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Biomedical subjects

Richard Aspinall

Publications and source records attributed to Richard Aspinall.

17 recordsLinked to original sources
PubMed2006

T cell development, ageing and Interleukin-7.

Interleukin-7 (IL-7) is a cytokine with a central role in the development and maintenance of the peripheral T cell pool. In the mouse, expression of the IL-7 gene in the thymus has been carefully followed from gestation onwards throughout the lifespan. One of the features of its expression in the thymus is that it changes with time, declining measurably as the animal ages. This reduction is associated with a decrease in thymic size, cellularity and output. Analysis of transgenic animals carrying either IL-7 or IL-7 receptor transgenes reveals that the intrathymic level of IL-7 has a critical effect on the production of T cells, and that this may not be a linear relationship. This is an important consideration for therapy involving treatment of old animals with IL-7 of which there are reports indicating some rejuvenation of the thymus following IL-7 treatment, which is never complete. The thymus does not appear to return to the size and cellularity seen in youth. Several possible scenarios could account for this, including the inability to maintain IL-7 within defined limits in the thymus during the therapy.

Aging↗
PubMed2006

Early immunological development and mortality from infectious disease in later life.

In rural Gambia the risk of mainly infection-related mortality is 10-fold higher for adults born in the nutritionally-debilitating 'hungry' season, suggesting that immune function may be compromised by events early in life. The current programme of research focuses on the biological mechanisms underlying this hypothesis, exploring early-life environmental influences on immune development and the long-term functional consequences these influences may have. Results obtained to date show that thymus development during infancy is critically sensitive to environmental exposures, with smaller thymuses observed in the hungry season. Measurement of the frequency of T-cell receptor excision circles indicate that thymus function is also sensitive to seasonal influences, with further studies implicating variations in breast-milk IL-7 as a possible mediator of these effects. Studies in adults have shown that size at birth is positively correlated with antibody responses to vaccination with polysaccharide antigens, thus providing evidence for long-term functional deficits. The present paper will review progress made to date within this field of research.

Adult↗
PubMed2005

An IL-7 fusion protein that shows increased thymopoietic ability.

The role of IL-7 during thymopoiesis has led to it being the focus of a number of therapeutic interventions. However, its small size and pleiotropic nature present problems for thymus-directed therapies. We have created a fusion molecule between the extracellular N-terminal domain of CCR9 and IL-7, which has the potential to overcome these difficulties. This novel fusion protein retains the thymopoietic activity of IL-7 and the ligand-binding ability of CCR9. As a thymopoietic agent, compared with IL-7, it shows an enhanced retention in the thymus, increased de novo T cell production, and increased thymic output. Old mice receiving the fusion protein show improved CD8 T cell responses and reduced viral load after infection with influenza virus compared with those receiving IL-7. This chimeric molecule offers a novel therapeutic strategy that may result in the production of an effective immunorestorative agent.

Animals↗
PubMed2005

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.

Aged↗
PubMed2005

Ageing and the immune system in vivo: commentary on the 16th session of British Society for Immunology Annual Congress, Harrogate, December 2004.

The problems associated with the ageing immune system coupled with possible solutions were discussed recently at the British Society for Immunology Annual Congress in Harrogate in December 2004. The session "Ageing and the Immune System in vivo" dealt in details with the immune risk phenotype and the potential methods of reversing the problems of an ageing immune system. This is a commentary on that session.

Editorial↗
PubMed2004

Reversal of thymic atrophy.

Age-associated thymic atrophy is a key event preceding the inefficient functioning of the immune system, resulting in a diminished capacity to generate new T-cells. This thymic involution has been proposed to be due to changes in the thymic microenvironment resulting in its failure to support thymopoiesis. A key cytokine in the early stages of thymocyte development is IL-7 and expression levels are greatly reduced with age. The ability of IL-7 to restore the immune system by enhancing thymic output remains controversial. In this review, we highlight the advances in molecular approaches used to evaluate recent thymic emigrants and assess the success of these strategies in determining whether IL-7 can lead to immune reconstitution.

Aging↗
PubMed2004

Modelling land use change with generalized linear models--a multi-model analysis of change between 1860 and 2000 in Gallatin Valley, Montana.

This paper develops an approach to modelling land use change that links model selection and multi-model inference with empirical models and GIS. Land use change is frequently studied, and understanding gained, through a process of modelling that is an empirical analysis of documented changes in land cover or land use patterns. The approach here is based on analysis and comparison of multiple models of land use patterns using model selection and multi-model inference. The approach is illustrated with a case study of rural housing as it has developed for part of Gallatin County, Montana, USA. A GIS contains the location of rural housing on a yearly basis from 1860 to 2000. The database also documents a variety of environmental and socio-economic conditions. A general model of settlement development describes the evolution of drivers of land use change and their impacts in the region. This model is used to develop a series of different models reflecting drivers of change at different periods in the history of the study area. These period specific models represent a series of multiple working hypotheses describing (a) the effects of spatial variables as a representation of social, economic and environmental drivers of land use change, and (b) temporal changes in the effects of the spatial variables as the drivers of change evolve over time. Logistic regression is used to calibrate and interpret these models and the models are then compared and evaluated with model selection techniques. Results show that different models are 'best' for the different periods. The different models for different periods demonstrate that models are not invariant over time which presents challenges for validation and testing of empirical models. The research demonstrates (i) model selection as a mechanism for rating among many plausible models that describe land cover or land use patterns, (ii) inference from a set of models rather than from a single model, (iii) that models can be developed based on hypothesised relationships based on consideration of underlying and proximate causes of change, and (iv) that models are not invariant over time.

