IL-4-producing CD8+ T cells with a CD62L++(bright) phenotype accumulate in a subgroup of older adults and are associated with the maintenance of intact humoral immunity in old age

An increased production of proinflammatory cytokines occurs in a high percentage of elderly persons and is associated with an impaired humoral immune response. However, high IL-4 production has also been observed in old age. We now demonstrate an IL-4-producing subpopulation of CD8+ T cells in a subgroup of healthy older adults. This T cell subset is substantial in size and has a characteristic phenotype expressing CD45RO, CD28, CD62L, and CD25. IL-4-producing CD8+ T cells produce large amounts of IL-2 but not IFN-gamma or perforin, and these cells do not have a regulatory suppressive effect on other T cells. In vivo IL-4-producing CD8+ T cells can be stably detected over a year. When put into culture they also have a stable cytokine production pattern but fail to produce perforin even in the presence of IL-12. This special T cell type does not occur in persons under the age of 40, but is present in 36% of the persons >60 years of age. In this age group, IL-4-producing CD8+ T cells are more frequent in persons who are still capable of raising a humoral immune response following immunization than in others who fail to produce protective Abs after vaccination. Our results suggest that CD8+ T cells with a CD62L++(bright) phenotype accumulate in a subgroup of older adults. Due to their phenotype that enables them to migrate into lymphoid tissues and to their capacity to produce IL-4, these cells may counterbalance the overproduction of proinflammatory cytokines in old age.     

Low T3 syndrome in cancer patients in relation to weight loss, intravenous hyperalimentation therapy and age

In order to investigate the relation of weight loss and intravenous hyperalimentation therapy to low T3 syndrome, serum T3, T4. rT3 and TBG were determined by radioimmunoassay in 105 cancer patients. The cancer patients were classified into 3 groups, Group I, II and III depending on the grade of weight loss, ranging up to a 5% change in weight loss from a healthy condition, from 5 to 9%, and more than 10%, respectively. Cancer patients under age 59 showed no significant difference in serum T3, T4, rT3 and TBG among these 3 groups. However serum T3 and T3/T4 in cancer patients at age 60 and over were significantly reduced in group III, compared to groups I and II. Serum rT3 values were significantly elevated in group III of elderly cancer patients. The incidence of low T3 syndrome in group III of elderly cancer patients was also significantly higher than in groups I and II. In three out of 5 cancer patients with low T3 syndrome, serum T3 values increased after the intravenous hyperalimentation therapy, whereas no significant change in serum T3 values was observed in two patients who died within one day after the final examination. It is concluded that weight loss produced different effects on peripheral conversion of T4 to T3 between cancer patients under age 59 and over age 60 and glucose plays an important role in the pathogenesis of low T3 syndrome except cases with very poor prognosis.     

Immunoprevention and immunotherapy of cancer in ageing

Over the last few years there has been a growing interest in geriatric oncology, mainly because of the evidence that advanced age is the greatest risk factor for the development of cancer and that, since the elderly population is rapidly expanding, so too will the number of cancer patients. This forecast necessitates the development of new and more specific strategies for the prevention and cure of cancer in the elderly and as a result an ever-increasing need for oncologists, geriatricians and researchers to work closely together. The increased incidence of cancer in elderly people has been related to the age-associated changes occurring in the immune system, the so-called immunosenescence. This phenomenon is best characterised by a remodelling of the immune system, which appears early on and progresses throughout a persons life and mainly involves a decrease in cellular functions. This review aims to provide a rationale for the development of specific immunotherapeutic and immunopreventive regimens for the elderly. We also include a discussion on the influence that immunosenescence has on the growth of tumours and the effectiveness of immunogene therapy and cancer vaccination following a brief analysis of the age-related alterations of the cell populations involved in antitumour immunity.     

Mechanisms of murine dendritic cell antitumor dysfunction in aging

Effective cancer immunotherapy depends on the body’s ability to generate tumor antigen-presenting cells and tumor-reactive effector lymphocytes. As the most potent antigen presenting cells (APCs), dendritic cells (DCs) are capable of sensitizing T cells to new and recall antigens. Clinical trials of antigen-pulsed autologous DCs have been conducted in patients with a number of hematological and solid cancers, including malignant melanoma, lymphoma, myeloma, and non-small cell lung cancer. These studies suggest that antigen-loaded DC vaccination is a potentially safe and effective cancer therapy. However, the clinical results have been variable. Since the elderly are preferentially affected by diseases targeted by DC-directed immunotherapy, it is quite striking that few studies to date have focused on the effect of aging on DC function, a key aspect of optimal immunotherapy design in an aging population. In the present paper, we will discuss the consequences of aging on murine bone marrow-derived DC function and their use in cancer immunotherapy.     

