Biomedical subjects

Graham Pawelec

Publications and source records attributed to Graham Pawelec.

At least 19 recordsLinked to original sources

PubMed2006

Zinc, oxidative stress, genetic background and immunosenescence: implications for healthy ageing.

The relevance of zinc for proper functioning of the entire immune system is already well documented. However, the identification of individuals who really need zinc supplementation is still debated in view of the fact that excessive zinc may also be toxic. The risk of developing zinc deficiency in people from industrialized countries is relatively low, except for elderly subjects where zinc intake may be suboptimal and inflammation is chronic. Thus, the role of zinc on the immune system and on the health of European elderly people is becoming of paramount importance, considering also that the elderly population is rapidly increasing. In particular, the factors contributing to and the biochemical markers of zinc deficiency in the elderly are still remain to be established. Epidemiological, functional, and genetic studies aimed at formulating a rationale for the promotion of healthy ageing through zinc supplementation was the subject of an International Conference held in Madrid from 11-13 February 2006 (3rd ZincAge Meeting) at the CNIO Institute (local organizer: Maria Blasco, partner of ZincAge).

Journal Article↗

PubMed2006

The immune risk phenotype is associated with IL-6 in the terminal decline stage: findings from the Swedish NONA immune longitudinal study of very late life functioning.

In the present NONA immune longitudinal study, we further examine the previously identified T cell immune risk phenotype (IRP), relative inflammatory activity, morbidity and 2-year mortality in very old individuals >90 years. T-cell subsets as well as the inflammatory markers IL-6, IL-10, C-reactive protein, transthyretin and albumin were evaluated. IRP and low-grade inflammation predicted 57% of observed deaths and 97% of survival over 2 years, and was not significantly affected by individuals' health status, suggesting that the physiological ageing processes of T-cell immunosenescence and low-grade inflammation are of primary importance in late life survival. IRP non-survivors showed only a minor inflammatory activity at baseline, but had in contrast to survivors developed increased activity at follow-up. The results suggest a sequence of stages for IRP individuals that begin with acquisition of CMV infection in earlier life, followed by generation of CD8+CD28- cells to control persistent CMV infection and eventually the development of an IRP. Intriguingly, we also found that rare individuals moved out of the IRP category by a process of immune suppression, including increases in IL-6 and IL-10 and decreases in the number of CD3+CD8+CD28- cells. The further characterisation of these exceptional individuals may allow insight into remedial approaches for those who remain in the IRP category until death.

Aged, 80 and over↗

PubMed2006

Human cytomegalovirus infection and T cell immunosenescence: a mini review.

The mammalian immune system defends the organism against pathogens, and possibly cancer, but is known to become dysregulated with increasing age. This results in greater morbidity and mortality due to infectious disease in old people. The most important changes occur in T cell immunity, manifested sometimes dramatically as altered clonal expansions of cells of limited antigen specificity and a marked shrinkage of the T cell antigen receptor repertoire. At the same time, it was independently reported that CMV seropositivity was associated with many of the same T cell changes that were being identified as biomarkers of immune ageing. It has now become clear that CMV is commonly the driving force behind the oligoclonal expansions and altered phenotypes and functions of CD8 cells seen in most old people. These changes are much less obvious in centenarians and most extreme in people whom longitudinal studies have shown to possess an "immune risk profile". This is a cluster of immunological parameters of which CMV seropositivity is one component and which predicts incipient mortality in an elderly population. Taken together, these findings suggest the hypothesis that persistence of CMV as a chronic antigenic stressor is a major contributor to immunosenescence and associated mortality.

Aged↗

PubMed2006

Age and immunity.

Longitudinal studies are defining progressive alterations to the immune system associated with increased mortality in the very elderly. Many of these changes are exacerbated by or even caused by chronic T cell stimulation by persistent antigen, particularly from Cytomegalovirus. The composition of T cell subsets, their functional integrity and representation in the repertoire are all markedly influenced by age and by CMV. How these findings relate to epidemiological, functional, genetic, genomic and proteomic studies of human T cell immunosenescence was the subject of intense debate at an international conference held just before Christmas 2005 in the Black Forest.

Journal Article↗

PubMed2006

Lymphocyte activation in response to melanoma: interaction of NK-associated receptors and their ligands.

