Evelyna Derhovanessian - Academia.edu (original) (raw)

Papers by Evelyna Derhovanessian

Molecular Immunology, 2009

Prothymosin α (ProTα) is a small acidic polypeptide with important immunostimulatory properties, ... more Prothymosin α (ProTα) is a small acidic polypeptide with important immunostimulatory properties, which we have previously shown to be exerted by its carboxyl (C)-terminus. It exerts immunoenhancing effects through stimulation of monocytes via toll-like receptor (TLR) triggering. Here, we assayed the activity of synthetic peptides homologous to ProTα’s C-terminus to stimulate lymphocyte functions, in particular natural killer cell cytotoxicity of

Journal of immunology (Baltimore, Md. : 1950), 2014

Influenza remains a major pathogen in older people. Infection with CMV and the accumulation of la... more Influenza remains a major pathogen in older people. Infection with CMV and the accumulation of late-differentiated T cells associated with it have been implicated in poor Ab responsiveness to influenza vaccination in the elderly, most of whom are CMV positive. However, whether CMV infection also affects memory T cell responses to influenza remains unknown. To investigate this, we assessed T cell responses to influenza A matrix protein and nucleoprotein ex vivo in 166 Dutch individuals (mean age 62.2 y, range 42-82) and validated the results in a second cohort from North America (mean age 73.1 y, range 65-81, n = 28). We found that less than half of the CMV-infected older subjects mounted a CD4 T cell response to influenza Ags, whereas ∼80% of uninfected elderly did so. A similar proportion of younger subjects possessed influenza A virus-responsive CD4 T cells, and, interestingly, this was the case whether they were CMV-infected. Thus, the effect of CMV was only seen in the older don...

In order to establish immunological biomarkers prospectively associating with survival in late-st... more In order to establish immunological biomarkers prospectively associating with survival in late-stage melanoma patients and to begin to investigate potential functional mechanisms contributing to this, we assessed responses of peripheral memory Tcells to peptides from NY-ESO-1 and Melan-A. Whereas existing immunomonitoringapproaches are usually only investigating whether T-cells, capable of recognizing certain antigens, are present or not, we additionally investigated here the exact phenotype and function of antigen-specific T-cells individually. The results show that the presence or absence of a response by CD4+ or CD8+ T-cells and the pattern of cytokines produced (IL-2, IFN-γ, TNF, IL-4, IL-10 and IL-17 measured simultaneously in each cell) associate with remaining survival time. Our observations might help to improve upcoming immunotherapeutic trials, especially those that aim to increase anti-cancer responses, and provide a rationale to investigate further the role of IL-17 and IL-4 producing T-cells in cancer malignancies.

Virus Research, 2011

a b s t r a c t "Immune senescence" is a descriptive term for the deleterious age-associated chan... more a b s t r a c t "Immune senescence" is a descriptive term for the deleterious age-associated changes to immunity observed in all mammals studied so far. While all components of innate and adaptive immunity are changed with age, the clinical impact of these changes is not clear, and mechanisms of and markers for immunosenescence are controversial. In humans, several cross-sectional studies have demonstrated that the major accepted age-associated changes to parameters used to assess adaptive immune status are markedly influenced by infection with cytomegalovirus (CMV). In the very limited longitudinal studies thus far carried out, a cluster of immune parameters associating with 2-, 4-and 6-year survival of the very elderly has been identified and termed the "immune risk profile" (IRP). This cluster includes seropositivity for CMV and is characterised by accumulations of clonal expansions of late-differentiated CD8+ T cells, many of which are specific for CMV antigens. Here we review the impact of CMV on "immune senescence" in humans.

