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Yi Zhang, M.D., Ph.D.
Assistant Professor of Internal Medicine
yizha@umich.edu


Current Research Activity

T cell-mediated immunity is a double-edge sword. T-cell immune response is clearly important for protecting the host from infections and tumors, but it also causes inflammatory disorders, such as autoimmune diseases and rejection of allogeneic grafts. Existing methods that induce pan-immunosuppression lack the efficacy to control T cell-mediated inflammation disorders. For example, although standard therapy that typically includes steroids could reduce acute rejection of allografts in patients, it fails to effectively inhibit chronic allograft rejection that becomes a leading cause of graft failure. In addition, pan-immunosuppression increases the risk of infection and causes other adverse effects. Novel approaches are urgently needed.

A major goal of our research program is to understand the molecular mechanisms regulating allogeneic T cell responses and their-mediated tissue injury (such as graft-versus-host disease (GVHD), a life-threatening complication after allogeneic bone marrow transplantation). This includes analysis of effector T cell development and functional activities of effector T cells that culminate in tissue inflammation. These studies are performed primarily in mouse models of allogeneic bone marrow transplantation. One emphasis is placed on defining the role of Ezh2 (which is a key component of polycomb repressive complex 2 and histone methyltransferase) in antigen-driven T cells. Another one is investigating the role of Notch ligands and inflammatory dendritic cells (i-DCs) in immune responses. We have recently established the beneficial effects of modulating alloimmunity by targeting Ezh2 and Notch signaling pathway on preventing T cell-mediated GVHD. Results from these studies will lead to new strategies to prevent and treat alloimmune inflammation and other T cell-mediated inflammatory disorders in a broad context. Several ongoing projects in our lab include:  

1. Epigenetics and genomics in alloimmune inflammation.      Although the etiological factors that trigger GVHD and allograft rejection of solid organs may vary, the common pathological outcome of alloimmunity is the destruction of allogeneic tissues by activated lymphoid and myeloid cells through a process named alloimmune inflammation. Development of alloimmune inflammation requires orchestrated expression of myriad genes that mediate activation, migration and effector activities of inflammatory cells. These include genes that encode antigen receptors, costimulatory molecules, Notch ligands and receptors, cytokines, chemokines, cytotoxic molecules and enzymes regulating cellular metabolism. Epigenetic effects are responsible for this coordinated gene expression in alloantigen-activated T cells without somatic gene mutations.

To identify the epigenetic regulators that are critical for orchestrating transcription programs responsible for T cell alloimmunity, our laboratory has performed gene profiling studies of alloantigen-activated T cells and revealed multiple and complex roles of Ezh2 in T-cell alloimmunity. In vivo administration of an Ezh2 inhibitor, 3-deazaneplanocin A, induced long-term acceptance of cardiac allografts and arrested ongoing GVHD in mice. Most importantly, inhibition of Ezh2 did not impair T cell responses against viral infections, tumors and other third party antigens. Therefore, Ezh2 appears to be an effective therapeutic target for modulating alloimmune inflammation. We are now investigating how Ezh2 regulate antigen-driven T cell responses. We hope to identify the molecular pathways / substrates that are critical for Ezh2 regulation of antigen-driven T cell responses. Accomplishment of these studies will lead to the development of novel and clinically relevant approaches to improve the efficacy of allogeneic bone marrow transplantation and cancer immunotherapy by targeting Ezh2 and its substrates. Both genetic and pharmacologic approaches are available for these studies in our lab.