In recent years, studies on the molecular and cellular mechanisms of immune responses against melanoma have contributed to a better understanding of how these tumours can be recognised by cytotoxic cells and the mechanisms they have developed to escape from innate and adaptive immunity. Lysis of melanoma cells by natural killer (NK) cells and cytolytic T cells is the result of a fine balance between signals transmitted by activating and inhibitory receptors. In addition to the T cell receptor, these were initially described as NK cell-associated receptors (NKRs) and were later also found on subsets of T lymphocytes, particularly effector-memory and terminally differentiated CD8 T cells. An increase of NKR(+)CD8(+) T cells has been found in melanoma patients, correlating with the expansion of differentiated effector CD8(+)CD28(null) CD27(null) T cells. NKRs can regulate the lysis of target cells expressing appropriate ligands. Activating receptors recognise ligands on tumours whereas inhibitory receptors are specific for MHC class I antigens and sense missing self. Altered expression of MHC class I antigens is frequently found on melanoma cells, preventing recognition by specific cytolytic T cells but favouring NK cell recognition. Changes in the expression of NKR-ligands in melanoma contribute in explaining the differences in the capacity of cytotoxic immune cells to control melanoma growth and dissemination.

Humans↗

PubMed2006

Longitudinal studies of clonally expanded CD8 T cells reveal a repertoire shrinkage predicting mortality and an increased number of dysfunctional cytomegalovirus-specific T cells in the very elderly.

The age-associated decrease in functionality of the human immune system is thought to have a negative impact on the capacity to provide protection against infection, in turn leading to increased incidence of mortality. In a previous longitudinal study of octogenarians, we identified an immune risk phenotype (IRP) in the very elderly defined by an inverted CD4/CD8 ratio, which was associated with increased mortality and persistent CMV infection. In this study, we analyzed the CD8 clonal composition of nonagenarians and middle-aged individuals. An increased number of CD8 T cell clones was observed in the nonagenarians, and was associated with CMV-seropositivity. Surprisingly, CMV-seropositive nonagenarians with the IRP had a significantly lower number of clones compared with non-IRP individuals. The decrease in clone numbers in IRP individuals was associated with shorter survival time. MHC/peptide multimer staining indicated that the frequency of CMV-specific T cells was higher in nonagenarians than in the middle-aged, but the ratio of functionally intact cells was significantly lower. The lowest ratio of functional CMV-specific T cells was found in an IRP individual. A thorough longitudinal analysis of the CMV-specific T cells in nonagenarians showed a stable pattern with respect to frequency, phenotype, and clonal composition. We hypothesize that the number of different CD8 T cell clonal expansions increases as the individual ages, possibly, as a compensatory mechanism to control latent infections, e.g., CMV, but eventually a point is reached where clonal exhaustion leads to shrinkage of the CD8 clonal repertoire, associated with decreased survival.

Aged, 80 and over↗

PubMed2006

ESTDAB: a collection of immunologically characterised melanoma cell lines and searchable databank.

Cancer immunologists working in humans often require panels of tumour cell lines expressing different combinations of HLA alleles and other characteristics. Sources of cell lines are usually large cell banks carrying little immunologically relevant information on the available cells and limited numbers of different lines from the same type of tumour. Access to cells with desired combinations of characteristics is, therefore, difficult. Here, we describe an interactive database of a large collection of melanoma cell lines which have been extensively characterised for HLA genotype and surface expression, oncogene and tumour antigen expression, cytokine secretion, surface molecule expression, adhesion to extracellular matrix components, cytokine gene polymorphisms and other factors of interest to immunologists. This enables investigators to search for cells with particular constellations of HLA alleles, tumour antigens, etc., and then request these from the cell bank. This European Searchable Tumour Cell Line and Data Bank (ESTDAB) was established as a Research Infrastructure of the European Commission. For access to the databank and further details, please go to http://www.ebi.ac.uk/ipd/estdab/ .

Animals↗

PubMed2006

T-cell dysregulation caused by chronic antigenic stress: the role of CMV in immunosenescence?

Dysfunctional T-cell immunity contributes to susceptibility to infectious disease in the elderly. A characteristic feature of this "immunosenescence" is the predominance of clonal expansions of CD8 cells and decreased diversity of the T-cell antigen receptor repertoire. Lifelong chronic antigenic stress commonly caused by infection with persistent activating herpes viruses causes the accumulation of anergic, apoptosis-resistant CD8 T cells. These dysfunctional cells are indirectly immunosuppressive by tasking up the "immunological space" as well as directly suppressive via blockade of antigen presenting cells or cytokine secretion. They are associated with an emerging "immunological risk profile" predicting mortality in longitudinal studies of very old people. It is therefore hypothesized that for that majority of elderly people infected with cytomegalovirus (CMV), which seems to act as the dominant chronic stressor, anti-viral strategies would be of benefit in abrogating some of the detrimental clinical manifestations of immunosenescence.