Agriculture↗
PubMed2004

Improved thymic function in exclusively breastfed infants is associated with higher interleukin 7 concentrations in their mothers' breast milk.

BACKGROUND: In rural Gambians, the season of birth strongly predicts adult mortality. Those born during the harvest season have longer life spans than do those born during the hungry season, and the deaths associated with infectious diseases suggest permanent early-life influences on immunity. Thymic measurements showed significantly smaller thymuses in infants born during the hungry season than in those born during the harvest season. The differences were greatest at 8 wk of age, a time when all infants were exclusively breastfed, which suggests the involvement of breast milk factors. OBJECTIVE: This study tested whether thymic size differences reflect thymic output and ascertained whether thymic output is associated with breast milk interleukin 7 (IL-7) concentrations. DESIGN: We studied thymic size and output in a prospective cohort of 138 Gambian infants born in either the hungry or the harvest season by measuring signal-joint T cell receptor-rearrangement excision circles (sjTRECs) at birth and at 8 wk of age. IL-7 concentrations in breast milk were measured by using an enzyme-linked immunosorbent assay. RESULTS: By age 8 wk, those born in the hungry season had significantly lower sjTREC counts than did those born in the harvest season (0.97 and 2.12 sjTRECs/100 T cells, respectively; P = 0.006). At 1 wk postpartum, the breast milk of mothers of infants born in the hungry season had significantly lower IL-7 than did that of mothers of infants born in the harvest season (79 and 100 pg/mL, respectively; P = 0.02). The findings were similar at 8 wk postpartum. CONCLUSION: These data show a plausible pathway linking external seasonal insults to mothers with thymic development in their infants, which suggests possible implications for long-term programming of immunity.

Breast Feeding↗
PubMed2004

Interleukin-7: an interleukin for rejuvenating the immune system.

Infection of an individual (aged 20-30 years) by a virus will cause a response from the T (thymus derived) lymphocytes of which there are approximately 3 x 10(11). If the individual has not met the virus before, the response will come from the naive T cell subset (50 +/- 10% of the total T cell pool at this age) containing recent thymic emigrants produced from the thymus at approximately 10(8) per day. Their antigen-specific receptor has a defined specificity governed by the conformation of its two chains (alpha and beta), and the repertoire of specificities is somewhere in the region of 2 x 10(7) to 10(8). A successful response leads to clonal expansion and the generation of memory T cells to the infecting agent.

Adult↗
PubMed2003

Age-related changes in the function of T cells.

At the start of the last century in the United Kingdom, only 24% of the 587,830 deaths registered were of individuals over 65, but by the end of the century these figures had changed markedly. Of the 558,052 deaths in 1997, 84% were in the population over 65. This "right shift" in the survival curve is projected to continue. The UK Government Actuary's Department forecast that by 2020, 11.75 million people (19% of the population) will be over 65 rising to 15.1 million people (25% of the population) by 2040. Older members of society show infections of the urinary tract, respiratory tract, skin, soft tissue or intra-abdominal region, infectious endocarditis, bacterial meningitis, tuberculosis, and herpes zoster, at a higher incidence than among younger adults. Moreover, mortality rates for these diseases are often 2-3 times higher among elderly patients than younger individuals with the same disease. The higher morbidity and mortality from these infections, plus the increased prevalence of specific cancers and certain autoimmune diseases point to an immune system deteriorating with age. At the core of the immune system are the T cells and this review analyses possible causes for the changes in T cell function that may account for the deterioration of the immune system. Any intervention to reverse the decline in the immune system must have a rational basis built on a hypothesis-driven inquiry, and one such intervention process is presented here.

Aging↗
PubMed2003

Thymic output during initial highly active antiretroviral therapy (HAART) and during HAART supplementation with interleukin 2 and/or with HIV type 1 immunogen (Remune).

The thymic output of patients receiving highly active antiretroviral therapy (HAART) was assessed by sjTREC (signal joint T cell receptor rearrangement excision circle) analysis to determine the thymic contribution to CD4(+) T cell reconstitution during initial therapy and during interleukin 2 (IL-2) and/or Remune supplementation of HAART. Levels of sjTRECs were observed to decline dramatically after the first 4 weeks of HAART and then increased without significant associated changes in CD4(+) T cell counts. HAART supplementation with IL-2 was observed to lead to rapid increases in CD4(+) T cells that were accompanied by sjTREC decreases. No notable changes in CD4(+) T cell counts and sjTRECs were seen in patients receiving HAART supplemented with Remune alone. The results indicate CD4(+) T cell maintenance during initial treatment of HIV-1 with HAART and early CD4(+) T cell reconstitution of patients receiving IL-2 with HAART is largely due to thymus-independent mechanisms, with the thymus making a limited contribution.

