The gene Bcl11b, which encodes zinc finger proteins, and its paralog, Bcl11a, are associated with immune-system malignancies. We have generated Bcl11b-deficient mice that show a block at the CD4-CD8- double-negative stage of thymocyte development without any impairment in cells of B- or gammadelta T cell lineages. The Bcl11b-/- thymocytes showed unsuccessful recombination of V(beta) to D(beta) and lacked the pre-T cell receptor (TCR) complex on the cell surface, owing to the absence of Tcrb mRNA expression. In addition, we saw profound apoptosis in the thymus of neonatal Bcl11b-/- mice. These results suggest that Bcl11b is a key regulator of both differentiation and survival during thymocyte development.

Coronary collateral vessels reduce damage to ischemic myocardium after coronary obstruction. Factors that stimulate collateral formation are expected to have ameliorating effects on myocardial infarction. In a canine experimental myocardial infarct model, intracoronary injection of basic fibroblast growth factor (bFGF) improved cardiac systolic function and reduced infarct size. Treatment with bFGF increased the number of arterioles and capillaries in the infarct. Thus, the angiogenic action of bFGF might lead to a reduction in infarct size. The application of bFGF might bring about a therapeutic modality for the salvage of infarcted myocardium.

PGD2 plays roles in allergic inflammation via specific receptors, the PGD receptor designated DP and CRTH2 (chemoattractant receptor homologous molecule expressed on Th2 cells). We generated mutant mice carrying a targeted disruption of the CRTH2 gene to investigate the functional roles of CRTH2 in cutaneous inflammatory responses. CRTH2-deficent mice were fertile and grew normally. Ear-swelling responses induced by hapten-specific IgE were less pronounced in mutant mice, giving 35–55% of the responses of normal mice. Similar results were seen in mice treated with a hemopoietic PGD synthase inhibitor, HQL-79, or a CRTH2 antagonist, ramatroban. The reduction in cutaneous responses was associated with decreased infiltration of lymphocytes, eosinophils, and basophils and decreased production of macrophage-derived chemokine and RANTES at inflammatory sites. In models of chronic contact hypersensitivity induced by repeated hapten application, CRTH2 deficiency resulted in a reduction by approximately half of skin responses and low levels (63% of control) of serum IgE production, although in vivo migration of Langerhans cells and dendritic cells to regional lymph nodes was not impaired in CRTH2-deficient mice. In contrast, delayed-type hypersensitivity to SRBC and irritation dermatitis in mutant mice were the same as in wild-type mice. These findings indicate that the PGD2-CRTH2 system plays a significant role in chronic allergic skin inflammation. CRTH2 may represent a novel therapeutic target for treatment of human allergic disorders, including atopic dermatitis.

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BackgroundGender-related differences in humans are commonly observed in behaviour, physical activity, disease, and lifespan. However, the notion that age-related changes in the immune system differ between men and women remains controversial. To elucidate the relationship between immunological changes and lifespan, peripheral blood mononuclear cells from healthy Japanese subjects (age range: 20–90 years; N = 356) were analysed by using three-colour flow cytometry. The proliferative activities and cytokine-producing capacities of T cells in response to anti-CD3 monoclonal antibody stimulation were also assessed.ResultsAn age-related decline in the number of T cells, certain subpopulations of T cells (including CD8+ T cells, CD4+CDRA+ T cells, and CD8+CD28+ T cells), and B cells, and in the proliferative capacity of T cells was noted. The rate of decline in these immunological parameters, except for the number of CD8+ T cells, was greater in men than in women (p < 0.05). We observed an age-related increase or increasing trend in the number of CD4+ T cells, CD4+CDRO+ T cells, and natural killer (CD56+CD16+) cells, as well as in the CD4+ T cell/CD8+ T cell ratio. The rate of increase of these immunological parameters was greater in women than in men (p < 0.05). T cell proliferation index (TCPI) was calculated from the T cell proliferative activity and the number of T cells; it showed an age-related decline that was greater in men than in women (p < 0.05). T cell immune score, which was calculated using 5 T cell parameters, also showed an age-related decline that was greater in men than in women (p < 0.05). Moreover, a trend of age-related decreases was observed in IFNγ, IL-2, IL-6, and IL-10 production, when lymphocytes were cultured with anti-CD3 monoclonal antibody stimulation. The rate of decline in IL-6 and IL-10 production was greater in men than in women (p < 0.05).ConclusionAge-related changes in various immunological parameters differ between men and women. Our findings indicate that the slower rate of decline in these immunological parameters in women than that in men is consistent with the fact that women live longer than do men.

The central event in thymic selection of T cells bearing alpha beta TCRs is their interaction with self-peptides bound to self-MHC molecules. With the use of transgenic mouse lines expressing a single peptide/MHC class II complex, we show that CD4+ T cells with the preferential usage of particular TCR V(alpha)s and V(beta)s were selected to mature on this complex in lines with the lower expression, whereas such CD4+ T cells were eliminated in the thymus in a line with the relatively high expression. When a low expressing line was crossed with a high expressing line, the frequency of CD4+ T cells selected by this complex markedly decreased. Thus, these results suggest that a single peptide/MHC class II complex, being affected by its cell surface density in the thymus, can serve as both positively and negatively selecting ligand in vivo.

The longer life span in dwarf mice suggests that a reduction in the growth hormone (GH)-insulin-like growth factor (IGF)-1 axis retards aging and extends the life span in mammals. We tested this hypothesis in a transgenic strain of rats whose GH gene was suppressed by an anti-sense GH transgene. Male rats homozygous for the transgene (tg/tg) had a reduced number of pituitary GH cells, a lower plasma concentration of IGF-1, and a dwarf phenotype. Heterozygous rats (tg/-) had an intermediate phenotype in plasma IGF-1, food intake, and body weight between tg/tg and control (-/-) rats. The life span of tg/tg rats was 5 to 10% shorter than -/- rats. In contrast, the life span of tg/- rats was 7 to 10% longer than -/- rats. Pathological analysis suggested that neoplasms caused earlier death in tg/tg rats; in contrast, tg/- rats had reduced nonneoplastic diseases and a prolonged life span. Immunological analysis revealed a smaller population and lower activity of splenic natural killer cells in tg/tg rats. The results of the present study support the hypothesis, but suggest that there is an optimal level of the GH-IGF-1 axis to maximize survival in mammals.

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