Aged↗

PubMed2006

Aging and innate immunity.

Adaptive immunity undergoes severe deterioration with age and represents the main problem in the elderly. However, evidence accumulated over the last decade supports the hypothesis that aging also has a profound impact on innate immunity, which in turn markedly impacts the health and longevity of older people.

Aging↗

PubMed2006

Immunorejuvenation in the elderly.

Dysregulated T-cell-mediated immunity contributes materially to the increased susceptibility to infectious disease, and possibly cancer, in the elderly. One hallmark of this state of "immunosenescence" in humans is the predominance of large clones of peripheral T cells with limited antigen receptor heterogeneity and a corresponding contraction of diversity in the T-cell antigen recognition repertoire. Surprisingly, a major driving force for these clonal expansions in humans is cytomegalovirus. The lifelong chronic antigenic stress caused by infection with this persistent activating virus results in clonal exhaustion of specific CD8 T cells, and their acquisition of a state of anergy and apoptosis resistance similar in many respects, and, the authors believe for similar reasons, to that commonly seen in the tumor-specific T cells of cancer patients. This excess of dysfunctional cells is indirectly immunosuppressive by filling the "immunologic space" and shrinking the T-cell repertoire for new antigens, as well as directly suppressive via cytokine secretion. It is associated with the "immunologic risk profile" predicting 2- and 4-year mortality in longitudinal studies of very old people. Therefore, it is hypothesized that deletion of such accumulations of dysfunctional cells would be beneficial to the individual. It may be possible to distinguish functional CMV-specific cells (which are essential to maintain immunosurveillance) from dysfunctional ones by their expression of certain surface molecules. This, coupled with methods directed at reinvigorating the thymus (e.g., use of interleukin 7), and targeting CMV by pharmacologic and immunotherapeutic interventions might result in a degree of "immunorejuvenation" sufficient to take elderly individuals out of the risk category and thereby extend healthy longevity.

Aged↗

PubMed2006

The genetics of human longevity.

Aging is due to a complex interaction of genetic, epigenetic, and environmental factors, but a strong genetic component appears to have an impact on survival to extreme ages. In order to identify "longevity genes" in humans, different strategies are now available. In our laboratory, we performed association studies on a variety of "candidate" polymorphisms in Italian centenarians. Many genes/polymorphisms gave negative results, while others showed a positive association with human longevity and a sometimes-positive association with unsuccessful aging (myocardial infarction, Alzheimer's disease, and type 2 diabetes). Results regarding genes involved in inflammation (IL-1 cluster, IL-6, IL-10, TNF-alpha, TGF-beta, TLR-4, PPARgamma), insulin/IGF-1 signaling pathway and lipid metabolism (apolipoproteins, CETP, PON1), and oxidative stress (p53, p66(shc)) will be described. In addition, a strong role of the interaction between nuclear and mitochondrial genomes (mtDNA haplogroups and the C150T mutation) emerged from our findings. Thus, the genetics of human longevity appears to be quite peculiar in a context where antagonistic pleiotropy can play a major role and genes can have a different biological role at different ages.

Adaptor Proteins, Signal Transducing↗

PubMed2005

When T cells get old.

Why is vaccination against infectious diseases less effective in older patients than in younger ones? Why do the elderly suffer from more frequent and severe infectious episodes than the young? The answer to both these questions is immunosenescence--the poorly defined changes that occur in the immune system as a result of the disrupted performance of multiple components of immunity. Presentations from a recent workshop, which are summarized here, examined these questions and provided some insights from the perspective of improving vaccination strategies among the elderly.

Aged↗

PubMed2005

T Cell Immunity and Aging.

The effect of age on the immune system is generally detrimental and results in "immunosenescence," a poorly-defined state inadequately reflected in clinical data and for which few reliable "biomarkers of aging" are available. The multinational consortium "T-Cell Immunity in Ageing," T-CIA, was set up to examine these issues specifically as applied to T lymphocytes. This Perspective discusses some of the outcomes of a recent conference that considered progress toward resolving these questions in humans.

Aging↗

PubMed2005

Immunosenescence and vaccination.

The problems associated with the ageing immune system and vaccination were discussed recently at an international workshop at the Jenner Institute for Vaccine Research, Compton, UK, 6-7 October, 2005. This is a commentary on that session. The meeting included discussions on T and B cell differentiation and ageing, as well as dendritic cell and neutrophil data, with the emphasis on T cell immunosenescence, perceived as the most important hindrance to satisfactory responses to vaccines in the elderly. The main questions to be addressed in this context are the reasons for dysfunctionality of T cells in the elderly and what to do to improve T cell function. Several of the major reasons for poor T cell responses in the elderly were discussed; however, many important questions remain: The next meeting at the Jenner Institute may already be able to provide some of the answers to these questions, which have serious implications for public health issues in increasingly elderly populations.

