): 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.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Scientist Development Award - Research & Training (K01)
Project #
1K01CA084132-01
Application #
6038178
Study Section
Subcommittee G - Education (NCI)
Program Officer
Eckstein, David J
Project Start
2000-05-15
Project End
2005-04-30
Budget Start
2000-05-15
Budget End
2001-04-30
Support Year
1
Fiscal Year
2000
Total Cost
$82,326
Indirect Cost
Name
Fred Hutchinson Cancer Research Center
Department
Type
DUNS #
075524595
City
Seattle
State
WA
Country
United States
Zip Code
98109
Yu, Xue-Zhong; Liang, Yaming; Nurieva, Roza I et al. (2006) Opposing effects of ICOS on graft-versus-host disease mediated by CD4 and CD8 T cells. J Immunol 176:7394-401
Yu, Xue-Zhong; Albert, Michael H; Anasetti, Claudio (2006) Alloantigen affinity and CD4 help determine severity of graft-versus-host disease mediated by CD8 donor T cells. J Immunol 176:3383-90
Albert, Michael H; Liu, Yan; Anasetti, Claudio et al. (2005) Antigen-dependent suppression of alloresponses by Foxp3-induced regulatory T cells in transplantation. Eur J Immunol 35:2598-607
Albert, Michael H; Yu, Xue-Zhong; Martin, Paul J et al. (2005) Prevention of lethal acute GVHD with an agonistic CD28 antibody and rapamycin. Blood 105:1355-61
Yu, Xue-Zhong; Levin, Steven D; Madrenas, Joaquin et al. (2004) Lck is required for activation-induced T cell death after TCR ligation with partial agonists. J Immunol 172:1437-43
Yu, Xue-Zhong; Albert, Michael H; Martin, Paul J et al. (2004) CD28 ligation induces transplantation tolerance by IFN-gamma-dependent depletion of T cells that recognize alloantigens. J Clin Invest 113:1624-30
Yu, Xue-Zhong; Martin, Paul J; Anasetti, Claudio (2003) CD28 signal enhances apoptosis of CD8 T cells after strong TCR ligation. J Immunol 170:3002-6
Yu, X; Carpenter, P; Anasetti, C (2001) Advances in transplantation tolerance. Lancet 357:1959-63
Yu, X Z; Bidwell, S J; Martin, P J et al. (2001) Anti-CD3 epsilon F(ab')2 prevents graft-versus-host disease by selectively depleting donor T cells activated by recipient alloantigens. J Immunol 166:5835-9