Background: The recovery of CD4 T cells after high-dose chemo/radiotherapy in adult patients with cancer or autoimmune diseases is very slow (years) and may result in only limited T cell repertoire. A similar problem exists in AIDS patients treated with highly active anti-retroviral therapy. With the ultimate goal of designing strategies to improve the T cell regeneration after T lymphocytopenia, here we propose to study the mechanism of the T cell regeneration. Hypothesis: We hypothesize that after T-lymphocytopenia a substantial number of regenerating T cells originate from hemopoietic progenitors in young individuals whereas only few, if any, T cells originate from hemopoietic progenitors in older individuals. Instead, in the older individuals, the vast majority of T cells originate from the expansion of preexisting T cells. Methods: This hypothesis will be tested in severely lymphocytopenic patients with autoimmune diseases who have received high-dose chemo/radiotherapy plus anti-thymocyte globulin followed by autologous transplantation of hemopoietic (CD34+) cells. An extremely limited number of T cell clones survive such transplant conditioning/ CD34+ cell purification. Therefore, it is relatively easy (easier and more informative than in patients with only moderate T lymphocytopenia) to track down the fate of the surviving T cell clones and to detect T cells newly generated from hemopoietic progenitors post-transplant, using the following techniques: spectratyping, sequencing of the T cell receptor genes within a single spectratyping band, and quantifying T cells that contain T cell receptor-rearrangement excision circles (TREC). Outcome: If the above hypothesis is true, the repertoire of T cells, that is severely limited within the first several months after transplant, will later diversify in young (less than 5-years-old) whereas it will stay severely limited in older (greater than 45-years-old) patients. Also, if the hypothesis is true, the number of TREC-containing T cells post-transplant will be significantly higher in the young compared to the older patients. This will give impetus for developing strategies to enable older patients to generate T cells from hemopoietic progenitors, e.g., using thymopoietic cytokines or thymus grafting.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Project (R01)
Project #
5R01AI046108-04
Application #
6510906
Study Section
Special Emphasis Panel (ZRG1-SSS-J (03))
Program Officer
Ridge, John P
Project Start
1999-07-01
Project End
2004-06-30
Budget Start
2002-07-01
Budget End
2003-06-30
Support Year
4
Fiscal Year
2002
Total Cost
$290,827
Indirect Cost
Name
Fred Hutchinson Cancer Research Center
Department
Type
DUNS #
075524595
City
Seattle
State
WA
Country
United States
Zip Code
98109
Woolfrey, Ann; Storek, Jan; Bowyer, Suzanne et al. (2010) Long-term response of juvenile idiopathic arthritis after conditioning with 8 Gy total body irradiation followed by autologous peripheral blood stem cells: case report. Pediatr Transplant 14:E65-9
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; Zhao, Zhao; Liu, Yiping et al. (2008) Early recovery of CD4 T cell receptor diversity after ""lymphoablative"" conditioning and autologous CD34 cell transplantation. Biol Blood Marrow Transplant 14:1373-9
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, J; Dawson, M A; Lim, L C-L et al. (2004) Efficacy of donor vaccination before hematopoietic cell transplantation and recipient vaccination both before and early after transplantation. Bone Marrow Transplant 33:337-46
Storek, Jan; Zhao, Zhao; Lin, Eugene et al. (2004) Recovery from and consequences of severe iatrogenic lymphopenia (induced to treat autoimmune diseases). Clin Immunol 113:285-98
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; Douek, Daniel C; Keesey, John C et al. (2003) Low T cell receptor excision circle levels in patients thymectomized 25-54 years ago. Immunol Lett 89:91-2

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