Avid Bioservices Inc (CDMO)

[jazzbeerman]

CMV burden / Immunosenescence / Aging




Biology of longevity: role of the innate immune system.

Rejuvenation Res. 2006


Candore G, Colonna-Romano G, Balistreri CR, Di Carlo D, Grimaldi MP, Listì F, Nuzzo D, Vasto S, Lio D, Caruso C.

Immunosenescence Unit, Department of Pathobiology and Biomedical Methodology, University of Palermo, Palermo, Italy.

Genetic factors play a relevant role in the attainment of longevity because they are involved in cell maintenance systems, including the immune system. In fact, longevity may be correlated with optimal functioning of clonotypic and natural immunity. The aging of the immune system, known as immunosenescence, is the consequence of the continuous attrition caused by chronic antigenic overload. The antigenic load results in the progressive generation of inflammatory responses involved in age-related diseases. Most of the parameters influencing immunosenescence appear to be under genetic control, and immunosenescence fits with the basic assumptions of evolutionary theories of aging, such as antagonistic pleiotropy. In fact, by neutralizing infectious agents the immune system plays a beneficial role until reproduction and parenting. However, by determining chronic inflammation, it can be detrimental later in life, a period largely unforeseen by evolution. In particular, the data coming from the long-lived male population under study show that genetic polymorphisms responsible for a low inflammatory response might result in an increased chance of long lifespan in an environment with a reduced pathogen burden. Such a modern and healthy environment also permits a lower grade of survivable atherogenic inflammatory response.

http://www.ncbi.nlm.nih.gov/pubmed/16608411?ordinalpos=1&itool=EntrezSystem2.PEntrez.Pubmed.Pubmed_ResultsPanel.Pubmed_DiscoveryPanel.Pubmed_Discovery_RA









Human immunosenescence: is it infectious?

Immunol Rev. 2005 Jun


Pawelec G, Akbar A, Caruso C, Solana R, Grubeck-Loebenstein B, Wikby A.

University of Tübingen Medical School, Center for Medical Research, ZMF, Germany.

Morbidity and mortality due to infectious disease is greater in the elderly than in the young, at least partly because of age-associated decreased immune competence, which renders individuals more susceptible to pathogens. This susceptibility is particularly evident for novel infectious agents such as in severe acute respiratory syndrome but is also all too apparent for common pathogens such as influenza. Many years ago, it was noted that the elderly possessed oligoclonal expansions of T cells, especially of CD8(+) cells. At the same time, it was established that cytomegalovirus (CMV) seropositivity was associated with many of the same phenotypic and functional alterations to T-cell immunity that were being reported as biomarkers associated with aging. It was discovered that CMV was the prime driving force behind most of the oligoclonal expansions and altered phenotypes and functions of CD8 cells. Independently, longitudinal studies of a free-living population of the very old in Sweden over the past decade have led to the emerging concept of an 'immune risk phenotype' (IRP), predicting mortality, which was itself found to be associated with CMV seropositivity. These findings support our hypothesis that the manner in which CMV and the host immune system interact is critical in determining the IRP and hence is predictive of mortality. In this sense, then, we suggest that immunosenescence is contagious.

http://www.ncbi.nlm.nih.gov/pubmed/15882359?ordinalpos=1&itool=EntrezSystem2.PEntrez.Pubmed.Pubmed_ResultsPanel.Pubmed_DiscoveryPanel.Pubmed_Discovery_RA









Human immunosenescence: does it have an infectious component?

Ann N Y Acad Sci. 2006 May


Pawelec G, Koch S, Franceschi C, Wikby A.

University of Tübingen Medical School, Center for Medical Research, ZMF, Germany.

