A novel JAK/ROCK inhibitor, CPL409116, demonstrates potent efficacy in the mouse model of systemic lupus erythematosus.

Systemic lupus erythematosus is a chronic inflammatory disease, in which treatment is still limited due to suboptimal efficacy and toxicities associated with the available therapies. JAK kinases are well known to play an important role in systemic lupus erythematous. There is growing evidence that ROCK kinases are also important in disease development. In this paper, we present the results of the development of CPL409116, a dual JAK and ROCK inhibitor. The studies we performed demonstrate that this molecule is an effective JAK and ROCK inhibitor which efficiently blocks disease progression in NZBWF1/J mouse models of systemic lupus erythematous.

Preclinical characterization of CPL302-253, a selective inhibitor of PI3Kδ, as the candidate for the inhalatory treatment and prevention of Asthma.

Asthma is a common chronic inflammatory disease. Although effective asthma therapies are available, part of asthmatic population do not respond to these treatment options. In this work we present the result of development of CPL302-253 molecule, a selective PI3Kδ inhibitor. This molecule is intended to be a preclinical candidate for dry powder inhalation in asthma treatment. Studies we performed showed that this molecule is safe and effective PI3Kδ inhibitor that can impact many immune functions. We developed a short, 15-day HDM induced asthma mouse model, in which we showed that CPL302-253 is able to block inflammatory processes leading to asthma development in vivo.

Mannose Metabolism Is Essential for Th1 Cell Differentiation and IFN-γ Production.

Glucose-derived mannose is a common component of glycoproteins, and its deficiency leads to a severe defect in protein glycosylation and failure in basic cell functions. In this work, we show that mannose metabolism is essential for IFN-γ production by mouse Th1 cells. In addition, we demonstrate that the susceptibility of Th1 cells to glycolysis restriction depends on the activation conditions and that under diminished glycolytic flux, mannose availability becomes the limiting factor for IFN-γ expression. This study unravels a new role for glucose metabolism in the differentiation process of Th1 cells, providing a mechanistic explanation for the importance of glycolysis in immune cell functions.

NKT cell stimulation with α-galactosylceramide results in a block of Th17 differentiation after intranasal immunization in mice.

In a previous study we demonstrated that intranasal (i.n.) vaccination promotes a Th17 biased immune response. Here, we show that co-administration of a pegylated derivative of α-galactosylceramide (αGCPEG) with an antigen, even in the presence of Th17-polarizing compounds, results in a strong blocking of Th17 differentiation. Additional studies demonstrated that this phenomenon is specifically dependent on soluble factors, like IL-4 and IFNγ, which are produced by NKT cells. Even NK1.1 negative NKT cells, which by themselves produce IL-17A, are able to block Th17 differentiation. It follows that the use of αGCPEG as adjuvant would enable to tailor Th17 responses, according to the specific clinical needs. This knowledge expands our understanding of the role played by NKT cells in overall control of the cytokine microenvironment, as well as in the overall shaping of adaptive immune responses.

Peritoneal cavity is dominated by IFNγ-secreting CXCR3+ Th1 cells.

The chemokine receptor CXCR3, which was shown to take part in many inflammatory processes, is considered as a Th1 specific marker. Here, we show in a mouse model that CXCR3 expressing CD4(+) cells preferentially migrate to the peritoneal cavity under steady-state conditions. The peritoneal cavity milieu leads to an up-regulated expression of CXCR3. However, blocking of known ligands of this chemokine receptor did not alter the preferential migration. The peritoneal cavity environment also results in an increased percentage of memory cells producing cytokines. Up-regulation of IFNγ production occurs mostly in CXCR3(+) cells considered as Th1, whereas the up-regulation of IL-4 affects mostly in CXCR3(-) cells which are considered as Th2. We conclude that the peritoneal cavity does not change the Th-lineage of the cells, but that domination of this anatomic niche by Th1 cells rather results from preferential migration to this compartment.

Intranasal immunization promotes th17 immune responses.

Th17 cells are a lineage of CD4+ T cells characterized by IL-17 secretion, which plays a crucial role in immune responses against important respiratory pathogens, such as Mycobacterium tuberculosis. In this study, we demonstrated that intranasal (i.n.) immunization leads per se to Th17-biased immune responses, regardless of the adjuvant used. The activated CD4+ T cells also showed an up-regulated expression of the chemokine receptor CCR6, which is a marker for murine Th17 cells. These results have important implications in the context of optimizing rational vaccine design, since i.n. immunization appears to be the strategy of choice for situations where the induction of a Th17 phenotype would be beneficial.