Sci. Aging Knowl. Environ., 6 July 2005
Vol. 2005, Issue 27, p. pe21
[DOI: 10.1126/sageke.2005.27.pe21]

PERSPECTIVES

T-CIA: Investigating T Cells in Aging

Sven Koch, Juergen Kempf, and Graham Pawelec

The authors are at the Center for Medical Research at the University of Tuebingen, D-72072 Tuebingen, Germany. E-mail: graham.pawelec{at}uni-tuebingen.de (G.P.)

http://sageke.sciencemag.org/cgi/content/full/2005/27/pe21

Key Words: adaptive immunity • T cells • immunosenescence • biomarkers • immune risk profile

The immune system is our main defense against infections and cancer, but it also causes autoimmune disease and allergy (see "Immunity Challenge" and Wollscheid-Lengeling Perspective). It consists of two major components, innate and adaptive immunity. The latter includes B cell (antibody-mediated) and T cell (cell-mediated) responses against pathogens. From our and others' previous studies, it is known that T lymphocyte responses are particularly susceptible to dysregulation in aging (see "Bad Influence" and "T Cell Tunnel Vision"), making us more susceptible to infections and possibly cancer. Earlier EU projects [EUCAMBIS (European Union Concerted Action on the Molecular Biology of Immunosenescence) and ImAginE (Immunology and Ageing in Europe)] coordinated from Tuebingen, Germany, and their successor, the current EU project T-CIA (T Cell Immunity and Ageing), sought to investigate these age-associated changes. T-CIA, a 5th Framework cost-shared research and technical development project, includes seven European centers (with the associated principal investigators indicated): (i) University of Tuebingen, Germany [Graham Pawelec (Coordinator)]; (ii) University Hospital "Alexandrovska," Sofia, Bulgaria (Elissaveta Naumova); (iii) University of Bologna, Italy (Claudio Franceschi and Michela Pierini); (iv) University of Córdoba, Spain (Rafael Solana and Olga Dela Rosa); (v) University of Jönköping, Sweden (Anders Wikby and Jan Strindahl); (vi) Nottingham Trent University, United Kingdom (Yvonne Barnett and Paul Hyland); and (vii) Unilever PLC, United Kingdom (Dawn Mazzatti and Jonathan Powell).

The main scientific tasks of T-CIA are (i) to define the basic processes of dysregulated T lymphocyte function in aging and diseases of chronic antigenic stimulation (chronic infection, cancer, and autoimmunity), (ii) to model such changes longitudinally in monoclonal human T lymphocyte cultures, (iii) to develop interventions in vitro to allay such T cell dysfunction, and (iv) to recommend interventions that might do the same in vivo, as well as (v) to define biomarkers applicable to monitoring the success of such interventions.

T-CIA investigators have studied peripheral blood lymphocytes from young and old donors, and from those subject to chronic antigenic stress, in order to define T lymphocyte dysfunction in these situations. Cell samples were collected from individuals taking part in longitudinal studies of aging, young and elderly healthy and less healthy cohorts, centenarians, and cancer patients, and distributed to the partners specializing in different analytical techniques for detailed assessment. Data from these ex vivo samples are being compared with those obtained from a longitudinal model of aging represented by cultured monoclonal T lymphocytes. Genomic, proteomic, macromolecular, functional, and other assays are being performed on the same samples in the different partners' laboratories. The genomic approach uses novel bioinformatic pattern recognition schemes being developed in Bologna and Nottingham to analyze microarray data. Similar analyses are being applied to proteomics data generated by the Ciphergen SELDI (surface enhanced laser/desorption ionization) mass spectrometry system. Macromolecular analyses include telomere length and telomerase assays and surface marker phenotyping. Functional studies are being performed to look at proliferation, cytokine production, cytotoxicity, and the control of apoptosis. The aim of these studies is to identify and validate alterations to T lymphocytes occurring during normal healthy aging in contrast to those caused by disease, including cancer, and in comparison with those occurring in the in vitro cell culture model of aging. This approach will enable the separate identification of alterations caused by aging or caused by disease versus those only occurring in vitro. In this way, in vivo age-relevant changes that also occur in vitro (representing "biomarkers of aging") can be identified for more detailed study using cultured cells. Combining these data with information obtained from genetic analyses at the population level, we aim to define clusters of parameters that will predict longevity and mortality of the individual [the "immune risk profile" (IRP)]. Interventions to extend normal functional life-span in the clonal culture model will be tested, including (i) gene therapy involving genes encoding telomerase, heat shock proteins, proteasome components, and DNA repair enzymes; (ii) the use of antioxidants, hormones, and cytokines; (iii) the use of antibodies that block the functions of certain proteins; and (iv) small interfering RNA approaches. Cultures will be monitored for changes in biomarker expression corresponding to successful life span extension. The applicability of these biomarkers for monitoring any in vivo interventions to influence or counteract the IRP will be considered and recommendations will be made.

At the end of this year (2005) when the T-CIA project terminates, we are organizing a final conference on "Immunosenescence and T cells in Aging" in Freudenstadt, Germany. All are cordially invited to join us on the edge of the Black Forest shortly before Christmas for a stimulating 3-day meeting (as well as visiting the Christmas market). For further details, please contact T-CellsInAgeing{at}web.de.


July 6, 2005 Citation: S. Koch, J. Kempf, G. Pawelec, T-CIA: Investigating T Cells in Aging. Sci. Aging Knowl. Environ. 2005 (27), pe21 (2005).








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