The rate of acceleration of the frequency of death due to cardiovascular disease or cancer increases with age from middle age up to around 75-80 years, plateauing thereafter. Mortality due to infectious disease, however, does not plateau, but continues to accelerate indefinitely. The elderly are particularly susceptible to novel infectious agents such as SARS, as well as to previously encountered pathogens. Why is this? The elderly commonly possess oligoclonal expansions of T cells, especially of CD8 cells, which, surprisingly, are associated with cytomegalovirus (CMV) seropositivity. This in turn is associated with many of the same phenotypic and functional alterations to T cell immunity that have been suggested as biomarkers of immune system aging. We suggest that, in fact, CMV, not age per se, is the prime driving force behind many or most of the oligoclonal expansions and altered phenotypes and functions of CD8 cells in the elderly. Thus, the manner in which CMV and the host immune system interact (over which period? on which genetic background? with which co-infections?) is critical in determining the "age" of adaptive immunity and hence human longevity. In this respect, immunosenescence is infectious.

http://www.ncbi.nlm.nih.gov/pubmed/16803971?ordinalpos=1&itool=EntrezSystem2.PEntrez.Pubmed.Pubmed_ResultsPanel.Pubmed_DiscoveryPanel.Pubmed_Discovery_RA









Immunological biomarkers of ageing in man: changes in both innate and adaptive immunity are associated with health and longevity.

Biogerontology. 2006 Oct-Dec


DelaRosa O, Pawelec G, Peralbo E, Wikby A, Mariani E, Mocchegiani E, Tarazona R, Solana R.

Immunology Unit, Department of Cellular Biology, Physiology and Immunology, University of Córdoba, Avda. Menéndez Pidal, s/n. 14071, Cordoba, Spain.

Scientific and clinical advances in the last century have led to increased numbers of individuals living to older ages. Thus a major concern is how to live these years with a high quality of life. The ageing immune system is less well able to cope with infectious diseases than the youthful immune system probably as a consequence of altered immune response to pathogens. Thus, both innate and adaptive immune responses show age-related changes that could be decisive for healthy ageing and survival. Longitudinal studies in healthy elderly have allowed the definition of the ''immune risk phenotype" (IRP) a predictor of mortality in elderly individuals that is based on several parameters of the adaptive immune response. Here, we hypothesize that failures in innate immunity observed in frail elderly are related to those alterations described in adaptive immunity defined as the IRP. It will be important to include assays of NK cell markers and functions in future longitudinal studies in order to investigate this point in detail as well as to consider the trace element zinc as an essential co-factor for optimal NK cell activity.

http://www.ncbi.nlm.nih.gov/pubmed/16957868?ordinalpos=1&itool=EntrezSystem2.PEntrez.Pubmed.Pubmed_ResultsPanel.Pubmed_DiscoveryPanel.Pubmed_Discovery_RA










Immunity and ageing in man.

Exp Gerontol. 2006 Dec


Pawelec G.

University of Tübingen Center for Medical Research, Waldhörnlestr. 22, D-72072 Tübingen, Germany.

Immunosenescence resulting in decreased ability to control infectious disease contributes to morbidity and mortality not only in the very elderly, but in all likelihood already from middle age. Studying immunity in humans is therefore essential for developing treatments to restore dysregulated immune responses and assure healthy longevity. The past year has seen many significant advances in our knowledge of age-associated alterations to immunity in elderly people, only some of which can be briefly reviewed here.

http://www.ncbi.nlm.nih.gov/pubmed/17118601?ordinalpos=20&itool=EntrezSystem2.PEntrez.Pubmed.Pubmed_ResultsPanel.Pubmed_RVDocSum








Analyses of immunosenescent markers in patients with autoimmune disease.

Clin Immunol. 2007 May


Thewissen M, Somers V, Venken K, Linsen L, van Paassen P, Geusens P, Damoiseaux J, Stinissen P.

Hasselt University, Biomedical Research Institute and Transnationale Universiteit Limburg, School of Life Sciences, Agoralaan, Diepenbeek, Belgium, and Department of Clinical and Experimental Immunology, University Hospital Maastricht, The Netherlands.