Vaccine, 2013

Influenza vaccination is less effective in the elderly compared to the young. Studies that have a... more Influenza vaccination is less effective in the elderly compared to the young. Studies that have attempted to identify immune parameters correlating with satisfactory vaccine responses have yielded inconclusive results. Here, we correlate the distribution of different circulating CD4+ and CD8+ T-cell phenotypes with the humoral response to vaccination with Intanza, an intradermal seasonal vaccine, in 54 individuals of different ages. Subjects were stratified according to age (below or over 60) and presence of a latent infection with Cytomegalovirus (CMV). CMV-seropositivity was significantly associated with a lower response rate to the vaccine in people over but not below 60 yr of age. Unlike reported data, late-differentiated (CD45RA+CCR7−CD27−CD28−) CD4+, but not CD8+ T-cells associated with a poorer vaccine response. Thus, latent CMV infection has a deleterious effect on influenza antibody responses in the elderly, which might be mediated through CD4 T-cells lacking CCR7, CD27 and CD28 and re-expressing CD45RA.

Reviews in Medical Virology, 2009

'Immunosenescence&amp... more 'Immunosenescence' is an imprecise term used to describe deleterious age-associated changes to immune parameters observed in all mammals studied so far. Primarily anecdotal evidence implies that failing immunity is responsible for the increased incidence and severity of infectious disease in old people. However, there is a serious dearth of accurate hard data concerning the actual cause of death in the elderly and the contribution thereto of the multitude of age-associated alterations measured in the immune system. Cross-sectional studies comparing those currently young with those currently old reveal a large number of differences in the distribution of immune cell types in the blood, and to some extent the functional integrity of those cells. Many of these parameters differ markedly between individuals infected with CMV and uninfected people, regardless of infection with other persistent herpesviruses. The adaptive arm of immunity appears to be more seriously affected than the innate arm, particularly the T lymphocytes. However, cross-sectional studies suffer the disadvantage that like is not being compared with like, because the conditions applied during the entire life course of the currently elderly were different from those applied now to the young. These differences in environment, nutrition, pathology and possibly genetics, rather than merely age, may be expected to influence the parameters studied. Moreover, pathogen exposure of the currently elderly was also different from contemporary exposure, probably including CMV. Some of the problems associated with cross-sectional studies can be overcome by performing longitudinal studies, as pointed out in an earlier analysis of the Baltimore Longitudinal Ageing study looking at lymphocyte numbers. However, longitudinal studies are challenging in humans. Nonetheless, the pioneering Swedish OCTO/NONA studies of the very elderly which for the first time included a range of immune parameters, have identified a set of immune parameters predicting mortality at 2, 4 and 6 year follow-up; CMV infection makes a material contribution to this so-called 'immune risk profile (IRP)'. Whether the IRP is informative in younger individuals and the mechanism of the CMV effect is discussed in this review.

Nature Medicine, 2012

1 2 5 4 VOLUME 18 | NUMBER 8 | AUGUST 2012 nAture medicine Therapeutic cancer vaccines hold the p... more 1 2 5 4 VOLUME 18 | NUMBER 8 | AUGUST 2012 nAture medicine Therapeutic cancer vaccines hold the promise of combining meaningful efficacy (prolongation of survival) with very good safety and tolerability, as has been shown in several recent randomized trials 1-3 . However, development of cancer vaccines remains a major challenge, with little knowledge of (i) the optimal tumor antigens to target, (ii) suitable agents to counteract regulatory mechanisms opposing successful immunotherapy and (iii) surrogate and predictive biomarkers that can improve our understanding of these regulatory mechanisms and predict a patient's response to therapy. The first major issue addressed in this work is whether relevant HLArestricted peptides for immunotherapeutic intervention in patients with RCC can be identified and clinically validated. We defined the relevance of the antigens as their natural presence on the tumor in the majority of RCC samples, their immunogenicity (induction of T cell responses in clinical studies) and the association of the vaccine-induced T cell responses with clinical benefit. For the identification, selection and preclinical immunological validation of such antigens, we used the antigen discovery platform XPRESIDENT 4,5 to create a multipeptide vaccine designated IMA901 for immunotherapy of RCC. We tested IMA901 in HLA-A*02 + subjects with advanced RCC in two clinical trials, a phase 1 (n = 28) and a randomized phase 2 (n = 68) trial, both of which assessed the association of T cell responses to IMA901 with clinical benefit.

