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.
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.
|Schleicher, Ulrike; Paduch, Katrin; Debus, Andrea et al. (2016) TNF-Mediated Restriction of Arginase 1 Expression in Myeloid Cells Triggers Type 2 NO Synthase Activity at the Site of Infection. Cell Rep 15:1062-75|
|Le Texier, LaÃ«titia; Lineburg, Katie E; Cao, Benjamin et al. (2016) Autophagy-dependent regulatory T cells are critical for the control of graft-versus-host disease. JCI Insight 1:e86850|
|SchÃ¶nle, Anne; Hartl, Frederike A; Mentzel, Jan et al. (2016) Caveolin-1 regulates TCR signal strength and regulatory T-cell differentiation into alloreactive T cells. Blood 127:1930-9|
|Zeiser, Robert; SociÃ©, Gerard; Blazar, Bruce R (2016) Pathogenesis of acute graft-versus-host disease: from intestinal microbiota alterations to donor T cell activation. Br J Haematol 175:191-207|
|Zeiser, Robert; Blazar, Bruce R (2016) Preclinical models of acute and chronic graft-versus-host disease: how predictive are they for a successful clinical translation? Blood 127:3117-26|
|Lu, Yunjie; Hippen, Keli L; Lemire, Amanda L et al. (2016) miR-146b antagomir-treated human Tregs acquire increased GVHD inhibitory potency. Blood 128:1424-35|
|Hippen, Keli L; Watkins, Benjamin; Tkachev, Victor et al. (2016) Preclinical testing of anti-human CD28 Fab' antibody in a novel nonhuman primate (NHP) small animal rodent model of xenogenic graft-versus-host disease (GVHD). Transplantation :|
|Li, Wei; Liu, Liangyi; Gomez, Aurelie et al. (2016) Proteomics analysis reveals a Th17-prone cell population in presymptomatic graft-versus-host disease. JCI Insight 1:|
|Matta, B M; Reichenbach, D K; Blazar, B R et al. (2016) Alarmins and Their Receptors as Modulators and Indicators of Alloimmune Responses. Am J Transplant :|
|Mochizuki, Kazuhiro; Meng, Lijun; Mochizuki, Izumi et al. (2016) Programming of donor T cells using allogeneic Î´-like ligand 4-positive dendritic cells to reduce GVHD in mice. Blood 127:3270-80|
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