The objective of this study was to evaluate the degree of immunosenescence in patients with autoimmune disease. T cell receptor excision circles (TREC) and the percentage of CD4+CD28null T cells were studied as markers of immunosenescence in 175 patients with chronic autoimmune arthritis, other connective tissue autoimmune diseases, multiple sclerosis and 60 healthy controls. In both the rheumatoid arthritis (RA) and multiple sclerosis patient group, TREC numbers were age-inappropriately declined which points to an accelerated thymic output. Furthermore, enhanced percentages of CD4+CD28null T cells could be detected in a significant proportion of patients included in this study. These immunosenescent phenomena seemed to be present already early in the disease process. High percentages of CD4+CD28null T cells were associated with the presence of RA linked HLA DR4 alleles and with plasma reactivity to cytomegalovirus. Further analysis of CD4+CD28null T cells provided indications for a restricted T cell receptor (TCR) BV gene expression and cytoplasmic stores of various cytotoxic molecules. This study indicates that the immune system of patients with autoimmune diseases shows signs of an accelerated aging. Both genetic factors, such as HLA DR4, and environmental factors, like CMV infection, might speed up this immunosenescence and contribute in this way to disease pathogenesis.

http://www.ncbi.nlm.nih.gov/pubmed/17317320?ordinalpos=15&itool=EntrezSystem2.PEntrez.Pubmed.Pubmed_ResultsPanel.Pubmed_RVDocSum











Healthy aging and latent infection with CMV lead to distinct changes in CD8+ and CD4+ T-cell subsets in the elderly.

Hum Immunol. 2007 Feb


Weinberger B, Lazuardi L, Weiskirchner I, Keller M, Neuner C, Fischer KH, Neuman B, Würzner R, Grubeck-Loebenstein B.

Immunology Division, Institute for Biomedical Aging Research, Austrian Academy of Sciences, Innsbruck, Austria.

Despite general acceptance that immunologic changes are associated with aging and latent infection with Cytomegalovirus (CMV), no clear-cut distinction has so far been made between strictly age-related and CMV-induced changes. We therefore compared CD4+ and CD8+ naïve (CD45RA+CD28+), memory (CD45RA-CD28+), and effector (CD28-) T cells in CMV-positive (n = 164) and CMV-negative (n = 87) elderly persons and correlated CD8+ and CD4+ effector T cells with other T-cell subpopulations. Percentages of CD8+ as well as CD4+ effector T cells were higher, but percentages of naïve and memory cells were lower in CMV-positive compared to CMV-negative elderly persons. Negative correlations within CD8+ T-cell subsets were found to be present in both CMV-positive and CMV-negative elderly individuals. In contrast, correlations within CD4+ T-cell subpopulations and a positive correlation between CD8+ and CD4+ effector T cells were found in CMV-positive individuals only. Our results demonstrate that (a) in the elderly different T-cell subsets compete for space within the CD8+, but not the CD4+ T-cell population; (b) CMV induces changes in the CD4+ compartment that differ from the solely age-related changes seen in CMV-negative elderly population; and (c) the CMV-status of a population has to be taken into account before a conclusion on the effect of aging on the composition of the T-cell pool can be reached.

http://www.ncbi.nlm.nih.gov/pubmed/17321897?ordinalpos=14&itool=EntrezSystem2.PEntrez.Pubmed.Pubmed_ResultsPanel.Pubmed_RVDocSum









Role of persistent CMV infection in configuring T cell immunity in the elderly.

Immun Ageing. 2007 Mar


Vasto S, Colonna-Romano G, Larbi A, Wikby A, Caruso C, Pawelec G.

Gruppo di Studio sull'Immunosenescenza, Dipartimento di Biopatologia e Metedologie Biomediche, University of Palermo, Italy.

Ageing is associated with declines in many physiological parameters, including multiple immune system functions. The rate of acceleration of the frequency of death due to cardiovascular disease or cancer seems to increase with age from middle age up to around 80 years, plateauing thereafter. Mortality due to infectious disease, however, does not plateau, but continues to accelerate indefinitely. The elderly commonly possess oligoclonal expansions of T cells, especially of CD8 cells, which, surprisingly, are often associated with cytomegalovirus (CMV) seropositivity. This in turn is associated with many of the same phenotypic and functional alterations to T cell immunity that have been suggested as biomarkers of immune system aging. Thus, the manner in which CMV and the host immune system interact is critical in determining the "age" of specific immunity. We may therefore consider immunosenescence in some respects as an infectious state. This implies that interventions aimed at the pathogen may improve the organ system affected. Hence, CMV-directed anti-virals or vaccination may have beneficial effects on immunity in later life.

http://www.ncbi.nlm.nih.gov/pubmed/17376222?ordinalpos=13&itool=EntrezSystem2.PEntrez.Pubmed.Pubmed_ResultsPanel.Pubmed_RVDocSum










The cytomegalovirus-specific CD4+ T-cell response expands with age and markedly alters the CD4+ T-cell repertoire.

