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.

National Institute of Health (NIH)
National Heart, Lung, and Blood Institute (NHLBI)
Research Project (R01)
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Cancer Immunopathology and Immunotherapy Study Section (CII)
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Di Fronzo, Nancy L
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University of Minnesota Twin Cities
Schools of Medicine
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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
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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
Aoyama, Kazutoshi; Saha, Asim; Tolar, Jakub et al. (2013) Inhibiting retinoic acid signaling ameliorates graft-versus-host disease by modifying T-cell differentiation and intestinal migration. Blood 122:2125-34
Gleason, Michelle K; Lenvik, Todd R; McCullar, Valarie et al. (2012) Tim-3 is an inducible human natural killer cell receptor that enhances interferon gamma production in response to galectin-9. Blood 119:3064-72
Zanin-Zhorov, Alexandra; Lin, Jiqiang; Scher, Jose et al. (2012) Scaffold protein Disc large homolog 1 is required for T-cell receptor-induced activation of regulatory T-cell function. Proc Natl Acad Sci U S A 109:1625-30

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