Molecular Immunology, 2009

Prothymosin ␣ (ProT␣) is a small acidic polypeptide with important immunostimulatory properties, ... more Prothymosin ␣ (ProT␣) is a small acidic polypeptide with important immunostimulatory properties, which we have previously shown to be exerted by its carboxyl (C)-terminus. It exerts immunoenhancing effects through stimulation of monocytes via toll-like receptor (TLR) triggering. Here, we assayed the activity of synthetic peptides homologous to ProT␣'s C-terminus to stimulate lymphocyte functions, in particular natural killer cell cytotoxicity of peripheral blood mononuclear cells isolated from healthy donors. A synthetic decapeptide TKKQKTDEDD was identified as the most potent lymphocyte stimulator. The activity of this peptide was sequence-specific and comparable to that of the intact molecule, suggesting that ProT␣'s immunoactive segment encompasses the nuclear localization signal sequence of the polypeptide. Because ProT␣ stimulates immune responses in a monocyte-dependent manner, we further investigated whether the entire molecule and its peptide TKKQKTDEDD specifically act on monocytes and show that both can promote maturation of monocyte-derived dendritic cells (DC). Finally, knowing that, under specific conditions, ProT␣ forms amyloid fibrils, we studied the amyloidogenic properties of its C-terminal peptide segments, utilizing ATR FT-IR spectroscopy and transmission electron microscopy (negative staining). Although the peptide TKKQKTDEDD adopts an antiparallel ␤-sheet conformation under various conditions, it does not form amyloid fibrils; rather it aggregates in globular particles. These data, in conjunction with reports showing that the peptide TKKQKTDEDD is generated in vivo upon caspase-cleavage of ProT␣ during apoptosis, strengthen our hypothesis that immune response stimulation by ProT␣ is in principle exerted via its bioactive C-terminal decapaptide, which can acquire a sequence-specific ␤-sheet conformation and induce DC maturation.

Microbial Biotechnology, 2012

There is a general consensus that the elderly do not respond as well to vaccination as the young,... more There is a general consensus that the elderly do not respond as well to vaccination as the young, but robust studies are few and far between. Most refer to influenza vaccination, but even here, adequate immunological and clinical data are surprisingly thin on the ground. The meta-analysis by Goodwin et al. from 2006 is still the most comprehensive that we have. They reviewed 31 antibody response studies comparing influenza vaccination efficacy in groups of elderly and younger adults. They reported that the adjusted odds ratio (OR) of responses in elderly versus young adults ranged from 0.24 to 0.59 for the three influenza antigens used in the vaccines. They concluded that rather than the estimated 70-90% clinical vaccine efficacy in younger adults, this figure was only 17-53% in the elderly, depending on which viruses were prevalent that year. They stated that 'this highlights the need for more immunogenic vaccine formulations for the elderly'. How to achieve this? There are three areas where we may consider alterations to increase vaccine efficacy: (i) make the vaccine more potent; (ii) use adjuvants to enhance immunity; and (iii) apply immune modulators or other interventions to alter host immunity generally. We will consider these three options, focusing on influenza vaccination, in this mini-review.

The Journals of Gerontology Series A: Biological Sciences and Medical Sciences, 2014

