Lack of immune reconstitution, and specifically T cell reconstitution, is one of the four major barriers to the application of allogeneic hematopoietic stem cell transplantation as a therapy for the treatment of cancer. It is also a limiting feature in the treatment of other diseases such as HIV. The biology of reconstitution of T cell populations following acute loss has, in the past, been extremely poorly characterized. Using murine models, we first identified two primary pathways of T cell immune reconstitution, the classic, thymic-dependent pathway, and a second, thymic-independent pathway. We then identified T cell surface markers which allowed identification, by phenotyping of reconstituted T cell populations, of the pathways which had given rise to them, and then applied this information to the characterization of T cell reconstitution in patients. Initial work established the applicability to the study of T cell population regeneration in humans. Current work has demonstrated validity of the approach and has, for the first time, established the time course of T cell immune reconstitution in humans over time for each of the two primary pathways. This work has also shown an essential role for the thymus in regenerating repertoire diversity for CD4+ T cells. CD8+ T cells depend more strongly on peripheral expansion for immune reconstitution. This understanding has led in turn to a research emphasis on understanding mechanisms which control thymic function, and new treatments, including vaccine strategies, to treat cancer in the setting of a regenerating immune system. Four models of thymic regulation have been developed. These models demonstrate a common critical point of regulation, namely entry of early thymocyte progenitors.

Agency
National Institute of Health (NIH)
Institute
Division of Basic Sciences - NCI (NCI)
Type
Intramural Research (Z01)
Project #
1Z01BC010525-03
Application #
7291877
Study Section
(ETIB)
Project Start
Project End
Budget Start
Budget End
Support Year
3
Fiscal Year
2005
Total Cost
Indirect Cost
Name
Basic Sciences
Department
Type
DUNS #
City
State
Country
United States
Zip Code
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
Kochenderfer, James N; Chien, Christopher D; Simpson, Jessica L et al. (2007) Maximizing CD8+ T cell responses elicited by peptide vaccines containing CpG oligodeoxynucleotides. Clin Immunol 124:119-30
Kochenderfer, James N; Simpson, Jessica L; Chien, Christopher D et al. (2007) Vaccination regimens incorporating CpG-containing oligodeoxynucleotides and IL-2 generate antigen-specific antitumor immunity from T-cell populations undergoing homeostatic peripheral expansion after BMT. Blood 110:450-60
Gress, Ronald E; Komanduri, Krishna V; Einsele, Hermann et al. (2007) Lymphoid reconstruction and vaccines. Biol Blood Marrow Transplant 13:17-22
Hakim, F T; Gress, R E (2007) Immunosenescence: deficits in adaptive immunity in the elderly. Tissue Antigens 70:179-89
Baatar, Dolgor; Olkhanud, Purevdorj; Sumitomo, Kenya et al. (2007) Human peripheral blood T regulatory cells (Tregs), functionally primed CCR4+ Tregs and unprimed CCR4- Tregs, regulate effector T cells using FasL. J Immunol 178:4891-900
Williams, Kirsten M; Hakim, Frances T; Gress, Ronald E (2007) T cell immune reconstitution following lymphodepletion. Semin Immunol 19:318-30
Lucas, Philip J; Kim, Seong-Jin; Mackall, Crystal L et al. (2006) Dysregulation of IL-15-mediated T-cell homeostasis in TGF-beta dominant-negative receptor transgenic mice. Blood 108:2789-95
El-Asady, Riham; Yuan, Rongwen; Liu, Kechang et al. (2005) TGF-{beta}-dependent CD103 expression by CD8(+) T cells promotes selective destruction of the host intestinal epithelium during graft-versus-host disease. J Exp Med 201:1647-57
Sportes, Claude; McCarthy, Nicole J; Hakim, Frances et al. (2005) Establishing a platform for immunotherapy: clinical outcome and study of immune reconstitution after high-dose chemotherapy with progenitor cell support in breast cancer patients. Biol Blood Marrow Transplant 11:472-83

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