2. Targeting Notch signaling to modulate alloimmunity. Notch signaling controls cell fate, differentiation and proliferation in many contexts. Notch receptors (Notch 1, 2, 3, and 4) interact with Notch ligands of the Delta-like (i.e., Dll1, Dll3 and Dll4) and Jagged families (i.e., J1 and J2). In the canonical pathway, binding of a Notch ligand to its receptor results in the cleavage of the receptor by g-secretase complex and the subsequent release of intracellular Notch. Our previously studies demonstrate that Notch is critical to the generation of alloreactive effector T cells producing high levels of effector cytokines (e.g., TNF-a, IFN-g, and IL-17). Blockade of Notch signaling in T cells causes reduction of GVHD while preserving the anti-tumor activity of T cells, leading to significantly improved survival of mice of allogeneic transplant and leukemia. Most recently, we discovered a population of previously uncharacterized i-DCs expressing high levels of Dll4. These Dll4-positive i-DCs have greater ability than Dll4-negative i-DCs to induce Th1 and Th17 cell responses. In vivo administration of anti-Dll4 Ab leads to reduction of GVHD in mice after allogeneic bone marrow transplantation. We want to understand at the molecular level how these Dll4-positive i-DCs develop during inflammation and elicit allogeneic T cell responses, and how immunization using Dll4-positive i-DCs may improve the efficacy of cancer immunotherapy.


Representative Publications


Zhang Y, Joe G, Hexner E, Zhu J, Emerson SG.  Host-reactive CD8+ memory stem cells in Graft-versus-host Disease. Nat Med 2005, 11:1299. PMID:16288282

Schuettrumpf J, Zhou J,
Zhang Y, Schlachterman A, Liu YL, Edmonson S, Xiao W, Arruda VR.  The inhibitory effects of anticoagulation on in vivo gene transfer by adeno-associated viral or adenoviral vectors. Mol Ther. 2006; 13:88-97. PMID:16230049

Zhu LQ, Ji F, Wang Y,
Zhang Y, Liu Q, Zhang JWZ, Yoneyama H, Matsushima K, Zhu TY, Zhang YY.  Synovial autoreactive T cells in rheumatoid arthritis patient resist Indoleamine 2,3 dioxygenase (IDO)-mediated inhibition. J Immunol. 2006, 177:8266. PMID:17114500

Federick SK, Glasser DL, Shore EM, Pignolo RJ, Xu M,
Zhang Y, Senitzer D, Forman SJ, Emerson SG.  Hematopoietic stem cell contribution to Ectopic Skeletogenesis. J Bone Joint Surgery (American). 2007;89:347-357. PMID:17272450

Zhu J, Garrett R, Jung Y,
Zhang Y, Kim N, Wang J, Joe GJ, Hexner E, Choi Y, Taichman R, Emerson SG.  Osteoblasts support B lymphocyte commitment and differentiation from hematopoietic stem cells. Blood. 2007, 109:3706-12. PMID:17227831

Nakata Y, Shetzline S, Sakashita C, Kalota A, Rallapalli R, Rudnick SI,
Zhang Y, Emerson SG, Gewirtz AM.  c-Myb contributes to G2/M cell cycle transition in human hematopoietic cells by direct regulation of cyclin B1 expression. Mol Cell Biol. 2007, 27:2048-58. PMID:17242210  PMCID:PMC1820494

Zhang Y, Hexner E, Frank D, Emerson SG.  CD4+ T Cells generated de novo from donor hematopoietic stem cells mediate the evolution from acute to chronic Graft-versus-host Disease, J Immunol. 2007, 179:3305-14. PMID:17709547

Hexner EO, Daner-Desnoyers GA,
Zhang Y, Frank DM, Riley JL, Levine BL, Porter DL, June CH, Emerson SG. Umbilical cord blood xenografts in immunodeficient mice reveal that T cells enhance hematopoietic engraftment beyond overcoming immune barriers by stimulating stem cell differentiation. Biol Blood Marrow Transplant 2007, 13:1135-44. PMID:17889349

Patel A,
Zhang Y, Croyle M, Tran K, Gray M, Strong J, Feldmann H, Wilson JM, Kobinger GP.  Mucosal delivery of adenovirus-based vaccine protects against Ebola virus infection in mice. J Infect Dis. 2007 Nov 15;196 Suppl 2:S413-20. PMID:17940978

He S, Cao Q, Yoneyama H, Ge H,
Zhang Y, Zhang YY.  MIP-3{alpha} and MIP-1{alpha} rapidly mobilize dendritic cell precursors into the peripheral blood. J Leukoc Biol 2008, 84:1549-56. PMID:18791167