A subset of older people is at increased risk of hospitalization and dependency. Emerging evidenc... more A subset of older people is at increased risk of hospitalization and dependency. Emerging evidence suggests that immunosenescence reflected by an inverted CD4:8 ratio and cytomegalovirus (CMV) seropositivity plays an important role in the pathophysiology of functional decline. Nevertheless, the relation between CD4:8 ratio and functional outcome has rarely been investigated. Here, CD4:8 ratio and T-cell phenotypes of 235 community-dwelling persons aged ≥81.5 years in the BELFRAIL study and 25 younger persons (mean age 28.5 years) were analyzed using polychromatic flow cytometry. In the elderly persons, 7.2% had an inverted CD4:8 ratio, which was associated with CMV seropositivity, less naive, and more late-differentiated CD4+ and CD8+ T cells. However, 32.8% had a CD4:8 ratio >5, a phenotype associated with a higher proportion of naive T cells and absent in young donors. In CMV seropositives, this subgroup had lower proportions of late-differentiated CD4+ and CD8+ T cells and weaker anti-CMV immunoglobulin G reactivity. This novel naive T-cell-dominated phenotype was counterintuitively associated with a higher proportion of those with impaired physical functioning in the very elderly people infected with CMV. This underscores the notion that in very elderly people, not merely CMV infection but also the state of its accompanying immune dysregulation is of crucial importance with regard to physical impairment.

International Journal of Cancer, 2009

Additional Supporting Information may be found in the online version of this article.

Immunity & Ageing, 2008

Compromised immunity contributes to the decreased ability of the elderly to control infectious di... more Compromised immunity contributes to the decreased ability of the elderly to control infectious disease and to their generally poor response to vaccination. It is controversial as to how far this phenomenon contributes to the well-known age-associated increase in the occurrence of many cancers in the elderly. However, should the immune system be important in controlling cancer, for which there is a great deal of evidence, it is logical to propose that dysfunctional immunity in the elderly would contribute to compromised immunosurveillance and increased cancer occurrence. The chronological age at which immunosenescence becomes clinically important is known to be influenced by many factors, including the pathogen load to which individuals are exposed throughout life. It is proposed here that the cancer antigen load may have a similar effect on "immune exhaustion" and that pathogen load and tumor load may act additively to accelerate immunosenescence. Understanding how and why immune responsiveness changes in humans as they age is essential for developing strategies to prevent or restore dysregulated immunity and assure healthy longevity, clearly possible only if cancer is avoided. Here, we provide an overview of the impact of age on human immune competence, emphasizing T-cell-dependent adaptive immunity, which is the most sensitive to ageing. This knowledge will pave the way for rational interventions to maintain or restore appropriate immune function not only in the elderly but also in the cancer patient.

Experimental Gerontology, 2014

Immunosenescence, defined as the age-associated dysregulation and dysfunction of the immune syste... more Immunosenescence, defined as the age-associated dysregulation and dysfunction of the immune system, is characterized by impaired protective immunity and decreased efficacy of vaccines. An increasing number of immunological, clinical and epidemiological studies suggest that persistent Cytomegalovirus (CMV) infection is associated with accelerated aging of the immune system and with several age-related diseases. However, current evidence on whether and how human CMV (HCMV) infection is implicated in immunosenescence and in age-related diseases remains incomplete and many aspects of CMV involvement in immune aging remain controversial. The attendees of the 4th International Workshop on "CMV & Immunosenescence", held in Parma, Italy, 25-27th March, 2013, presented and discussed data related to these open questions, which are reported in this commentary.

European Journal of Cancer, 2012

Current Opinion in Immunology, 2014

Acute inflammatory responses are essential for pathogen control and tissue repair but can also ca... more Acute inflammatory responses are essential for pathogen control and tissue repair but can also cause severe collateral damage. Tight regulation of the response is required to minimize host injury, but in the face of chronic infections and age-associated immune dysregulation, inflammatory processes may exert multiple detrimental effects on the organism. The signs of low level systemic inflammation commonly detectable in elderly people are associated with many chronic diseases of ageing and may even contribute to their causation. The purpose of this article is to review recent literature from the past two years providing new data on the inter-relationships between inflammatory status and chronic diseases of ageing.

Current Opinion in Immunology, 2009

Effects at the cellular level. Age and CMV seropositivity are both associated with several immune... more Effects at the cellular level. Age and CMV seropositivity are both associated with several immune changes especially those involving T cell phenotypes. Major surface receptors showing changes (increase or decrease) are illustrated.

