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
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
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
Ding, Zhi-Chun; Lu, Xiaoyun; Yu, Miao et al. (2014) Immunosuppressive myeloid cells induced by chemotherapy attenuate antitumor CD4+ T-cell responses through the PD-1-PD-L1 axis. Cancer Res 74:3441-53
May, Sarah L; Zhou, Qing; Lewellen, Mitzi et al. (2014) Nfatc2 and Tob1 have non-overlapping function in T cell negative regulation and tumorigenesis. PLoS One 9:e100629
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
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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