Posted December 19, 2013
Dr. Yi Zhang, University of Michigan, Ann Arbor, Michigan

Dr. Yi Zhang Cellular immunity is mediated by T cells that respond to "foreign" materials in the body. During primary immune response, naïve T cells become activated through their interaction with antigen-presenting cells. Long-term immunity is established by memory T cells derived from the antigen-activated T cells, which rapidly expand into effector T cells upon re-encounter of the specific antigen. Aplastic anemia most often results from autoimmunity where the body's immune system attacks its own blood stem cells within the bone marrow by failing to recognize the bone marrow as "self," leading to the body's inability to produce and replenish blood cells. One of the main treatment strategies for aplastic anemia is immunosuppressive therapies. Unfortunately, immunosuppression has significant consequences including a higher risk of infections and cancer. Moreover, while 60% of aplastic anemia patients respond to immunosuppression, up to 35% of treated patients relapse when the drugs are withdrawn. Allogeneic bone marrow transplantation has the potential to cure aplastic anemia; however, it can lead to life-threatening graft-versus-host disease (GVHD).

To improve long-term management of acquired aplastic anemia, Dr. Yi Zhang seeks to unveil the mechanisms underlying aplastic anemia relapse after immunosuppressive treatment. Previously, Dr. Zhang found evidence that immunosuppressive therapy augments the generation of functionally dormant memory T cells that expand into bone marrow-destructing effector T cells when therapy is discontinued, suggesting that memory T cells may be responsible for disease relapse. Interestingly, he found that suppression of Notch signaling in these cells left them unable to destroy the bone marrow in mice, thus leading to the hypothesis that if immunosuppressive therapy indeed leads to the production of memory T cells that lay dormant until therapy is discontinued, they could be treated with Notch inhibitors to prevent them from destroying the bone marrow.

With support from a Fiscal Year 2010 Bone Marrow Failure Research Program New Investigator Award, Dr. Zhang is assessing the role of memory T cells in mediating bone marrow failure, determining how marrow-destructive memory T cells may be generated and maintained during immunosuppression, and evaluating Notch inhibition as a potential therapeutic strategy to prevent the reactivation of memory T cells into destructive effector T cells. Since Notch signaling is involved in multiple cellular processes, complete blockade may be severely toxic to patients; therefore, identifying specific ligands critical for eliciting autoimmunity is paramount. Although the research is in progress, Dr. Zhang has already made a critical discovery that the Dll4 Notch ligand is implicated in the generation of bone marrow-destructive effector T cells, and Dll4-positive inflammatory dendritic cells play important roles in eliciting allogeneic T cell responses in mice. Blocking Dll4 led to the decreased production of effector T cells, reduced GVHD, and significantly improved survival of mice after allogeneic bone marrow transplantation. Based on these results, Dr. Zhang plans on further investigating the impact of pharmacological modulation of Dll4 on immune cell-mediated bone marrow failure in experimental mouse models via anti-Dll4 antibodies, which are already in clinical trials for experimental treatment of cancer. The success of this research may lead to significant improvements in long-term management of acquired aplastic anemia.


Public and Technical Abstracts: Modulation of Memory T Cells to Control Acquired Bone Marrow Failure

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