Critical Reviews in Oncology/Hematology, 2008

Molecular Immunology, 2009

Prothymosin α (ProTα) is a small acidic polypeptide with important immunostimulatory properties, ... more Prothymosin α (ProTα) is a small acidic polypeptide with important immunostimulatory properties, which we have previously shown to be exerted by its carboxyl (C)-terminus. It exerts immunoenhancing effects through stimulation of monocytes via toll-like receptor (TLR) triggering. Here, we assayed the activity of synthetic peptides homologous to ProTα’s C-terminus to stimulate lymphocyte functions, in particular natural killer cell cytotoxicity of

Journal of immunology (Baltimore, Md. : 1950), 2014

Influenza remains a major pathogen in older people. Infection with CMV and the accumulation of la... more Influenza remains a major pathogen in older people. Infection with CMV and the accumulation of late-differentiated T cells associated with it have been implicated in poor Ab responsiveness to influenza vaccination in the elderly, most of whom are CMV positive. However, whether CMV infection also affects memory T cell responses to influenza remains unknown. To investigate this, we assessed T cell responses to influenza A matrix protein and nucleoprotein ex vivo in 166 Dutch individuals (mean age 62.2 y, range 42-82) and validated the results in a second cohort from North America (mean age 73.1 y, range 65-81, n = 28). We found that less than half of the CMV-infected older subjects mounted a CD4 T cell response to influenza Ags, whereas ∼80% of uninfected elderly did so. A similar proportion of younger subjects possessed influenza A virus-responsive CD4 T cells, and, interestingly, this was the case whether they were CMV-infected. Thus, the effect of CMV was only seen in the older don...

In order to establish immunological biomarkers prospectively associating with survival in late-st... more In order to establish immunological biomarkers prospectively associating with survival in late-stage melanoma patients and to begin to investigate potential functional mechanisms contributing to this, we assessed responses of peripheral memory Tcells to peptides from NY-ESO-1 and Melan-A. Whereas existing immunomonitoringapproaches are usually only investigating whether T-cells, capable of recognizing certain antigens, are present or not, we additionally investigated here the exact phenotype and function of antigen-specific T-cells individually. The results show that the presence or absence of a response by CD4+ or CD8+ T-cells and the pattern of cytokines produced (IL-2, IFN-γ, TNF, IL-4, IL-10 and IL-17 measured simultaneously in each cell) associate with remaining survival time. Our observations might help to improve upcoming immunotherapeutic trials, especially those that aim to increase anti-cancer responses, and provide a rationale to investigate further the role of IL-17 and IL-4 producing T-cells in cancer malignancies.

Virus Research, 2011

a b s t r a c t "Immune senescence" is a descriptive term for the deleterious age-associated chan... more a b s t r a c t "Immune senescence" is a descriptive term for the deleterious age-associated changes to immunity observed in all mammals studied so far. While all components of innate and adaptive immunity are changed with age, the clinical impact of these changes is not clear, and mechanisms of and markers for immunosenescence are controversial. In humans, several cross-sectional studies have demonstrated that the major accepted age-associated changes to parameters used to assess adaptive immune status are markedly influenced by infection with cytomegalovirus (CMV). In the very limited longitudinal studies thus far carried out, a cluster of immune parameters associating with 2-, 4-and 6-year survival of the very elderly has been identified and termed the "immune risk profile" (IRP). This cluster includes seropositivity for CMV and is characterised by accumulations of clonal expansions of late-differentiated CD8+ T cells, many of which are specific for CMV antigens. Here we review the impact of CMV on "immune senescence" in humans.

