Parallel session IVB. Chair: Hans Wildiers
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1 Parallel session IVB Biology of ageing and cancer Chair: Hans Wildiers
2 IMMUNOSENESCENCE AND AGEING Tamas Fulop M.D., PhD Research Center on Aging, Division of Geriatrics, University of Sherbrooke, Sherbrooke, Canada SIOG, Paris, 4 November 2011
3 The immune system adaptive (memory) non-adaptive (innate) B cells (humoral via antibodies) T cells (cellular effectors; cytokines) dendritic cells phagocytes NK cells antigen-presenting cells A.E. 1998
4 Cooperation between innate and adaptive immune responses
5 Immunosurveillance\immunoediting Innate + adaptive adaptive + immunosenescence Zitvogel L. Nat Rev Immunol. 2006
6 users.rcn.com/.../ D/Death_Rate_by_age.gif
7 WHAT IS IMMUNOSENESCENCE?
8 IMMUNITY AND AGEING AGEING: Immune deregulation CAUSE: multifactorial -genetic -intrinsic -environmental: nutrition BASIC ALTERATION : cellular immunity MODULABLE
9 Major changes in T cells with age many changes have been reported over the years but there is little agreement between cross-sectional studies Decreased Increased CD3+ cells (slightly) CD3+DR+ cells TCR1 (γδ) cells (slightly) TCR oligoclonality CD4+CD7+ cells TCR variants (mutants) CD4+ cells (slightly or unchanged) CD4+CD8 (αα)+ cells CD45RA+ cells CD45RO+ cells CD28+ cells CD28-negative cells CD95+ cells CD152 (CTLA-4)+ cells i.e. naive T cells i.e. memory T cells - have never seen antigen - are sensitised to antigen Pawelec. G et al
10 Functions Decreased Increased Proliferation with mitogens TCR signal transduction Nuclear transcription factor activation (AP-1, NF-AT, NF-κB) IL 2 secretion IL 10 secretion soluble IL 2R secretion IL 6 secretion IL 2R expression after activation TNF-α secretion CTL generation CD40L (CD154) upregulation and thus B cell help Telomere lengths DNA damage Telomerase induction DNA repair hprt & HLA mutations; Pawelec. G et al
11 CELLULAR IMMUNITY: T Lymphocytes CAUSES OF ALTERATIONS: INTRINSIC Chronic antigenic stimulation Changes in T lymphocytes sub-populations Thymic involution Alteration in T cell intracellular signalling
12 Chronic antigenic stress It is suggested that many of these changes are caused by: chronic antigenic stress and oxidative stress stimulation by tumour antigens in cancer patients stimulation by persistent viruses in the elderly. CMV, Herpes Varicella-Zoster Virus (VZV) The CD8 cells are characterised by increased resistance to apoptosis and the CD4 cells by increased susceptibility Hence dysfunctional CD8 cells accumulate and specific CD4 cells are clonally deleted; the CD4:8 ratio can become inverted
13 CMV infection is associated with accumulation of the most late-differentiated CD8 cells CD57 expression on CD8+ T-cells CD57+KLRG1+ CD8+T-cells % positive cells Seropositive Seronegative Seropositive Seronegative KLRG1+ CD8+T-cells Seropositive Seronegative Most age-associated changes are exacerbated by or even caused by, chronic antigenic stressors, commonly CMV Derhovanessian 2008
14 Involution of the thymus
15 Result: an accumulation of dysfunctional cells Antigen Compromised in the elderly Dysfunctional cells Activation of naive cells Expansion (ca. 28 PD Contraction Memory in IM) Apoptosis Cytokines (IL-15) - Hypothesis: Because T cell homeostasis maintains constant numbers of T cells in the periphery, even if naive cells continue to be generated from the thymus, the T cell repertoire will be shrunken, contributing to increased susceptibility to infectious disease and cancer and Inflamaging. Pawelec. G et al
16
17 Derhovanessian et al.immum. Age. 2008
18 18 High et al.jags
19 Schröder and Rink MAD 2003
20 The immune system and aging Elimination of pathogen Control of inflammation Cell homeostasis N E E N Immune memory T N T mainly T lymphocytes V I E I L L I S S E M V V I I E E IL I L LI L S I S S E S E M M E T IMMUNOSENESCENCE Is accompanied with a greater susceptibility to Inflam-aging, infections, autoimmune diseases, Alzheimer disease and cancers.
21 Immune stimulation IMMUNOSENESCENCE monocyte macrophage functional IL 1 IL 6 TNF Functional deficit lymphocyte 20% CD3 and CD4 60% capacities of proliferation Inadequate response Prolonged inflammatory syndrome: Inflam-aging Groupe de travail sur la vaccination en gériatrie
22 Fulop et al.
23 Fulop et al.
24 AGING Immune system dysregulation Endocrine function Neural function Cardiovascular health Muscle homeostasis Glucose metabolism Oxidative stress Immunosenescence CD8+CD28-CD57+ CD4:CD8 < 1 CMV seropositivity T-cell proliferation + Immune Risk Phenotype Naïve CD4+ T cells Immunosurveillance Inflam-Aging Loss of specificity Nutrition Infection Cancer Chronic inflammatory diseases: AD, CVD Autoimmune disorders Frailty Fulop et al. CIA, 2008
25 Conclusion Elderly are immunocompromised with few naive cells and dysfunctional (exhausted) memory cells, due to chronic antigenic stress (CMV, cancer antigens, ) and thymic involution with altered innate immune response resulting in inflamm-aging as well as cancer development.
26
27 Acknowledgements Dr Anis Larbi Prof Gilles DUPUIS Prof Abdelouahed KHALIL Dre Nadine DOUZIECH Dre Krassimira Tsvetkova FUNDS: IRSC CRSNG CDA RQRV Nancy Allard Dr Carl Fortin Prof Eric Frost Prof Graham Pawelec Thank you!
28
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