Abstract

This application is based on the hypothesis that immunologic senescence of T-cells is the results of two concurrent and interrelated events. The T-cell repertoire is reshaped by an expanded memory lymphocyte pool. The memory T-cells themselves reach a refractory (anergic) state manifested by further resistance to further activation, cell cycle entry and apoptosis. The first effect is attributed to the dilution of naive cells by the accumulated memory phenotype cells that leads to overall repertoire constrictions. The second effect is attributed to a generational clock that records an allocated number of activations and cell divisions by memory T-cells before promoting replicative senescence primarily by the buildup of cyclin kinase inhibitors. These studies of cell cycle and apoptosis of aged T-cells will be instrumental to defining the molecular defects associated with immunologic senescence.

  Funding Agency

Agency
National Institute of Health (NIH)
Institute
National Institute on Aging (NIA)
Type
Research Project (R01)
Project #
5R01AG015061-02
Application #
2855850
Study Section
Immunobiology Study Section (IMB)
Project Start
1998-01-01
Project End
2002-12-31
Budget Start
1999-02-01
Budget End
1999-12-31
Support Year
2
Fiscal Year
1999
Total Cost
Indirect Cost

  Institution

Name
Scripps Research Institute
Department
Type
DUNS #
City
La Jolla
State
CA
Country
United States
Zip Code
92037

  Publications

Wickramarachchi, Dilki C; Theofilopoulos, Argyrios N; Kono, Dwight H (2010) Immune pathology associated with altered actin cytoskeleton regulation. Autoimmunity 43:64-75
Lawson, Brian R; Baccala, Roberto; Song, Jianxun et al. (2004) Deficiency of the cyclin kinase inhibitor p21(WAF-1/CIP-1) promotes apoptosis of activated/memory T cells and inhibits spontaneous systemic autoimmunity. J Exp Med 199:547-57
Mageed, R A; Prud'homme, G J (2003) Immunopathology and the gene therapy of lupus. Gene Ther 10:861-74
Dummer, Wolfgang; Niethammer, Andreas G; Baccala, Roberto et al. (2002) T cell homeostatic proliferation elicits effective antitumor autoimmunity. J Clin Invest 110:185-92
Gorgani, Nick N; Smith, Brian A; Kono, Dwight H et al. (2002) Histidine-rich glycoprotein binds to DNA and Fc gamma RI and potentiates the ingestion of apoptotic cells by macrophages. J Immunol 169:4745-51
Scheuring, Urban J; Sabzevari, Helen; Theofilopoulos, Argyrios N (2002) Proliferative arrest and cell cycle regulation in CD8(+)CD28(-) versus CD8(+)CD28(+) T cells. Hum Immunol 63:1000-9
Lawson, Brian R; Kono, Dwight H; Theofilopoulos, Argyrios N (2002) Deletion of p21 (WAF-1/Cip1) does not induce systemic autoimmunity in female BXSB mice. J Immunol 168:5928-32
Theofilopoulos, A N; Kono, D H (2002) A genetic analysis of lupus. Allergy 57 Suppl 72:67-74
Lawson, B R; Koundouris, S I; Barnhouse, M et al. (2001) The role of alpha beta+ T cells and homeostatic T cell proliferation in Y-chromosome-associated murine lupus. J Immunol 167:2354-60
Santiago-Raber, M L; Lawson, B R; Dummer, W et al. (2001) Role of cyclin kinase inhibitor p21 in systemic autoimmunity. J Immunol 167:4067-74

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