J Virol. 2007 Jul


Pourgheysari B, Khan N, Best D, Bruton R, Nayak L, Moss PA.

C.R. U.K. Institute for Cancer Studies, Vincent Drive, Edgbaston, University of Birmingham, Birmingham B15 2TA, United Kingdom.

Immune function in the elderly is associated with a number of phenotypic and functional abnormalities, and this phenomenon of immune senescence is associated with increased susceptibility to infection. The immune response to pathogens frequently declines with age, but the CD8(+) T-cell response to cytomegalovirus (CMV) is unusual, as it demonstrates a significant expansion over time. Here we have documented the CD4(+) T-cell immune response to CMV in healthy donors of different ages. The magnitude of the CMV-specific CD4(+) T-cell immune response increases from a mean of 2.2% of the CD4(+) T-cell pool in donors below 50 years of age to 4.7% in donors aged over 65 years. In addition, CMV-specific CD4(+) T cells in elderly donors demonstrate decreased production of interleukin-2 and less dependence on costimulation. CMV seropositivity is associated with marked changes in the phenotype of the overall CD4(+) T-cell repertoire in healthy aged donors, including an increase in CD57(+) expression and a decrease in CD28 and CD27 expression, a phenotypic profile characteristic of immune senescence. This memory inflation of CMV-specific CD4(+) T cells contributes to evidence that CMV infection may be damaging to immune function in elderly individuals.

http://www.ncbi.nlm.nih.gov/pubmed/17409149?ordinalpos=9&itool=EntrezSystem2.PEntrez.Pubmed.Pubmed_ResultsPanel.Pubmed_RVDocSum











No Immune Risk Profile among individuals who reach 100 years of age: findings from the Swedish NONA immune longitudinal study.

Exp Gerontol. 2007 Aug


Strindhall J, Nilsson BO, Löfgren S, Ernerudh J, Pawelec G, Johansson B, Wikby A.

Department of Natural Science and Biomedicine, School of Health Sciences, Jönköping University, Box 1026, 551 11 Jönköping, Sweden.

In the present NONA immune longitudinal study, we investigate the previously identified Immune Risk Profile (IRP), defined by an inverted CD4/CD8 ratio and associated with persistent cytomegalovirus infection and increased numbers of CD8+CD28- cells, relative 6-year survival and age in NONA individuals. These subjects have now reached age 92, 96, and for the first time in this study, 100 years at follow-up. A 55 year old middle-aged group was used for comparison. Immunological monitoring included the analysis of numbers of lymphocytes and neutrophils, the T-cell subsets CD3+CD4+, CD3+CD8+, CD8+CD28+, CD8+CD28-, and the CD4/CD8 ratio. Longitudinal data were analysed by multivariate analyses of variance (MANOVA) from four measurement occasions at 2-year inter-intervals. One-way ANOVA was used for cross-sectional comparisons at baseline and the 6-year follow-up. The results confirmed the importance of the IRP as a major predictor of mortality in this population of very old. Moreover, the results suggested that survival to the age of 100 years is associated with selection of individuals with an "inverted" IRP that was stable across time, i.e., maintenance of a high CD4/CD8 ratio and low numbers of CD8+CD28- cells. The results underlines the importance of a longitudinal study design in dissecting immune parameters predictive of survival and show for the first time that centenarian status is associated with avoidance of the IRP over at least the previous 6 years and probably throughout life.

http://www.ncbi.nlm.nih.gov/pubmed/17606347?ordinalpos=6&itool=EntrezSystem2.PEntrez.Pubmed.Pubmed_ResultsPanel.Pubmed_RVDocSum








Massive load of functional effector CD4+ and CD8+ T cells against cytomegalovirus in very old subjects.