Journal Article↗

PubMed2005

An investigation of DNA mismatch repair capacity under normal culture conditions and under conditions of supra-physiological challenge in human CD4+T cell clones from donors of different ages.

T cells undergo rapid clonal expansion upon antigenic stimulation to produce an effective immune response. Any defect in the DNA mismatch repair (MMR) system may have a detrimental effect on T cell proliferation. This study employed an in vitro model of human CD4+T cell ageing to investigate MMR capacity at various stages of T cell lifespan. A novel modification of the alkaline comet assay, which utilised T4 endonuclease VII to detect single base DNA mismatches, was used to assess DNA mismatch frequency. No clear pattern in DNA mismatch frequency with increasing culture age was observed. However, the ability to repair induced DNA mismatches (following treatment with acridine mutagen ICR-191) revealed an age-related decline in the efficiency of the MMR system in clones derived from a 26 and a 45-year-old donor, but not from an 80-year-old very healthy SENIEUR donor. This study suggests that unchallenged, dividing human T cell clones have variable levels of DNA mismatches throughout their lifespan, not affecting proliferation. However, when challenged with supra-physiological levels of DNA mismatches, deficiencies were found in ageing T cell clones in MMR capacity, with the exception of T cell clones from a SENIEUR donor previously shown to maintain effective DNA excision repair.

Adult↗

PubMed2005

T-CIA: investigating T cells in aging.

Over the past few decades it has become clear that the immune system and especially T cells are instrumental in achieving a long and healthy life. The European Union (EU) previously supported several pan-European research projects coordinated from Tuebingen, Germany, aimed at providing a better understanding of immunosenescence. For 3 years, until the end of 2005, the EU is supporting a project called T cells in aging (T-CIA). The aim of T-CIA is to spy out and combine current efforts in immunology, molecular biology, and gerontology for a better understanding of why the elderly often have dysregulated immune responses and are more susceptible to infections and cancer.

Aging↗

PubMed2005

High frequencies of functionally impaired cytokeratin 18-specific CD8+ T cells in healthy HLA-A2+ donors.

Combining cell surface phenotyping with functional analysis, human CD8+ T cells have been divided into several subsets which are being studied extensively in diverse physiological situations, such as viral infection, cancer and ageing. In particular, so-called terminally differentiated effector cells possess a CD45RA+ CCR7- CD27- CD28- phenotype, contain perforin and, in different models, have been shown to exert direct ex vivo killing and to release interleukins upon both antigen-nonspecific and -specific stimulation. Using HLA class I multimers, we have identified a high frequency of peripheral CD8+ T cells that recognize a peptide derived from the self protein cytokeratin 18 presented by the HLA-A*0201 molecule. These cells can be detected in approximately 15% of the HLA-A2-positive healthy donors tested. A detailed analysis revealed that they must have divided extensively in vivo, have an effector cell phenotype and express various natural killer cell-associated receptors. Interestingly, however, they remained unresponsive to antigen-specific stimulation in vitro in terms of cytotoxicity and cytokine secretion. Thus, cytokeratin 18-specific cells constitute a frequently encountered, new CD8+ T lymphocyte subpopulation without classical effector status and with so far unknown function.

CD8-Positive T-Lymphocytes↗

PubMed2005

The concept of telomeric non-reciprocal recombination (TENOR) applied to human fibroblasts grown in serial cultures: concordance with genealogical data.

Since the discovery of the limited life span of human fibroblasts some 50 years ago, many genealogical studies have been undertaken to describe growth kinetics of fibroblasts in serial cultures by their individual division behavior. It is now accepted that proliferation capacities of human fibroblasts strongly depend on their telomere lengths and integrity. Telomeres shorten with each replication round, and there is a direct correlation between cell division capacity and telomere lengths; that is, the consumption of disposable telomeric DNA repeats during cell divisions progresses until critically short telomeres determining the replicative senescence of the cells are present. Recently, we have suggested that telomeres in fibroblasts can also become elongated during DNA replication by telomeric non-reciprocal recombination (TENOR). Here we discuss genealogical data collected over the last decades as well as more recent findings on the telomere-driven replicative senescence process, and we summarize both to give an integrated picture.

Animals↗