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Biomedical subjects

Malcolm H A Rustin

Publications and source records attributed to Malcolm H A Rustin.

7 recordsLinked to original sources
PubMed2006

Mantoux Test as a model for a secondary immune response in humans.

The Mantoux Test (MT) is a classical delayed-type hypersensitivity (DTH) response to the intradermal injection of tuberculin purified protein derivative (PPD). It represents a cutaneous T cell mediated memory recall immune response. The test is typically used to determine immunity to tuberculosis in humans and positive reactions develop in individuals previously exposed to Mycobacterium tuberculosis, and those immunised with the Bacillus of Calmette and Guérin (BCG) vaccine. In view of its relative accessibility human skin represents a convenient tissue for the investigation of human immune responses. Using the MT, we have been able to determine that significant cellular proliferation and clonal expansion occur at the site of antigen deposition in the skin. Furthermore, cells undergoing proliferation in the skin also undergo accelerated differentiation. Taken together with other studies, in humans and in mice, these observations shed new light on the importance of the microenvironment at the site of the immune response for the proliferation and differentiation of memory T cells.

Animals↗
PubMed2006

Women living with facial hair: the psychological and behavioral burden.

OBJECTIVE: While unwanted facial hair is clearly distressing for women, relatively little is known about its psychological impact. This study reports on the psychological and behavioral burden of facial hair in women with suspected polycystic ovary syndrome. METHODS: Eighty-eight women (90% participation rate) completed a self-administered questionnaire concerning hair removal practices; the impact of facial hair on social and emotional domains; relationships and daily life; anxiety and depression (Hospital Anxiety and Depression Scale); self-esteem (Rosenberg Self-esteem Scale); and quality of life (WHOQOL-BREF). RESULTS: Women spent considerable time on the management of their facial hair (mean, 104 min/week). Two thirds (67%) reported continually checking in mirrors and 76% by touch. Forty percent felt uncomfortable in social situations. High levels of emotional distress and psychological morbidity were detected; 30% had levels of depression above the clinical cut off point, while 75% reported clinical levels of anxiety; 29% reported both. Although overall quality of life was good, scores were low in social and relationship domains--reflecting the impact of unwanted facial hair. CONCLUSION: Unwanted facial hair carries a high psychological burden for women and represents a significant intrusion into their daily lives. Psychological support is a neglected element of care for these women.

Activities of Daily Living↗
PubMed2006

Human CD4+ CD25hi Foxp3+ regulatory T cells are derived by rapid turnover of memory populations in vivo.

While memory T cells are maintained by continuous turnover, it is not clear how human regulatory CD4+ CD45RO+ CD25hi Foxp3+ T lymphocyte populations persist throughout life. We therefore used deuterium labeling of cycling cells in vivo to determine whether these cells could be replenished by proliferation. We found that CD4+ CD45RO+ Foxp3+ CD25hi T lymphocytes were highly proliferative, with a doubling time of 8 days, compared with memory CD4+ CD45RO+ Foxp3- CD25- (24 days) or naive CD4+ CD45RA+ Foxp3- CD25- populations (199 days). However, the regulatory population was susceptible to apoptosis and had critically short telomeres and low telomerase activity. It was therefore unlikely to be self regenerating. These data are consistent with continuous production from another population source. We found extremely close TCR clonal homology between regulatory and memory CD4+ T cells. Furthermore, antigen-related expansions within certain TCR Vbeta families were associated with parallel numerical increases of CD4+ CD45RO+ CD25hi Foxp3+ Tregs with the same Vbeta usage. It is therefore unlikely that all human CD4+ CD25+ Foxp3+ Tregs are generated as a separate functional lineage in the thymus. Instead, our data suggest that a proportion of this regulatory population is generated from rapidly dividing, highly differentiated memory CD4+ T cells; this has considerable implications for the therapeutic manipulation of these cells in vivo.

Adult↗
PubMed2005

Quiescence and functional reprogramming of Epstein-Barr virus (EBV)-specific CD8+ T cells during persistent infection.