J Immunol. 2007 Sep 15


Vescovini R, Biasini C, Fagnoni FF, Telera AR, Zanlari L, Pedrazzoni M, Bucci L, Monti D, Medici MC, Chezzi C, Franceschi C, Sansoni P.

Department of Internal Medicine and Biomedical Sciences, University of Parma, Parma, Italy.

A progressive, systemic, and low-grade proinflammatory status is one of the major characteristics of immunosenescence. Emerging data suggest a possible contribution of CMV, known to chronically infect a large proportion of humans, lifelong from newborns to centenarians. To test this hypothesis, we evaluated functional T cell responses to two CMV immunogenic proteins, pp65 and IE-1, in 65 chronically infected subjects aged 25-100 years. PBMC were stimulated with mixtures of peptides spanning the entire sequence of both proteins, and Ag specificity and magnitude of intracellular IFN-gamma- and TNF-alpha-positive cells were then analyzed within both CD4+ and CD8+ T cells. Results indicate that pp65 and, to a lesser extent, IE-1 constitute major Ags against which aged people target functionally efficient T cell effector responses with massive production of Th1 cytokines and exhibition of CD107a degranulation marker. As a result, the production of IFN-gamma induced in T cells by both Ags was seven to eight times greater in very old than in young subjects. The comparative analysis of pp65-specific responses in these very long-term carriers revealed a reciprocal relationship between CD4+ and CD8+ producing IFN-gamma in the same individuals. These results indicate that CMV represents an important pathogen responsible for a strong immune activation in human aging. Such a remarkable burden of effector CD4+ and CD8+ T cells may be necessary to protect the elderly from CMV endogenous reactivation, but can turn detrimental by giving a substantial contribution to the proinflammatory status that accompanies the main age-related diseases.

http://www.ncbi.nlm.nih.gov/pubmed/17785869?ordinalpos=5&itool=EntrezSystem2.PEntrez.Pubmed.Pubmed_ResultsPanel.Pubmed_RVDocSum








Dynamics of T cell memory in human cytomegalovirus infection.

Med Microbiol Immunol. 2008 Feb


Waller EC, Day E, Sissons JG, Wills MR.

Department of Medicine, Level 5, Addenbrookes Hospital, University of Cambridge, Hills Rd, Cambridge, CB2 2QQ, UK.

Primary human cytomegalovirus (HCMV) infection of an immunocompetent individual leads to the generation of a robust CD4+ and CD8+ T cell response which subsequently controls viral replication. HCMV is never cleared from the host and enters into latency with periodic reactivation and viral replication, which is controlled by reactivation of the memory T cells. In this article, we discuss the magnitude, phenotype and clonality of the T cell response following primary HCMV infection, the selection of responding T cells into the long-term memory pool and maintenance of this memory T cell population in the face of a latent/persistent infection. The article also considers the effect that this long-term surveillance of HCMV has on the T cell memory phenotype, their differentiation, function and the associated concepts of T cell memory inflation and immunosenescence.

http://www.ncbi.nlm.nih.gov/pubmed/18301918?ordinalpos=2&itool=EntrezSystem2.PEntrez.Pubmed.Pubmed_ResultsPanel.Pubmed_RVDocSum








The immune system in extreme longevity.

Exp Gerontol. 2008 Feb


Sansoni P, Vescovini R, Fagnoni F, Biasini C, Zanni F, Zanlari L, Telera A, Lucchini G, Passeri G, Monti D, Franceschi C, Passeri M.

Dipartimento di Medicina Interna e Scienze Biomediche, Università di Parma, Via Gramsci 14, 43100 Parma, Italy.

