Background: Infections are frequent after high dose chemotherapy or total body irradiation followed by hematopoietic cell transplantation (HCT). This is due at least in part to the slow reconstitution of CD4 cells. In adult patients, the T cell repertoire is restricted and counts of phenotypically na?ve T cells are low for years. This is primarily due to the limited ability of adult patients to regenerate T cells de novo (from hematopoietic stem cells). Hypothesis: Interleukin-7 (IL7) hastens the regeneration of T cells de novo. Research design and Methods: Autologous HCT transplantation of irradiated baboons will be performed, using yellow fluorescent protein (YFP) gene-transduced CD34 cells and green fluorescent protein (GFP) gene-transduced T cells. After transplant, de novo T cell generation in IL7-treated versus placebo-treated animals will be evaluated by 1. enumerating YFP+ T cells, 2. determining functional T cell repertoire through the detection of various antigen-specific T cells after immunization with multiple antigens, 3. enumerating phenotypically na?ve (e.g., CD45RA high) CD4 T cells, 4. assessing the size and histology of the thymus, including RAG and TdT immunostains, thymocyte subsets and T cell receptor rearrangement excision circle (TREC) levels in thymocytes, and 5. determining TREC levels in peripheral T cells. To rule out the possibility that the expected result of increased YFP+/CD45RA high/TREC+ T cell counts in the blood of the IL7-treated animals is due to IL7-induced shift of stem cell-derived T cells from organs to the blood, YFP+, CD45RA high and TREC+ cells will be enumerated in both the blood and lymphatic tissues. We will also evaluate whether IL7 stimulates peripheral expansion of primate T cells by enumerating GFP+ T cells. Moreover, we will determine the efficacious (de novo regeneration-stimulating) dose of IL7 in primates and potentially toxicity including osteoporosis or a lymphoproliferative disorder. These results will be used for the design of clinical studies.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
5R01HL069710-02
Application #
6528196
Study Section
Experimental Therapeutics Subcommittee 1 (ET)
Program Officer
Jensen, Lee Ann
Project Start
2001-08-15
Project End
2004-07-31
Budget Start
2002-08-01
Budget End
2003-07-31
Support Year
2
Fiscal Year
2002
Total Cost
$693,960
Indirect Cost
Name
Fred Hutchinson Cancer Research Center
Department
Type
DUNS #
075524595
City
Seattle
State
WA
Country
United States
Zip Code
98109
Storek, Jan (2008) Immunological reconstitution after hematopoietic cell transplantation - its relation to the contents of the graft. Expert Opin Biol Ther 8:583-97
Storek, Jan; Kiem, Hans-Peter (2006) Transgene expression by a large fraction of dendritic cells following autologous transplantation of retrovirally transduced CD34 cells. Stem Cells Dev 15:619-21
Storek, Jan; Nash, Richard A; McSweeney, Peter A et al. (2006) Normal interleukin-7 (IL7) levels and normal IL7 response to CD4 T lymphopenia in patients with multiple sclerosis and systemic sclerosis. Clin Immunol 121:118-9
Kalina, Tomas; Lu, Hailing; Zhao, Zhao et al. (2005) De novo generation of CD4 T cells against viruses present in the host during immune reconstitution. Blood 105:2410-4
Storek, Jan; Gillespy 3rd, Thurman; Lu, Hailing et al. (2003) Interleukin-7 improves CD4 T-cell reconstitution after autologous CD34 cell transplantation in monkeys. Blood 101:4209-18
Storek, Jan; Viganego, Federico; Dawson, Monja A et al. (2003) Factors affecting antibody levels after allogeneic hematopoietic cell transplantation. Blood 101:3319-24
Storek, Jan; Joseph, Ansamma; Dawson, Monja A et al. (2002) Factors influencing T-lymphopoiesis after allogeneic hematopoietic cell transplantation. Transplantation 73:1154-8