Vaccine, 2013

Influenza vaccination is less effective in the elderly compared to the young. Studies that have a... more Influenza vaccination is less effective in the elderly compared to the young. Studies that have attempted to identify immune parameters correlating with satisfactory vaccine responses have yielded inconclusive results. Here, we correlate the distribution of different circulating CD4+ and CD8+ T-cell phenotypes with the humoral response to vaccination with Intanza, an intradermal seasonal vaccine, in 54 individuals of different ages. Subjects were stratified according to age (below or over 60) and presence of a latent infection with Cytomegalovirus (CMV). CMV-seropositivity was significantly associated with a lower response rate to the vaccine in people over but not below 60 yr of age. Unlike reported data, late-differentiated (CD45RA+CCR7−CD27−CD28−) CD4+, but not CD8+ T-cells associated with a poorer vaccine response. Thus, latent CMV infection has a deleterious effect on influenza antibody responses in the elderly, which might be mediated through CD4 T-cells lacking CCR7, CD27 and CD28 and re-expressing CD45RA.

Reviews in Medical Virology, 2009

'Immunosenescence&amp... more 'Immunosenescence' is an imprecise term used to describe deleterious age-associated changes to immune parameters observed in all mammals studied so far. Primarily anecdotal evidence implies that failing immunity is responsible for the increased incidence and severity of infectious disease in old people. However, there is a serious dearth of accurate hard data concerning the actual cause of death in the elderly and the contribution thereto of the multitude of age-associated alterations measured in the immune system. Cross-sectional studies comparing those currently young with those currently old reveal a large number of differences in the distribution of immune cell types in the blood, and to some extent the functional integrity of those cells. Many of these parameters differ markedly between individuals infected with CMV and uninfected people, regardless of infection with other persistent herpesviruses. The adaptive arm of immunity appears to be more seriously affected than the innate arm, particularly the T lymphocytes. However, cross-sectional studies suffer the disadvantage that like is not being compared with like, because the conditions applied during the entire life course of the currently elderly were different from those applied now to the young. These differences in environment, nutrition, pathology and possibly genetics, rather than merely age, may be expected to influence the parameters studied. Moreover, pathogen exposure of the currently elderly was also different from contemporary exposure, probably including CMV. Some of the problems associated with cross-sectional studies can be overcome by performing longitudinal studies, as pointed out in an earlier analysis of the Baltimore Longitudinal Ageing study looking at lymphocyte numbers. However, longitudinal studies are challenging in humans. Nonetheless, the pioneering Swedish OCTO/NONA studies of the very elderly which for the first time included a range of immune parameters, have identified a set of immune parameters predicting mortality at 2, 4 and 6 year follow-up; CMV infection makes a material contribution to this so-called 'immune risk profile (IRP)'. Whether the IRP is informative in younger individuals and the mechanism of the CMV effect is discussed in this review.

Nature Medicine, 2012

1 2 5 4 VOLUME 18 | NUMBER 8 | AUGUST 2012 nAture medicine Therapeutic cancer vaccines hold the p... more 1 2 5 4 VOLUME 18 | NUMBER 8 | AUGUST 2012 nAture medicine Therapeutic cancer vaccines hold the promise of combining meaningful efficacy (prolongation of survival) with very good safety and tolerability, as has been shown in several recent randomized trials 1-3 . However, development of cancer vaccines remains a major challenge, with little knowledge of (i) the optimal tumor antigens to target, (ii) suitable agents to counteract regulatory mechanisms opposing successful immunotherapy and (iii) surrogate and predictive biomarkers that can improve our understanding of these regulatory mechanisms and predict a patient's response to therapy. The first major issue addressed in this work is whether relevant HLArestricted peptides for immunotherapeutic intervention in patients with RCC can be identified and clinically validated. We defined the relevance of the antigens as their natural presence on the tumor in the majority of RCC samples, their immunogenicity (induction of T cell responses in clinical studies) and the association of the vaccine-induced T cell responses with clinical benefit. For the identification, selection and preclinical immunological validation of such antigens, we used the antigen discovery platform XPRESIDENT 4,5 to create a multipeptide vaccine designated IMA901 for immunotherapy of RCC. We tested IMA901 in HLA-A*02 + subjects with advanced RCC in two clinical trials, a phase 1 (n = 28) and a randomized phase 2 (n = 68) trial, both of which assessed the association of T cell responses to IMA901 with clinical benefit.

