This study shows that immunotherapy shifted cytokine responses to allergen from a TH-2 to a TH-1 dominant pattern, suggesting direct effects on T cells. How these cytokine changes relate to clinical desensitization is not clear. In the longer term they would result in an isotype switch from IgE to IgG. Early changes in cytokine or chemokine production might downregulate mast cell or basophil reactivity and explain the rapid desensitization in rush VIT.

WHAT IS ALREADY KNOWN ABOUT THIS SUBJECT• P2X7 receptors are involved in the production of pro-inflammatory cytokines, such as Il-1b, by central and peripheral immune cells. Il-1b has been implicated as an important mediator of inflammation. Therefore, the P2X7 receptor is an attractive therapeutic target for inflammatory diseases. WHAT THIS STUDY ADDS• Findings in pharmacokinetics, pharmacodynamics, safety and tolerability of a P2X7 receptor modulator, GSK1482160, from the first human study for the molecule are described. A pharmacokinetic/ pharmacodynamic model for LPS-stimulated ATP-induced Il-1b production in blood allowed the integration of all relevant data and provided in vivo evidence of the nature of the drug-receptor interaction. The model has the potential to be used to simulate future trials. AIMSThis paper describes findings from the first-in-human study for GSK1482160, an orally available allosteric P2X7 receptor modulator. The study aimed to assess the pharmacokinetics (PK), pharmacodynamics (PD), safety and tolerability of the compound in healthy subjects. METHODSEscalating single doses of up to 1 g were administered to healthy subjects in a single-blind and placebo-controlled fashion. Safety, tolerability, blood drug concentrations and ex vivo Il-1b production in blood were evaluated. RESULTSDrug concentration peaked within 3.5 h of dosing under fasting conditions and declined thereafter with a relatively short half-life of less than 4.5 h. Exposure was proportional to dose with between subject variability of less than 60%. A PK/PD model quantified Il-1b as a function of drug exposure. The model allowed simulation of in vivo pharmacology for various untested dose levels and regimens. Furthermore, the mechanistic model supported the hypothesis that the compound reduces the efficacy of ATP at the P2X7 receptor without affecting its affinity. No major safety or tolerability concerns were identified in this small study (n = 29), except for one case of asymptomatic accelerated idioventricular rhythm at the top dose. CONCLUSIONThe model-based approach maximized analysis power by integrating all biomarker data and revealed mechanistic insight into the pharmacology of P2X7 modulation by GSK1482160. Simulations by this model ultimately led to the discontinuation of the development of this compound. The therapeutic relevance of the P2X7 receptor remains to be tested in patients. The mechanistic-model-based approach can be applied widely to drug development.

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SUMMARYThalidomide is an effective immunomodulatory drug in man, but its mechanism of action remains unclear. We hypothesized that, in addition to its reported inhibitory effects on production of monocyte-derived tumour necrosis factor-alpha (TNF-a), thalidomide might be effective at the level of Th immunoregulation. In a comparative study with the immunosuppressant cyclosporin A. we have demonstrated a potent and specific effect of thalidomide on cytokine production relating to the distinct Th 1 and Th2 subsets. It induced and enhanced the production of IL-4 and IL-5 and, at the same dose (lOOOng/ml), significantly inhibited interferon-gamma (IFN-7) production in phytohaemagglutinin (PHA)-stimuIated human peripheral blood mononuclear cell (PBMC) cultures. Stimulation of PBMC with recall antigen (streptokinase:streptodorn:ise (SKSD))at i44h in the absence of thalidomide resulted in a predominantly Thl response, with the production of IFN-7 and IL-2. Thalidomide switched this response from a Thl to a Th2 type. The effect was most pronounced at lOOOng/ml thalidomide, where inhibition of IFN--. and enhancement of IL-4 production was maximal. In unstimulated Lulturcs thalidomide alone induced IL-4 production. Cyclosporin A, in contrast, inhibited both Thl and Th2 cytokine production by PHAstimulated PBMC. Time course data from thalidomide-treatcd cultures revealed that the augmented IL-4 production diminished as the culture time increased, whereas IFN--> production was significantly increased. This response might be due to activation-induced apoptosis of Th2 cells or the induction of Th2 cell anergy. in the continued presence of stimulating agents, with the emergence of IFN-->-secreting Th I cells when Th2 antagonism declines. The effects of thalidomide and related compounds may enhance our understanding of the mechanisms of T helper cell selection, offer the possibility of controlled therapeutic switching between Thl and Th2 responses, and may lead to a rational approach for the treatment of some T cell-mediated immunological disorders.