Effects of dietary fats on bone health in advanced age

Evidence is accumulating that dietary lipids play an important role in bone health. Most of the data supporting the effects of lipids on bones have been collected in young adult and/or developing animals. Based upon this work, mechanisms have been proposed to explain how lipids act to enhance or inhibit bone resorption and deposition. Little work, however, has been done in older models. Since osteoporosis primarily afflicts the elderly, such work is needed in order to determine if mechanisms relevant to the young differ in advanced age, and to develop effective interventions for this especially vulnerable segment of the population. This article reviews evidence that dietary lipids are important to bone health in older individuals, and describes possible mechanisms that may be of particular relevance to the elderly. Specifically, studies supporting the influence of dietary lipids on calcium excretion, growth hormone secretion, fatty acid metabolism, and osteoblast formation are reviewed.     

The effect of aging on OX40 agonist-mediated cancer immunotherapy

Agents that enhance T cell co-stimulatory signaling have emerged as promising cancer immunotherapies. Our laboratory has been evaluating the TNF receptor co-stimulatory molecule, OX40, which has the capacity to augment critical aspects of T cell function and induce tumor regression in animal models. Effective stimulation of OX40 expressing T cells was accomplished with agonist antibodies to OX40 that were eventually translated into a clinical trial for cancer patients. A recent attempt to assess the affect of immune senescence on OX40 therapy, revealed a dramatic loss of efficacy of the agonist therapy in older tumor-bearing mice. The deficiency in OX40-enhanced anti-tumor responses in older mice correlated with a decrease in the number of differentiated effector T cells. Further investigation suggests that the underlying age-related decline in the agonist OX40-mediated T cell responses was not inherent to the T cells themselves, but related to the host environment. Thus, effective use of immunotherapies based on T cell co-stimulatory molecules may require additional modifications, such as immune stimulants to increase innate immunity, to address age-related defects that reside outside of the T cell and within the host environment.     

The combination of DNA methyltransferase inhibitor therapy and immunotherapy for acute myeloid leukemia

Acute myeloid leukemia (AML), the most common form of acute leukemia in adults, is characterized by abnormal proliferation and blocked maturation and differentiation of myeloid precursor cells. AML is an aggressive cancer that progresses rapidly without treatment. Therefore, effective treatment modalities should be implemented immediately after diagnosis. The mainstay of classical AML therapy has been chemotherapy, which is not suitable for relapsing or refractory patients, especially elderly patients. Among emerging novel therapeutic approaches for AML, epigenetic therapy and immunotherapy represent two exciting therapeutic developments. This review focuses on discussion of the therapeutic considerations for AML from the perspective of combination treatment, which incorporates both DNA methyltransferase inhibitor therapy, as one of the most promising epigenetic therapies, and immune checkpoint inhibitor or dendritic cell-based vaccination treatments, as examples of immunotherapy. Both challenges and rationale in the optimization of therapeutic approaches, as well as recent clinical trial developments, along this line are summarized.     

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

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.     

Vaccine and antibody-directed T cell tumour immunotherapy

Clearer evidence for immune surveillance in malignancy and the identification of many new tumour-associated antigens (TAAs) have driven novel vaccine and antibody-targeted responses for therapy in cancer. The exploitation of active immunisation may be particularly favourable for TAA where tolerance is incomplete but passive immunisation may offer an additional strategy where the immune repertoire is affected by either tolerance or immune suppression. This review will consider how to utilise both active and passive types of therapy delivered by T cells in the context of the failure of tumour-specific immunity by presenting cancer patients. This article will outline the progress, problems and prospects of several different vaccine and antibody-targeted approaches for immunotherapy of cancer where proof of principle pre-clinical studies have been or will soon be translated into the clinic. Two examples of vaccination-based therapies where both T cell- and antibody-mediated anti-tumour responses are likely to be relevant and two examples of oncofoetal antigen-specific antibody-directed T cell therapies are described in the following sections: (1) therapeutic vaccination against human papillomavirus (HPV) antigens in cervical neoplasia; (2) B cell lymphoma vaccines including against immunoglobulin idiotype; (3) oncofoetal antigens as tumour targets for redirecting T cells with antibody strategies.     

Breast cancer in the elderly—Should it be treated differently?

Breast cancer risk increases with age and about a third of female breast cancers are diagnosed in patients aged older than 70. Breast cancer in the elderly has, however, poorer outcome with lower survival rate compared to younger subjects. This may be partly explained by the delay in diagnosis and the ‘under-treatment’ of elderly breast cancer patients. In this review I try to provide recommendations for screening, surgery, radiotherapy, (neo)adjuvant hormone treatment and chemotherapy, and also the treatment of metastatic disease. Since large randomised trials usually exclude elderly patients with breast cancer, there is still an insufficient evidence for the treatment of such patients.     