Molecular Immunology, 2009

Prothymosin ␣ (ProT␣) is a small acidic polypeptide with important immunostimulatory properties, ... more Prothymosin ␣ (ProT␣) is a small acidic polypeptide with important immunostimulatory properties, which we have previously shown to be exerted by its carboxyl (C)-terminus. It exerts immunoenhancing effects through stimulation of monocytes via toll-like receptor (TLR) triggering. Here, we assayed the activity of synthetic peptides homologous to ProT␣'s C-terminus to stimulate lymphocyte functions, in particular natural killer cell cytotoxicity of peripheral blood mononuclear cells isolated from healthy donors. A synthetic decapeptide TKKQKTDEDD was identified as the most potent lymphocyte stimulator. The activity of this peptide was sequence-specific and comparable to that of the intact molecule, suggesting that ProT␣'s immunoactive segment encompasses the nuclear localization signal sequence of the polypeptide. Because ProT␣ stimulates immune responses in a monocyte-dependent manner, we further investigated whether the entire molecule and its peptide TKKQKTDEDD specifically act on monocytes and show that both can promote maturation of monocyte-derived dendritic cells (DC). Finally, knowing that, under specific conditions, ProT␣ forms amyloid fibrils, we studied the amyloidogenic properties of its C-terminal peptide segments, utilizing ATR FT-IR spectroscopy and transmission electron microscopy (negative staining). Although the peptide TKKQKTDEDD adopts an antiparallel ␤-sheet conformation under various conditions, it does not form amyloid fibrils; rather it aggregates in globular particles. These data, in conjunction with reports showing that the peptide TKKQKTDEDD is generated in vivo upon caspase-cleavage of ProT␣ during apoptosis, strengthen our hypothesis that immune response stimulation by ProT␣ is in principle exerted via its bioactive C-terminal decapaptide, which can acquire a sequence-specific ␤-sheet conformation and induce DC maturation.

Microbial Biotechnology, 2012

There is a general consensus that the elderly do not respond as well to vaccination as the young,... more There is a general consensus that the elderly do not respond as well to vaccination as the young, but robust studies are few and far between. Most refer to influenza vaccination, but even here, adequate immunological and clinical data are surprisingly thin on the ground. The meta-analysis by Goodwin et al. from 2006 is still the most comprehensive that we have. They reviewed 31 antibody response studies comparing influenza vaccination efficacy in groups of elderly and younger adults. They reported that the adjusted odds ratio (OR) of responses in elderly versus young adults ranged from 0.24 to 0.59 for the three influenza antigens used in the vaccines. They concluded that rather than the estimated 70-90% clinical vaccine efficacy in younger adults, this figure was only 17-53% in the elderly, depending on which viruses were prevalent that year. They stated that 'this highlights the need for more immunogenic vaccine formulations for the elderly'. How to achieve this? There are three areas where we may consider alterations to increase vaccine efficacy: (i) make the vaccine more potent; (ii) use adjuvants to enhance immunity; and (iii) apply immune modulators or other interventions to alter host immunity generally. We will consider these three options, focusing on influenza vaccination, in this mini-review.

The Journals of Gerontology Series A: Biological Sciences and Medical Sciences, 2014