AIDS Vaccines↗
PubMed2003

Intracellular adhesion molecule 1 plays a key role in acquired immunity to salmonellosis.

This study investigated the role of intracellular adhesion molecule 1 (ICAM-1) during Salmonella enterica serovar Typhimurium infection of mice. We show that ICAM-1 is expressed in and around granulomas on day 4 of infection in wild-type mice. However, when naive ICAM-1(-/-) mice were challenged with a sublethal dose of serovar Typhimurium, there were no detectable differences in systemic bacterial burden over the first 9 days of infection compared to wild-type control mice. When mice were immunized with the S. enterica serovar Typhimurium vaccine strain SL2361 and then challenged with the virulent S. enterica serovar Typhimurium strain C5, 100% of the ICAM-1(-/-) mice succumbed to infection, compared to 30% of wild-type mice. T-cell responses, as measured by activation via interleukin-2 production, as well as antibody responses were comparable in the ICAM-1(-/-) and wild-type mice. Following challenge, counts in organs were significantly higher in the ICAM-1(-/-) mice, and histological examination of organs showed pathological differences. Strain SL3261-immunized wild-type mice had cellular infiltrate and normal granuloma formation in the liver and spleen on days 5 and 10 after challenge with strain C5. ICAM-1(-/-) mice had a similar infiltrate on day 5, whereas on day 10 the infiltrate was more widespread and there were fewer macrophages associated with the granulomas. High circulating levels of tumor necrosis factor alpha and gamma interferon, as well as a high burden of strain C5 in the blood, accompanied the differences in histopathology. In this study we show that ICAM-1 plays a critical role during rechallenge of immunized mice with virulent S. enterica serovar Typhimurium.

Animals↗
PubMed2002

Molecular quantitation of thymic output in mice and the effect of IL-7.

Aging of the murine thymus is accompanied by a measurable loss of weight and cellularity and a marked reduction in its output of T lymphocytes. This study employs a molecular approach to determine changes in the output of the murine thymus using a novel assay system based on the detection and quantitation of the excised TCRdelta DNA locus from within the TCRalpha chain genes. In alpha beta(+) T cells such delta excision circles (deltaEC) are present at higher levels in naive T cells as compared with memory T cell populations, are non-replicating, and diluted within the total peripheral alpha beta(+) T cell pool with advancing age. This assay permits the assessment of thymic output in older animals where previous analysis was hampered by the transient nature of the naive T cell surface phenotype, and so allows the assessment of the efficacy of IL-7 as an agent to reverse thymic atrophy. Treatment of old mice with IL-7 although producing no overall change in the total number of alpha beta(+) T cells in the peripheral T cell pool altered the component subsets. Mice treated with IL-7 showed increases in the number of alpha beta(+)TCR cells possessing deltaEC commensurate with improved thymic output, and the splenic T cells from IL-7-treated mice performed significantly better in in vitro functional assays compared to those from age-matched saline-treated controls.

Aging↗
PubMedDate not supplied

Thymic output, ageing and zinc.

The role of the thymus is vital for orchestration of T-cell development and maturation. With increasing age the thymus undergoes a process of involution which results in a reduction in thymic size, function and output. Until relatively recent it was not feasible to accurately measure the magnitude of age-related loss of thymic function. With the discovery of T-cell receptor excision circles (TRECs), which are the stable by-products of the newly generated T-cells, it is now possible to quantitatively measure the extent of thymic output. This review examines the available data on immune function and zinc deficiency and places them in the context of the aims of the ZINCAGE project which include the evaluation of the role played by zinc in maintaining thymic output in healthy elderly individuals.

Aging↗
PubMedDate not supplied

Age-associated thymic atrophy is linked to a decline in IL-7 production.

Age-associated thymic atrophy results in a decline in T lymphocyte output and has been identified as one of the key events that precede inefficient functioning of the immune system in later life. Thymic atrophy is thought to result from a failure of the thymic microenvironment to support thymopoiesis in old age and recent evidence suggests that a decline in interleukin-7 (IL-7) expression may limit thymocyte development by restricting combinations of survival, proliferation and rearrangement of the TCRbeta chain. Using RT-PCR and the RNase protection assay, we show that the expression of IL-7 declines with age. Analysis of Connexin 43 expression, a component molecule of gap junctions, whose function is to connect epithelial cells, does not markedly decline with age. These observations suggest that a decline in IL-7 expression is not matched by a similar loss of epithelial cells. These results in conjunction with other studies lead us to speculate that IL-7 producing MHC class II positive TECs are being replaced by cells that do not have this capacity.

Aging↗