Yi Zhang, M.D., Ph.D.
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.
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.