A subset of older people is at increased risk of hospitalization and dependency. Emerging evidenc... more A subset of older people is at increased risk of hospitalization and dependency. Emerging evidence suggests that immunosenescence reflected by an inverted CD4:8 ratio and cytomegalovirus (CMV) seropositivity plays an important role in the pathophysiology of functional decline. Nevertheless, the relation between CD4:8 ratio and functional outcome has rarely been investigated. Here, CD4:8 ratio and T-cell phenotypes of 235 community-dwelling persons aged ≥81.5 years in the BELFRAIL study and 25 younger persons (mean age 28.5 years) were analyzed using polychromatic flow cytometry. In the elderly persons, 7.2% had an inverted CD4:8 ratio, which was associated with CMV seropositivity, less naive, and more late-differentiated CD4+ and CD8+ T cells. However, 32.8% had a CD4:8 ratio >5, a phenotype associated with a higher proportion of naive T cells and absent in young donors. In CMV seropositives, this subgroup had lower proportions of late-differentiated CD4+ and CD8+ T cells and weaker anti-CMV immunoglobulin G reactivity. This novel naive T-cell-dominated phenotype was counterintuitively associated with a higher proportion of those with impaired physical functioning in the very elderly people infected with CMV. This underscores the notion that in very elderly people, not merely CMV infection but also the state of its accompanying immune dysregulation is of crucial importance with regard to physical impairment.

International Journal of Cancer, 2009

Additional Supporting Information may be found in the online version of this article.

Immunity & Ageing, 2008

Compromised immunity contributes to the decreased ability of the elderly to control infectious di... more Compromised immunity contributes to the decreased ability of the elderly to control infectious disease and to their generally poor response to vaccination. It is controversial as to how far this phenomenon contributes to the well-known age-associated increase in the occurrence of many cancers in the elderly. However, should the immune system be important in controlling cancer, for which there is a great deal of evidence, it is logical to propose that dysfunctional immunity in the elderly would contribute to compromised immunosurveillance and increased cancer occurrence. The chronological age at which immunosenescence becomes clinically important is known to be influenced by many factors, including the pathogen load to which individuals are exposed throughout life. It is proposed here that the cancer antigen load may have a similar effect on "immune exhaustion" and that pathogen load and tumor load may act additively to accelerate immunosenescence. Understanding how and why immune responsiveness changes in humans as they age is essential for developing strategies to prevent or restore dysregulated immunity and assure healthy longevity, clearly possible only if cancer is avoided. Here, we provide an overview of the impact of age on human immune competence, emphasizing T-cell-dependent adaptive immunity, which is the most sensitive to ageing. This knowledge will pave the way for rational interventions to maintain or restore appropriate immune function not only in the elderly but also in the cancer patient.

Experimental Gerontology, 2014

Immunosenescence, defined as the age-associated dysregulation and dysfunction of the immune syste... more Immunosenescence, defined as the age-associated dysregulation and dysfunction of the immune system, is characterized by impaired protective immunity and decreased efficacy of vaccines. An increasing number of immunological, clinical and epidemiological studies suggest that persistent Cytomegalovirus (CMV) infection is associated with accelerated aging of the immune system and with several age-related diseases. However, current evidence on whether and how human CMV (HCMV) infection is implicated in immunosenescence and in age-related diseases remains incomplete and many aspects of CMV involvement in immune aging remain controversial. The attendees of the 4th International Workshop on "CMV & Immunosenescence", held in Parma, Italy, 25-27th March, 2013, presented and discussed data related to these open questions, which are reported in this commentary.

European Journal of Cancer, 2012

Current Opinion in Immunology, 2014

Acute inflammatory responses are essential for pathogen control and tissue repair but can also ca... more Acute inflammatory responses are essential for pathogen control and tissue repair but can also cause severe collateral damage. Tight regulation of the response is required to minimize host injury, but in the face of chronic infections and age-associated immune dysregulation, inflammatory processes may exert multiple detrimental effects on the organism. The signs of low level systemic inflammation commonly detectable in elderly people are associated with many chronic diseases of ageing and may even contribute to their causation. The purpose of this article is to review recent literature from the past two years providing new data on the inter-relationships between inflammatory status and chronic diseases of ageing.

Current Opinion in Immunology, 2009

Effects at the cellular level. Age and CMV seropositivity are both associated with several immune... more Effects at the cellular level. Age and CMV seropositivity are both associated with several immune changes especially those involving T cell phenotypes. Major surface receptors showing changes (increase or decrease) are illustrated.

Critical Reviews in Oncology/Hematology, 2008