Recent observations indicate that immunosenescence is not accompanied by an unavoidable and progressive deterioration of the immune function, but is rather the result of a remodeling where some functions are reduced, others remain unchanged or even increased. In addition, it appears that the ancestral/innate compartment of the immune system is relatively preserved during aging in comparison to the more recent and sophisticated adaptive compartment that exhibit more profound modifications. The T-cell branch displays an age-dependent decline of the absolute number of total T-cells (CD3+), involving both CD4+ and CD8+ subsets, accompanied by an increase of NK cells with well-preserved cytotoxic function and by a reduction of B-cells. One of the main characteristics of the immune system during aging is a progressive, age-dependent decline of the virgin T-cells (CD95-), which is particularly profound at the level of the CD8+ subpopulation of the oldest old subjects. The progressive exhaustion of this important T-cell subpopulation dedicated primarily to the defense against new antigenic challenges (viral, neoplastic, bacterial ones), could be a consequence of both the thymic involution and the lifelong chronic antigenic stimulation. The immune function of the elderly, is therefore weakened by the exhaustion of CD95- virgin cells that are replaced by large clonal expansions of CD28- T-cells. The origin of CD28- cells has not been completely clarified yet, but it is assumed that they represent cells in the phase of replicative senescence characterized by shortening telomers and reduced proliferative capacity. A major characteristic of the immune system during aging is the up-regulation of the inflammatory responses which appears to be detrimental for longevity. In this regard, we have recently observed a progressive age-dependent increase of type 1(IL-2, IFN-gamma, TNF-alpha) and type 2 (IL-4, IL-6, IL-10) positive CD8+ T-cells; in particular, type 1 cytokine-positive cells significantly increased, with age, in all CD8+ subsets particularly among effector/cytotoxic and memory cells. A major force able to drive a chronic pro-inflammatory state during aging may be represented by persistent viral infections by EBV and CMV. Therefore, we have determined the frequency and the absolute number of viral antigen-specific CD8+ T-cells in subjects older than 85 years, who were serologically positive for CMV or EBV. In the majority of these subjects we detected the presence of T lymphocytes positive for epitopes of CMV or EBV. In all subjects the absolute number of CMV-positive CD8+ cells outnumbered that of EBV-positive ones. In addition, the majority of CMV+ T cells were included within the CD28- subpopulation, while EBV+ T cells belonged mainly to the CD28+ subset. These data indicate that the chronic antigenic stimulation induced by persistent viral infections during aging bring about important modifications among CD8+ subsets, which are particularly evident in the presence of CMV persistence. The age-dependent expansions of CD8+CD28- T-cells, mostly positive for pro-inflammatory cytokines and including the majority of CMV-epitope-specific cells, underlines the importance of chronic antigenic stimulation in the pathogenesis of the main immunological alterations of aging and may favour the appearance of several pathologies (arteriosclerosis, dementia, osteoporosis, cancer) all of which share an inflammatory pathogenesis.

http://www.ncbi.nlm.nih.gov/pubmed/17870272?ordinalpos=1&itool=EntrezSystem2.PEntrez.Pubmed.Pubmed_ResultsPanel.Pubmed_DiscoveryPanel.Pubmed_Discovery_RA









The immunological burden of human cytomegalovirus infection.

Arch Immunol Ther Exp (Warsz). 2007


Khan N.

Division of Immunology, School of Infection and Host Defence, University of Liverpool, UK.

Cytomegalovirus (CMV) is a persistent DNA virus that has evolved with humans to establish a finely balanced host-virus relationship. This balance is maintained by host immune surveillance since deficiencies in these processes can result in life-threatening disease, as observed in immunologically immature neonates and pharmacologically immunosuppressed transplant recipients. Both T cells and natural killer cells are intimately involved in maintaining asymptomatic infection by specific and non-specific recognition of infected cells. Under pressure from such host immune responses, CMV appears to have evolved elaborate strategies to subvert these responses in order to persist in the host. CMV target antigens are well characterized, with many CD8 T cell and CD4 T cell epitopes reported. This information is now being exploited to treat immunocompromised patients in order to boost virus-specific immunity. This review also discusses our current understanding of how virus carriage may skew lymphocyte populations in immunocompetent subjects and the association of CMV-seropositivity with immunosenescence.

http://www.ncbi.nlm.nih.gov/pubmed/18219760?ordinalpos=9&itool=EntrezSystem2.PEntrez.Pubmed.Pubmed_ResultsPanel.Pubmed_RVDocSum



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