Our long-term goal is to investigate the mechanisms responsible for graft-versus-host disease (GVHD) pathogenesis, which will lead to new approaches designed to inhibit GVHD. Emerging data have indicated that the presence of pro- or anti-inflammatory signals in the local environment control naove T cell differentiation into pathogenic or suppressor cells, respectively, which have a reciprocal relationship. Recent data indicate that there is a cellular regulatory network operating at the tissue level to control the decision and fate of naove T cells. The network is created by the interaction of T cell immunoglobulin, mucin-containing type I membrane glycoproteins (TIM family) present on T cells and S-type lectins (galectins) that recognize TIM carbohydrates present on immune system cells and on a wide range of tissue cells. Tim-3 is expressed on differentiated T effector cells with the highest density on pathogenic Th1 and Th17 cells. Galectin-9 (gal-9) has been identified the ligand for Tim-3, and is upregulated in inflamed tissues. A major function of the Tim-3/gal-9 is to limit immune responses under conditions of tissue inflammation and injury. Conversely, in vivo blockade of Tim- 3/gal-9 interaction increases Th1 cells within inflamed tissues. In contrast to the inhibitory Tim-3 signals on T effectors, gal-9 signals appear to support CD4+25+ regulatory T cell (Treg) generation and function. Our preliminary data indicate that the Tim-3/gal-9 pathway is upregulated in GVHD tissues and on T effector cells. We have found that the Tim-3/gal-9 pathway is a major regulator of GVHD lethality. Surprisingly dichotomous effects of pathway blockade were seen in recipients of unmanipulated vs. Treg-depleted T cell grafts.
Two aims are proposed that will provide insights into GVHD pathogenesis, Treg cell biology, and further elucidate the unique mechanisms by which the Tim-3/gal-9 pathway regulates immune responses.
In aim 1, we will define the Tim-3/gal-9 dependent mechanisms regulating GVHD pathogenesis and severity.
In aim 2, we will devise novel Tim-3/gal-9 based clinically relevant therapeutic approaches to inhibit GVHD early and to augment graft- versus-leukemia later post-BMT.

Public Health Relevance

Our goal is to develop clinically relevant approaches that will facilitate adoptive T cell immunotherapy to treat patients with cancer. The fundamental insights gained from these studies will have broad implications relevant to both cancer therapy and treatment of infectious diseases.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
5R01HL056067-18
Application #
8313904
Study Section
Cancer Immunopathology and Immunotherapy Study Section (CII)
Program Officer
Di Fronzo, Nancy L
Project Start
1995-08-01
Project End
2014-08-31
Budget Start
2012-09-01
Budget End
2014-08-31
Support Year
18
Fiscal Year
2012
Total Cost
$366,487
Indirect Cost
$118,987
Name
University of Minnesota Twin Cities
Department
Pediatrics
Type
Schools of Medicine
DUNS #
555917996
City
Minneapolis
State
MN
Country
United States
Zip Code
55455
Bunting, Mark D; Varelias, Antiopi; Souza-Fonseca-Guimaraes, Fernando et al. (2017) GVHD prevents NK-cell-dependent leukemia and virus-specific innate immunity. Blood 129:630-642
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
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
Dant, Trisha A; Lin, Kaifeng L; Bruce, Danny W et al. (2017) T-cell expression of AhR inhibits the maintenance of pTreg cells in the gastrointestinal tract in acute GVHD. Blood 130:348-359
Ranganathan, Parvathi; Ngankeu, Apollinaire; Zitzer, Nina C et al. (2017) Serum miR-29a Is Upregulated in Acute Graft-versus-Host Disease and Activates Dendritic Cells through TLR Binding. J Immunol 198:2500-2512
Varelias, Antiopi; Ormerod, Kate L; Bunting, Mark D et al. (2017) Acute graft-versus-host disease is regulated by an IL-17-sensitive microbiome. Blood 129:2172-2185
Zhang, Ping; Lee, Jason S; Gartlan, Kate H et al. (2017) Eomesodermin promotes the development of type 1 regulatory T (TR1) cells. Sci Immunol 2:
Kamphorst, Alice O; Wieland, Andreas; Nasti, Tahseen et al. (2017) Rescue of exhausted CD8 T cells by PD-1-targeted therapies is CD28-dependent. Science 355:1423-1427
Bachanova, Veronika; Sarhan, Dhifaf; DeFor, Todd E et al. (2017) Haploidentical natural killer cells induce remissions in non-Hodgkin lymphoma patients with low levels of immune-suppressor cells. Cancer Immunol Immunother :
Koehn, Brent H; Blazar, Bruce R (2017) Role of myeloid-derived suppressor cells in allogeneic hematopoietic cell transplantation. J Leukoc Biol 102:335-341

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