Prospective study of breast cancer risk for mutation negative women from BRCA1 or BRCA2 mutation positive families.

Published studies have reached contradictory conclusions regarding breast cancer risk for women from families segregating a BRCA1 or BRCA2 mutation who do not carry the family-specific mutation. Accurate estimation of breast cancer risk is crucial for appropriate counselling regarding risk management. The aim of this study is to prospectively assess whether breast cancer risk for mutation negative women from families segregating BRCA1 or BRCA2 mutations is greater than for women in the general population. Eligible women were 722 first-, second- and third-degree relatives of a BRCA1 or BRCA2 mutation carrier from 224 mutation positive (128 BRCA1, 96 BRCA2) families, had no personal cancer history at baseline, and had been tested and found not to carry the family-specific mutation. Self-reported family history of cancer, preventive interventions and verified cancer diagnoses were collected at baseline, and every 3 years thereafter. Median follow-up was 6.1 years (range 0.1-12.4 years). Time at risk of breast cancer was censored at cancer diagnosis or risk-reducing surgery. Standardised incidence ratios (SIR) were estimated by comparing observed to population incidences of invasive breast cancer using Australian Cancer Incidence and Mortality Books. Six cases of invasive breast cancer were observed. The estimated SIRs were 1.14 (95% CI: 0.51-2.53) overall (n = 722), 1.29 (95% CI: 0.58-2.88) when restricted to first- and second-degree relatives of an affected mutation carrier (n = 442) and 0.48 (95% CI: 0.12-1.93) when restricted to those with no family history of breast cancer in the non-mutation carrying parental lineage (n = 424). There was no evidence that mutation negative women from families segregating BRCA1 or BRCA2 mutations are at increased risk of breast cancer. Despite this being the largest prospective cohort to assess this issue, moderately increased breast cancer risk (2-fold) cannot be ruled out.

Relative impact of CD4+CD25+ regulatory T cells and tacrolimus on inhibition of T-cell proliferation in patients with atopic dermatitis.

BACKGROUND: It has been established recently that CD4+CD25+ regulatory T cells (Tregs) play an important role in controlling various immune responses. Immunosuppressive drugs are often used to treat immune dysregulation but are frequently associated with undesirable side-effects. OBJECTIVES: We examined the suppressive capacity of circulating Tregs in patients with atopic dermatitis (AD). Combined effects of Tregs and tacrolimus on the inhibition of T-cell proliferation in vitro were also assessed. METHODS: CD4+CD25+ and CD4+CD25- T cells were isolated from peripheral blood mononuclear cells using immunomagnetic beads. CD4+CD25- T cells were stimulated with purified protein derivative (PPD) or house dust mite allergen (Der p1) for 6 or 7 days, respectively. A dose range of tacrolimus and CD4+CD25+ T cells were added separately, or together. Proliferation was measured by (3)H-thymidine incorporation. RESULTS: CD4+CD25+ T cells from normal controls and patients with AD are anergic and inhibit the proliferation of CD4+CD25- T cells in response to PPD and Der p1 in vitro in a dose-dependent manner. Addition of tacrolimus and Tregs together showed significantly stronger inhibition of proliferation than either on their own. This was true for both antigens and both in normal controls and in patients with AD. CONCLUSIONS: CD4+CD25+ T cells in patients with AD have normal suppressive activity compared with healthy controls. Tregs and tacrolimus have additive effects on the inhibition of proliferation in response to PPD and Der p1.

The immunomodulatory effects of regulatory T cells: implications for immune regulation in the skin.

Regulatory T cells are thought to have a critical role in the suppression of immune responses. In addition to the prevention of the development of autoimmunity, they are also thought to have a role in the prevention of allergic responses to environmental allergens, immune responses to tumours and the development of memory responses to chronic infections. They have been isolated within the skin and have been shown to express surface markers that enable skin-specific migration, suggesting that regulatory T cells have a functional role in the skin. There is accumulating evidence to suggest that regulatory T cells may be involved in numerous skin disorders and may also be modified by various therapeutic agents used to treat these disorders. We review the evidence for the presence of this T-cell subset in humans, the suppressive effects of regulatory T cells, and their role in the skin.