After acute infection Epstein-Barr virus (EBV)-specific memory CD8+ T cells exit cell cycle, and a proportion of these antigen-experienced cells re-express CD45RA (CD45 which predominantly express exon A). However, the signals involved are not known. We investigated the roles of interleukin 15 (IL-15) and interferon-alpha/beta (IFN-I) in these processes, since these mediators have a crucial but undefined role in the maintenance of CD8+ T-cell memory. We show that IFN-I (but not IL-15) allows activated EBV-specific CD8+ T cells to leave cell cycle without entering apoptosis. This was associated with up-regulation of the cyclin inhibitor p27, but not of CD45RA. In contrast, IL-15 (but not IFN-I) induced "homeostatic" proliferation and CD45RA re-expression by these cells in vitro. Different signals, therefore, induce quiescence and CD45RA re-expression in activated EBV-specific CD8+ T cells. After T-cell receptor (TCR) activation freshly isolated CD45RA+ antigen-experienced CD8+ T cells show poor proliferative activity but are highly cytotoxic and secrete IFN-gamma efficiently. This suggests functional reprogramming toward effector function but away from proliferation. The induction of quiescence and the generation of proliferation-independent effector CD8+ T cells that re-express CD45RA may minimize the impact of replicative senescence in virus-specific populations that would otherwise occur during decades of persistent infection.

CD8-Positive T-Lymphocytes↗
PubMed2004

Telomere erosion in memory T cells induced by telomerase inhibition at the site of antigenic challenge in vivo.

The extent of human memory T cell proliferation, differentiation, and telomere erosion that occurs after a single episode of immune challenge in vivo is unclear. To investigate this, we injected tuberculin purified protein derivative (PPD) into the skin of immune individuals and isolated responsive T cells from the site of antigenic challenge at different times. PPD-specific CD4+ T cells proliferated and differentiated extensively in the skin during this secondary response. Furthermore, significant telomere erosion occurred in specific T cells that respond in the skin, but not in those that are found in the blood from the same individuals. Tissue fluid obtained from the site of PPD challenge in the skin inhibited the induction of the enzyme telomerase in T cells in vitro. Antibody inhibition studies indicated that type I interferon (IFN), which was identified at high levels in the tissue fluid and by immunohistology, was responsible in part for the telomerase inhibition. Furthermore, the addition of IFN-alpha to PPD-stimulated CD4+ T cells directly inhibited telomerase activity in vitro. Therefore, these results suggest that the rate of telomere erosion in proliferating, antigen-specific CD4+ T cells may be accelerated by type I IFN during a secondary response in vivo.

BCG Vaccine↗
PubMed2003

Expression of purinergic receptors in non-melanoma skin cancers and their functional roles in A431 cells.

We investigated the use of purinergic receptors as a new treatment modality for nonmelanoma skin cancers. Purinergic receptors, which bind adenosine 5'-tri-phosphate, are expressed on human cutaneous keratinocytes. Previous work in rat and human epidermis suggested functional roles for purinergic receptors in the regulation of proliferation, differentiation, and apoptosis. Immunohistochemical analysis of frozen sections in human basal cell carcinomas and squamous cell carcinomas for P2X5, P2X7, P2Y1, P2Y2, and P2Y4 receptors was performed, accompanied by detailed analysis of archive material of tumor subtypes in paraffin sections. Functional studies were performed using a human cutaneous squamous cell carcinoma cell line (A431), where purinergic receptor subtype agonists were applied to cells and changes in cell number were quantified via a colorimetric assay. Immunostaining in paraffin sections was essentially the same as that in frozen sections, although more detail of the subcellular composition was visible. P2X5 and P2Y2 receptors were heavily expressed in basal cell carcinomas and squamous cell carcinomas. P2X7 receptors were expressed in the necrotic center of nodular basal cell carcinomas and in apoptotic cells in superficial multifocal and infiltrative basal cell carcinomas, and squamous cell carcinomas. P2Y1 receptors were only expressed in the stroma surrounding tumors. P2Y4 receptors were found in basal cell carcinomas but not in squamous cell carcinomas. P2X5 receptors appear to be associated with differentiation. The P2X7 receptor agonist benzoylbenzoyl-adenosine 5'-triphosphate and high concentrations of adenosine 5'-triphosphate (1000-5000 microM) caused a significant reduction in A431 cell number (p<0.001), whereas the P2Y2 receptor agonist uridine 5'-triphosphate caused a significant amount of proliferation (p<0.001). We have demonstrated that non-melanoma skin cancers express functional purinergic receptors and that P2X7 receptor agonists significantly reduce cell numbers in vitro.

Aged↗