. Because ex vivo expanded Tregs can be converted to Teffectors under inflammatory conditions, we propose that MDSC suppression of inflammation will support Treg function and stability.
In aim 1 we will test the hypothesis that Teffector suppression by donor MDSC infusion is subverted by inflammasome activation, resulting in MDSC differentiation and loss of suppression. We will identify the inflammasome components in MDSC-IL13 and MDSC-IFNg cells and inflammasome inciting stimuli and proinflammatory cytokines driving differentiation of MDSCs into nonsuppressive or allostimulatory cells.
In aim 2, we will test the hypothesis that essential amino acid catabolic enzymes in donor MDSCs drive Teffectors into catastrophic metabolic stress, augmenting the function and stability of adoptively transferred Tregs, and cooperating with Tregs to maximally suppress GVHD. Further we will test the mechanisms of MDSC-mediated Treg function and stability, while inflammation and inflammasome activation in MDSCs is subdued by Tregs. With the optimal MDSC and Treg therapy, we will test whether the graft-versus-leukemia (GVL) can be retained. When complete, we will have developed new therapies to prevent GVHD and maintain GVL.

Public Health Relevance

Our team of experts will develop novel approaches and biological insights into GVHD pathogenesis, MDSC and Treg biology, inflammasome regulation of immune responsiveness, and potential clinical translation. We are focused on harnessing the full power of adoptive suppressor cell therapies for hematopoietic stem cell and solid transplantation and autoimmunity settings. Our studies may lead to ways to control inflammation translatable into the clinic in settings of immune dysregulation.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
5R01HL056067-22
Application #
9388380
Study Section
Cancer Immunopathology and Immunotherapy Study Section (CII)
Program Officer
El Kassar, Nahed
Project Start
1995-08-01
Project End
2018-12-31
Budget Start
2018-01-01
Budget End
2018-12-31
Support Year
22
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
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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
Zanin-Zhorov, Alexandra; Kumari, Sudha; Hippen, Keli L et al. (2017) Human in vitro-induced regulatory T cells display Dlgh1dependent and PKC-? restrained suppressive activity. Sci Rep 7:4258

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