Croyle MA, Patel A, Tran KN, Gray M,
Zhang Y, Strong JE, Feldmann H, Kobinger GP. Nasal delivery of an adenovirus-based vaccine bypasses pre-existing immunity to the vaccine carrier and improves the immune response in mice. PLoS ONE. 2008;3(10):e3548. PMID:18958172  PMCID:PMC2569416

He S, Cao Q, Qiu YH, Mi JQ, Zhang JZ, Jin M, Ge HL, Emerson SG,
Zhang Y, Zhang YY.  A new approach of blocking alloreactive T cell-mediated GVHD by in vivo Administration of Anti-CXCR3 Neutralizing Antibody. J Immunol 2008 181:7581-7592. PMID:19017947

Huang J,
Zhang Y, Bersenev A, O’Brien WT, Tong W, Emerson SG, Klein PS. Pivotal role for glycogen synthase kinase-3 in hematopoietic stem cell homeostasis in mice. J. Clin. Invest 2009, 119(12): 3519-3529. PMID:19959876  PMCID:PMC2786808

Kato K, Cui S, Kuick R, Mineishi S, Hexner E, Ferrara JLM, Emerson SG,
Zhang Y. Identification of stem cell transcriptional programs normally expressed in embryonic and neural stem cells in alloreactive CD8+ T cells mediating graft-versus-host disease.  Biology of Bone Marrow Transplantation. Biology of Bone Marrow Transplantation. 2010; 16(6):751-71. PMID:20116439  PMCID:PMC2913321

Zhang Y, Sandy AR, Wang J, Shan GT, Radojcic V, Tran I, Friedman A, Kato K, He S, Cui S, Hexner E, Frank D, Emerson SG, Pear WS, Maillard I. Notch signaling is a critical regulator of allogeneic CD4+ T cell responses mediating graft-versus-host disease. Blood, 2011, 117:299. PMID:20870902  PMCID:PMC3037751

He S, Kato K, Jiang J, Wahl DR, Mineishi S, Fisher EM, Murasko DM, Glick GD and
Zhang Y, Characterization of the metabolic phenotype of rapamycin-resistant CD8+ T cells with augmented ability to generate long-lasting memory cells. PLoS ONE, 2011; 6(5):e20107. PMID:21611151  PMCID:PMC3096660

He S, Wang J, Kato K, Varambally S, Xie F, Kuick R, Mineishi S, Liu Y, Nieves E, Mani R, Chinnaiyan AM, Marquez VE and
Zhang Y, Inhibition of histone methylation arrests ongoing graft-versus-host diseases in mice by selectively inducing apoptosis of alloreactive effector T cells. Blood, 2012, 119:1274. PMID:22117046   PMCID:PMC3338164

Wong G, Richardson JS, Pillet S, Patel A, Qiu X, Alimonti J, Hogan J,
Zhang Y, Takada A, Feldmann H, Kobinger GP. Immune Parameters Correlating with 1 Protection against Ebola Virus Infection in Rodents and Nonhuman Primates. Science Translational Medicine, 2012, Vol. 4, Issue 138, p. 138ra81. PMID:23115355

Singh L, Brennan TA, Kim JH, Egan KP, McMillan EA, Chen Q, Hankenson KD, Zhang Y, Emerson SG, Johnson FB, Pignolo RJ.Long-Term Functional Engraftment of Mesenchymal Progenitor Cells in a Mouse Model of Accelerated Aging. Stem Cells. 2012 Nov 29. doi: 10.1002/stem.1294. [Epub ahead of print] PMID:23193076.

Mochizuki K, Xie F, He S, Tong Q, Liu Y, Guo YJ, Kato K, Yagita H, Mineishi S, and Zhang Y. Delta-like Ligand 4 Identifies a Previously Uncharacterized Population of Inflammatory Dendritic Cells That Plays Important Roles in Eliciting Allogeneic T-cell Responses in Mice. Journal of Immunology (2013, in press).

 




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