Yi Zhang, M.D., Ph.D.
Assistant Professor,
Internal Medicine

yizha@umich.edu

Research Interests:

Hematopoietic stem cell transplantation, GVHD/GVL, Memory T cells,
Stem cell/T cell signaling

Current Research Activity:

Persistent T cell immune responses can be detrimental to the host. One important clinical example is graft-versus-host disease (GVHD) in patients receiving allogeneic hematopoietic stem cell transplantation (allo-HSCT). GVHD is caused by infused donor T cells that react to allogenic host antigens. A hallmark of GVH reactions is the persistence of heterogeneous populations of host-reactive effector and memory T cells throughout the disease course. Therapies using existing and newly developed immunosuppressive drugs and agents are common strategies for ablating pathogenic T cell responses; but they lack efficacy for the majority of patients with GVHD and increase the risk of relapse, infection and mortality in allo-HSCT recipients.

We have recently demonstrated that host-reactive T memory stem cells and memory T cells generate and sustain host-reactive effector T cells during GVH reaction. Several stem cell regulatory pathways, such as Notch and Wnt/GSK-3 among others , are associated with the continual generation of host-reactive T cells. We are investigating how these pathways regulate: (1) the generation and maintenance of T memory stem cells and memory T cells; (2) the effector functions of host-reactive T cells; and (3) the evolution of host-reactive T cells to treatment-refractory cells . The long-term goal of these studies is to develop more effective immunomodulatory agents and approaches for blocking T cell-mediated pathogenic injury and for improving the graft-versus-leukemia effect and immune reconstitution after allo-HSCT.

Representative Publications:

Zhang Y, Louboutin JP, Zhu J, Rivera AJ, Emerson SG: Rapid priming in vivo by pre-terminal host dendritic cells triggers donor CD8 T cell-mediated acute graft-versus-host disease in a mouse model. Journal Clinical Investigation 109:1335, 2002.

Zhang Y, Shlomchik W, Joe G, Louboutin JP, Zhu J, Rivera AJ, and Emerson SG: APCs in the liver and spleen recruit activated allogeneic CD8(+) T cells to elicit hepatic graft-versus-host disease. J Immunol 169(12):7111-8, 2002.

Zhang Y, Joe G, Zhu J, Carroll, R, Levine B, Hexner E, June C and Emerson SG. Dendritic Cell Activated CD44 hi CD8 + T Cells Are Defective in Mediating Acute Graft-versus-host Disease but Retain Graft-versus-leukemia Activity. Blood 103(10): 3970-3978, 2004.

Zhang Y, Joe G, Hexner E, Zhu J and Emerson SG. Allogeneic memory T cells are responsible for the persistence of graft-versus-host disease. Journal of Immunology 174(5):3051-8. 2005.

Zhu J, Zhang Y , Joe GJ, Pompetti R, Emerson SG. NF-Ya activates multiple hematopoietic stem cell (HSC) regulatory genes and promotes HSC self-renewal. Proc Natl Acad Sci U S A.102(33):11728-33; 2005.

Zhang Y, Gerard Joe, Elizabeth Hexner, Jiang Zhu, and Stephen G. Emerson, Host-reactive CD8 + Memory Stem Cells in Graft-versus-host Disease. Nature Medicine 2005, 11:1299.

Zhang Y, Elizabeth Hexner, Dale Frank, and Stephen G. Emerson , 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 Sep 1;179(5):3305-14.