Developing dendritic cell polynucleotide vaccination for prostate cancer immunotherapy.

Immunotherapy has been successfully used to treat some human malignancies, principally melanoma and renal cell carcinoma. Genetic-based cancer immunotherapies were proposed which prime T lymphocyte recognition of unique neo-antigens arising from specific mutations. Genetic immunization (polynucleotide vaccination, DNA vaccines) is a process whereby gene therapy methods are used to create vaccines and immunotherapies. Recent findings indicate that genetic immunization works indirectly via a bone marrow derived cell, probably a type of dendritic antigen presenting cell (APC). Direct targeting of genetic vaccines to these cells may provide an efficient method for stimulating cellular and humoral immune responses to infectious agents and tumor antigens. Initial studies have provided monocytic-derived dendritic cell (DC) isolation and culture techniques, simple methods for delivering genes into these cells, and have also uncovered potential obstacles to effective cancer immunotherapy which may restrict the utility of this paradigm to a subset of patients.     

CD25-expressing CD8+ T cells are potent memory cells in old age

We have recently described an IL-2/IL-4-producing CD8+CD25+ non-regulatory memory T cell population that occurs in a subgroup of healthy elderly persons who characteristically still have a good humoral response after vaccination. The present study addresses this specific T cell subset and investigates its origin, clonal composition, Ag specificity, and replicative history. We demonstrate that CD8+CD25+ memory T cells frequently exhibit a CD4+CD8+ double-positive phenotype. The expression of the CD8 alphabeta molecule and the occurrence of signal-joint TCR rearrangement excision circles suggest a thymic origin of these cells. They also have longer telomeres than their CD8+CD25- memory counterparts, thus indicating a shorter replicative history. CD8+CD25+ memory T cells display a polyclonal TCR repertoire and respond to IL-2 as well as to a panel of different Ags, whereas the CD8+CD25- memory T cell population has a more restricted TCR diversity, responds to fewer Ags, and does not proliferate in response to stimulation with IL-2. Molecular tracking of specific clones with clonotypic primers reveals that the same clones occur in CD8+CD25+ and CD8+CD25- memory T cell populations, demonstrating a lineage relationship between CD25+ and CD25- memory CD8+ T cells. Our results suggest that CD25-expressing memory T cells represent an early stage in the differentiation of CD8+ cells. Accumulation of these cells in elderly persons appears to be a prerequisite of intact immune responsiveness in the absence of naive T cells in old age.     

PCI comes to age as age increasingly comes to PCI

Percutaneous coronary intervention (PCI) has evolved as the standard procedure for the treatment of acute coronary syndromes and for the majority of situations with stable coronary artery disease. Patients aged 75 and older represent one third of those hospitalised with acute ischaemic events and account for more than half of all cardiac deaths. 1 However, evidence-based data to guide coronary revascularisation in the elderly have been limited to 1) the randomised clinical trials that routinely under-enrol elderly patients, and 2) observational studies that represent single institution experience with small samples. 2 Nevertheless, the Western society is an ageing population and the percentage of the population above 80 years of age, the so-called octogenarians, is rapidly increasing in Europe and will almost triple by 2050. 3     

Immunological risks of adult T-cell leukemia at primary HTLV-I infection

A small percentage of human T-cell leukemia virus type-I (HTLV-I)-infected individuals develop adult T-cell leukemia (ATL). In animal experiments, inoculation of HTLV-I via the oral route, which is the main route of mother-to-child viral transmission in humans as a result of breastfeeding, induced host HTLV-I-specific T-cell unresponsiveness and resulted in increased viral load. This strongly suggested that the known epidemiological risk factors for ATL (i.e. vertical HTLV-I infection and elevated viral load) are linked by an insufficient HTLV-I-specific T-cell response. Recent findings on the anti-tumor effects of Tax-targeted vaccination in rats and the reactivation of Tax-specific T cells in ATL patients as a result of hematopoietic stem cell transplantation imply promising immunological approaches for the prophylaxis and therapy of ATL.     

