): Dr. Yu is a Research Associate with the Immunogenetics Program in the Clinical Research Division at Fred Hutchinson Cancer Research Center (FRCRC) and has investigated mechanisms of peripheral T cell tolerance in the laboratory of Dr. Claudio Anasetti. The FHCRC is a premier biomedical research center dedicated to the cause of eliminating cancer as a major form of human suffering. This Center provides an exceptional opportunity for the research and intellectual development of physician scientists. The long-term goal of this project is to develop a strategy [of] inducing specific tolerance of alloreactive T cells responsible for graft-versus-host disease (GVHD) and graft rejection, while preserving T cells responsible for pathogens or tumor antigens. Being successful in this research project, it is expected that Dr. Yu's research career will be greatly enhanced, and he will realize his career goal, [i.e.,] to become an independent investigator. S t u dies proposed in this application are expected to determine the immunosuppressive mechanism of CD28-ligation with its specific monoclonal antibody (mAb) in vivo, to disclose a new approach exploiting the function of CD28 in regulation of T cell response, which may be highly beneficial to patients with leukemia.
The specific aims of this application are: 1) To determine whether treatment with anti-CD28 mAb can prevent GVHD and facilitate engraftment. Bone marrow and peripheral T cells from donors will be transplanted into irradiated MHC class I and class II-incompatible recipients, and the effects of treatment with anti-CD28 mAb on GVHD and graft rejection w i l l [ be] tested. 2) To determine whether anti-CD28 mAb induces immunosuppression in vivo by over-activating T cells, and/or promoting T cells to produce type-2 cytokines, especially IL-10. TCR transgenic 2C and DO11.10 mice will be used to test the hypothesis that anti-CD28 mAb facilitates, rather than inhibits, CD4 and CD8 T cell activation respectively. Neutralizing in mAb specific for mouse anti-IL-10 mAb will be used to neutralize IL-10 in vivo to assess the contribution of IL-10 in GVRD protection mediated by anti- CD28-treatment. 3) To determine whether treatment with anti-CD28 mAb can preserve GVL effects. The effects of anti-CD28 mAb on tumor rejection will be tested in syngeneic or allogenic hosts.
