Nadia Passini

Chromatin remodeling by the SWI/SNF-like BAF complex and STAT4 activation synergistically induce IL-12Rβ2 expression during human Th1 cell differentiation

Interleukin‐12 (IL‐12) is a key cytokine for the development of T helper type 1 (Th1) responses; however, naïve CD4+ T cells do not express IL‐12Rβ2, and are therefore unresponsive to IL‐12. We have examined the mechanisms that control Th1‐specific expression of the human IL‐12Rβ2 gene at early time points after T‐cell stimulation. We have identified a Th1‐specific enhancer element that binds signal transducer and activator of transcription 4 (STAT4) in vivo in developing Th1 but not Th2 cells. T‐cell receptor (TCR) signaling induced histone hyperacetylation and recruitment of BRG1, the ATPase subunit of the SWI/SNF‐like BAF chromatin remodeling complex, to the IL‐12Rβ2 regulatory regions and was associated with low‐level gene transcription at the IL‐12Rβ2 locus. However, high‐level IL‐12Rβ2 expression required TCR triggering in the presence of IL‐12. Our results indicate a synergistic role of TCR‐induced chromatin remodeling and cytokine‐induced STAT4 activation to direct IL‐12Rβ2 expression during Th1 cell development.

Calcitriol derivatives with two different side chains at C-20 III. An epimeric pair of the gemini family with unprecedented antiproliferative effects on tumor cells and renin mRNA expression inhibition.

The searches for drugs that exhibit antineoplastic activity and regulate blood pressure are among the most prevalent and compelling research activities today. Amazingly, there is ample precedence for the antiproliferative action of vitamin-D-related compounds and their role as endocrine suppressors of renin biosynthesis. We have recently synthesized a number of novel calcitriol analogs of the gemini family and originally selected for further studies an epimeric pair related to 19-nor-calcitriol whose 21-methyl group was replaced by a 5,5,5-trifluoro-4-hydroxy-4-(trifluoromethyl)-2-pentynyl group. While maintaining the acceptable calcemic responses, the IC50 concentrations of interferon-gamma release were reduced and the antiproliferative activity and inhibition of renin mRNA expression enhanced. Replacing the geminal methyl groups on the calcitriol-related side chain of these gemini compounds with trideuteriomethyl moieties further boosted the potency in the colon cancer model in mice some 10-fold, reduced NMU-induced breast cancer carcinogenesis in rats and decreased the IC(50) values for renin mRNA inhibition into the pM range.

The insulin-dependent diabetes mellitus-associated ICA 105 autoantigen in stiff-man syndrome patients

The pathogenetic role of anti-glutamic acid decarboxylase (GAD) antibodies found in up to 60% of patients with stiff-man syndrome (SMS) is still controversial. GAD, in fact, is also one of the major target antigen of insulin-dependent diabetes mellitus (IDDM), a disease affecting one third of anti-GAD antibody-positive patients with SMS. To better define the role of autoimmunity in SMS we looked for molecular and immunological evidence of an autoimmune recognition of a second IDDM-associated autoantigen, the pancreatic 37/40 kDa IDDM-autoantigen, whose gene called ICA 105 has been recently cloned. By Northern blot analysis we found that tissue distribution of human ICA 105 is restricted to pancreas and brain and within the central nervous system (CNS) its distribution is similar to GAD. We also measured anti-ICA 105 antibodies in 11 SMS patients and 56 control patients with other neurological diseases (OND). Anti-ICA 105 antibodies were found in 4/11 (36%) patients with SMS (a frequency similar to that of anti-GAD-antibodies in our SMS population) but in only 2/56 (3%) patients with OND (P < 0.001). Anti-ICA 105 and anti-GAD antibodies were associated in 3/4 (75%) patients with SMS but in none of the 2 anti-ICA 105 antibody-positive OND patients. Among anti-ICA 105 antibody-positive patients with SMS, only 1 suffered also from IDDM. In contrast, the only 2 anti-ICA 105 antibody-positive with OND had IDDM. Our results indicate that ICA 105 represents another putative neuroendocrine autoantigen in SMS. The presence of circulating anti-GAD and/or anti-ICA 105 antibodies might help the diagnosis of SMS. The absence, however, of antibodies recognising specific CNS autoantigens (e.g. GAD, ICA 105) does not rule out SMS.

Selective expression of an interleukin-12 receptor component by human T helper 1 cells

Interleukin-12 (IL-12), a heterodimeric cytokine produced by activated monocytes and dendritic cells, plays a crucial role in regulating interferon (IFN)-γ production and in the generation of IFN–γ–producing T helper 1 (Th1) cells. Here we show that the IL-12 receptor (IL12R) β2 subunit, a recently cloned binding and signal transducing component of the IL-12R, is expressed on human Th1 but not Th2 clones and is induced during differentiation of human naive cells along the Th1 but not the Th2 pathway. IL-12 and type I but not type II interferons induce expression of the IL-12R β2 chain during in vitro T cell differentiation after antigen receptor triggering. The selective expression and regulation of the IL-12R β2 subunit may help to understand the basis of Th1/Th2 differentiation and may provide therapeutic options for altering the Th1/Th2 balance in several immuno-pathological conditions such as autoimmune diseases and allergies.