Age-associated change in the frequency of memory CD4+ T cells impairs long term CD4+ T cell responses to influenza vaccine

We investigated the relationship of memory CD4+ T cells with the evolution of influenza virus-specific CD4+ T cell responses in healthy young and elderly people. Elderly individuals had a similar frequency of CD69+CD4+ T cells producing IFN-gamma and TNF-alpha at 1 wk, but a lower frequency of these CD4+ T cells at 3 mo after influenza vaccination. Although the elderly had a higher frequency of central memory (CM; CCR7+CD45RA-) CD4+ T cells, they had a significantly lower frequency of effector memory (EM; CCR7-CD45RA-) CD4+ T cells, and the frequency of the latter memory CD4+ T cells positively correlated with the frequency of influenza virus-specific CD69+CD4+ T cells producing IFN-gamma at 3 mo. These findings indicate that the elderly have an altered balance of memory CD4+ T cells, which potentially affects long term CD4+ T cell responses to the influenza vaccine. Compared with the young, the elderly had decreased serum IL-7 levels that positively correlated with the frequency of EM cells, which suggests a relation between IL-7 and decreased EM cells. Thus, although the healthy elderly mount a level of CD4+ T cell responses after vaccination comparable to that observed in younger individuals, they fail to maintain or expand these responses. This failure probably stems from the alteration in the frequency of CM and EM CD4+ T cells in the elderly that is related to alteration in IL-7 levels. These findings raise an important clinical question about whether the vaccination strategy in the elderly should be modified to improve cellular immune responses.     

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.     

Two defects in old New Zealand Black mice are involved in the loss of low-dose paralysis to type III pneumococcal polysaccharide

Treatment of normal mice with a subimmunogenic dose of type III pneumococcal polysaccharide (SSS-III) results in the development of an antigen-specific state of unresponsiveness termed low-dose paralysis. This unresponsiveness is mediated by T suppressor cells and can be transferred by Lyt-2+ T cells, but not by L3T4+ T cells, obtained 18 hr after priming. As autoimmune New Zealand Black (NZB) mice age, there is a progressive decrease in low-dose paralysis to SSS-III. The defect in older NZB mice resulting in decreased suppressive activity was investigated by transferring primed Lyt-2+ T cells from young into old mice, and vice versa. Enlarged Lyt-2+ T cells from old NZB mice could not suppress the SSS-III response of young recipients. However, Lyt-2+ T cells of normal cell size were efficient in inhibiting the antibody response upon transfer. Primed Lyt-2+ T cells from young NZB mice did not affect the response of old recipients, but effectively suppressed the response of young mice. These results suggest that there are two defects involved in the decline of low-dose paralysis to SSS-III in aging NZB mice: Enlarged Lyt-2+ T cells may lose their ability to function as mediators of suppression; and B cells may become resistant to T cell-mediated suppression.     

An analysis of T cell responsiveness in Indian kala-azar

The inability of most untreated patients with Kala-azar to control their visceral infections with Leishmania donovani has been attributed to a defective cell-mediated immune response to leishmanial antigens. We examined the in vitro response of T cells, including Leu-2+-depleted T cell populations, to determine whether unresponsiveness could be reversed. These studies on patients with visceral leishmaniasis in Bihar, north India, support previous observations regarding T cell unresponsiveness in patients with active disease: it is profound, it is specific, and it is reversible after successful chemotherapy. However, these studies also indicate that the specific unresponsiveness cannot be reversed by depletion of "suppressor" Leu-2+ T lymphocytes, nor by the addition of exogenously supplied human IL 2 to the cultures. One interpretation of these results is that in active cases of Kala-azar, there is an absence of Leishmania-specific T cells in the periphery. The possibility that reactive cells can be found in situ cannot be excluded. The observation that 13 of 25 family members of active cases were able respond to L. donovani in vitro or by skin testing suggests that the frequency of infection within an endemic area in Bihar is very high, and that assays for T cell responsiveness are far better epidemiologic tools for the detection of asymptomatic infection than is ELISA. Identification of such an exposed, Kala-azar-resistant population will be required to study host factors which influence the development of disease in infected individuals.     

Treating dyslipidemia in the elderly

PURPOSE OF REVIEW: The treatment of dyslipidemia has been dynamic over the past several years. Of special importance is the impact of recent clinical trial data on management strategies of dyslipidemia in the elderly. People 65 years and older are living longer and are the fastest growing subset of the US population, necessitating more attention to chronic disease conditions that manifest in this age group. This review addresses guidelines of lipid management, discusses data that support their use, and examines the benefits of lipid-lowering therapy in the elderly with attention to the chronic conditions that are common in this population. RECENT FINDINGS: Clinical trials completed since the publication of the 2001 National Cholesterol Education Program (NCEP) Adult Treatment Panel III guidelines support the use of lipid-lowering therapy in the elderly population. Lipid-lowering therapy has not only proven to be generally safe in the elderly, but has also proven effective in helping manage the chronic disease conditions that are common in this age group. SUMMARY: The elderly segment of our population continues to grow. Along with this growth in population is a growth in incidence of cardiovascular disease, the metabolic syndrome, chronic kidney disease, cerebrovascular disease, and diabetes mellitus. There is no known panacea for managing these chronic disease conditions; however, lipid-lowering therapy has been shown to prevent or delay the progression of these diseases and the mortality and morbidity that accompanies them.