Abstract

In allogeneic stem cell transplantation (SCT), donor T cells mediate beneficial immunity such as the graft-versus-leukemia (GVL) and graft-versus-tumor (GVT) effect and prevent graft rejection. However, donor T cells also initiate lethal GVHD. In murine studies, we have shown that CD4+ Th2 cells reduce GVHD. We have also shown that donor CD8+ Tc2 cells can mediate GVL and GVT effects and prevent marrow rejection with greatly reduced GVHD. As a translation of these results, we have initiated a clinical trial evaluating in vitro generated donor Th2 cells in the allogeneic SCT setting. Clinical trials evaluating Tc2 cells are also planned for the purpose of preventing graft rejection in the setting of HLA-disparate transplantation. Ongoing murine studies are evaluating the molecular mechanisms of Th2 and Tc2-mediated immunity in the transplant setting, and in developing approaches to modulate Th1- and Tc1-mediated GVHD. Our lab is additionally evaluating T cell subsets, in particular the Th1 and Tc1 subsets, in the syngeneic setting. These subsets are associated with GVHD in the allogeneic setting, but are likely important anti-tumor mediators in the syngeneic setting. Murine studies are ongoing to evaluate the role of Th1 and Tc1 cells in anti-tumor immunity, particularly in the vaccine setting.

  Funding Agency

Agency
National Institute of Health (NIH)
Institute
Division of Clinical Sciences - NCI (NCI)
Type
Intramural Research (Z01)
Project #
1Z01SC010288-05
Application #
6758292
Study Section
Project Start
Project End
Budget Start
Budget End
Support Year
5
Fiscal Year
2002
Total Cost
Indirect Cost

  Institution

Name
Clinical Sciences
Department
Type
DUNS #
City
State
Country
United States
Zip Code

  Publications

Granville, Courtney A; Memmott, Regan M; Balogh, Andria et al. (2009) A central role for Foxp3+ regulatory T cells in K-Ras-driven lung tumorigenesis. PLoS One 4:e5061
Vasu, Sumithira; Leitman, Susan F; Tisdale, John F et al. (2008) Donor demographic and laboratory predictors of allogeneic peripheral blood stem cell mobilization in an ethnically diverse population. Blood 112:2092-100
Pavletic, Steven Z; Fowler, Daniel H (2008) ""Regulating"" rheumatoid arthritis via autotransplantation. Blood 111:4838-9
Mossoba, Miriam E; Walia, Jagdeep S; Rasaiah, Vanessa I et al. (2008) Tumor protection following vaccination with low doses of lentivirally transduced DCs expressing the self-antigen erbB2. Mol Ther 16:607-17
Hardy, Nancy M; Hakim, Frances; Steinberg, Seth M et al. (2007) Host T cells affect donor T cell engraftment and graft-versus-host disease after reduced-intensity hematopoietic stem cell transplantation. Biol Blood Marrow Transplant 13:1022-30
Snyder, James T; Shen, Jijia; Azmi, Hooman et al. (2007) Direct inhibition of CD40L expression can contribute to the clinical efficacy of daclizumab independently of its effects on cell division and Th1/Th2 cytokine production. Blood 109:5399-406
Sato, Takeya; Neschadim, Anton; Konrad, Manfred et al. (2007) Engineered human tmpk/AZT as a novel enzyme/prodrug axis for suicide gene therapy. Mol Ther 15:962-70
Imanguli, Matin M; Atkinson, Jane C; Harvey, Kristen E et al. (2007) Changes in salivary proteome following allogeneic hematopoietic stem cell transplantation. Exp Hematol 35:184-92
Subramaniam, D S; Fowler, D H; Pavletic, S Z (2007) Chronic graft-versus-host disease in the era of reduced-intensity conditioning. Leukemia 21:853-9
Liang, Sheng-Ben; Yoshimitsu, Makoto; Poeppl, Armando et al. (2007) Multiple reduced-intensity conditioning regimens facilitate correction of Fabry mice after transplantation of transduced cells. Mol Ther 15:618-27

Showing the most recent 10 out of 14 publications