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International Association of Biomedical Gerontology 10th Congress Queens College/Cambridge September 2003 T cell Replicative senescence: pleiotropic effects on human aging Rita B. Effros Dept of Pathology & Laboratory Medicine David Geffen School of Medicine at UCLA Viral infections and aging increased incidence and severity (influenza, RSV, HIV, SARS) re-emergence of latent infections Cytotoxic ( CD8) T cells > 1018 different antigen receptors Replicative senescence Reduced apoptosis Effect of repeated stimulation on telomerase Effect of repeated stimulation on telomerase * X Immunobiology: The Immune System in Health & Disease, 3rd edition, by Janeway & Travers ( Current Biology Limited & Garland Publishing) CD28-negative T cells with age Boucher et al., Exp. Gerontol. 33:267, 1998 in CD4 in CD8 Neonates NT NT Young adult (20-40) 4% 42% Elderly (70-90) 12% 79% Mean TRF Length (kb) Mean TRF Length (kb) CD28- T cells have shortened telomeres 9 8 7 6 5 + CD28 A AB 9 BC 8 7 6 5 - CD28 ++ CD28 CD28 * -- CD28 unable to proliferate resistant to apoptosis + SN CEN CD28 -SP CD28 CD28 PBMC Do senescent CD8 T cells affect other cell types and organ systems in vivo ? CD8+ CD28- T cells correlate with poor response to flu vaccine suppress helper T cells disease progression in ankylosing spondilitis organ transplant patients-may suppress T cells that would reject the graft correlate with osteoporotic fractures REGULATION OF BONE RESORPTION Role of T cells REGULATION OF OC FORMATION AND FUNCTION Model T CELLS MONOCYTES Stimulatory Factors IL-1 TNFa RANKL TNFa Inhibitory Factors TNFa OC PRECURSORS Differentiation and activation ACTIVE OC OPG M-CSF IL-6 PGE2 GM-CSF RANKL RANKL STROMAL CELLS (Modified from SAGE KE/ B.L. Riggs) TGFb TGFb Effect of culture “age” on production of TNF alpha TNFa pg/ml 80 70 60 50 40 30 20 10 0 4 16 Population Doublings 25 Production of “RANKL” by activated T cells (Receptor Activator for NFkB Ligand) Production of RANKL by activated T cells Ectopic telomerase expression leads to lifespan extension of virus-specific CD8 T cells 80 Population Doublings (PD) 70 60 50 40 30 20 hTERT 10 vector 0 0 200 400 600 Days in culture 800 1000 1200 Telomere length stablization, prevents accumulation of p16, p21 Correction of senescenceassociated cytotoxic defect % Specific Lysis 100 80 60 40 20 0 0 1 2 3 4 5 6 7 8 Passage Untransduced CTL (Control) Empty Vector-Transduced CTL (Control) hTERT-Transduced CTL Replicative senescence end stage of normal T cell differentiation increased proportions in elderly reduced anti-viral function once generated, senescent CD8 T cells persist ? exert broad physiological effects hTERT corrects only some of the defects associated with CD8 T cell senescence (CD28, compounds that telomerase) Reversal of T cell replicative senescence can improve both immune function and bone status Collaborators and UCLA Xiaoming Zhu Hector Valenzuela Mirabelle Dagarag Lucia Graham Tankdik Evazyan Support Otto Yang Janis Giorgi Roger Detels Farhad Parhami Geron Corporation Calvin Harley, Choy-Pik Chiu (UC BioSTAR, NIH ,Plott Endowment, UCLA Center on Aging)