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There have been significant recent advances in our understanding of the role of the B7-CD28/CTLA-4 costimulatory pathway in T-cell activation and self-tolerance. Recent studies have begun to clarify how signaling through this pathway can influence cytokine production. The critical role for CTLA-4 in regulating T-cell activation and autoreactivity has been demonstrated, revealing a previously unsuspected means by which costimulation is involved in the maintenance and breakdown of self-tolerance. In vivo studies indicate the therapeutic potential of manipulating this important, but complex, immunoregulatory pathway.

CD40 and its ligand (gp39, CD40L, TBAM) is central to the control of thymus-dependent humoral immunity. However, in recent years it has become evident that CD40 signaling also is critical in the development of cell-mediated immune responses. How CD40 regulates cell-mediated immunity is discussed.

The interleukin-1 beta converting enzyme (ICE) was first identified as a unique cysteine protease that processes the inactive precursor of the pro-inflammatory cytokine IL-1 beta to its mature active form. Subsequent revelation that a C. elegans cell death gene ced-3 bears sequence homology to ICE has led to rapid identification of at least nine other members of this gene family in humans, some of which are involved in apoptosis. Analyses of ICE-deficient mice generated by gene targeting technology reveal that this enzyme is important in maturation of several cytokines. The ICE deficient mice are resistant in several models of localized and systemic inflammation. ICE itself, however, is not required for Fas-mediated apoptosis, a physiological process for elimination of activated lymphocytes. Selective inhibitors of ICE would be novel therapeutic agents for treatment of diseases where excess inflammation contributes to pathological processes.

The mechanisms of action of immunological adjuvants were studied using a system in which the behavior of adoptively transferred CD4+ T-cell receptor transgenic T-cells could be directly monitored following antigen administration. These studies revealed that adjuvant-induced inflammatory cytokines promote immunity by enhancing the clonal expansion, persistence and differentiation of antigen-activated CD4+ T-cells.

The TNF receptor fusion protein, Ro 45-2081, inhibited allergic and non-allergic inflammatory responses in the airways. Treatment of sensitized guinea-pigs with Ro 45-2081 reduced allergen-induced influx of inflammatory cells into the lungs, abolished edema formation and inhibited hyperreactivity to substance P. Administration of Ro 45-2081 after allergen challenge reversed the influx of inflammatory cells into the lungs. Sephadex-induced neutrophil influx into the lungs of rats was also blocked by Ro 45-2081. The effects of Ro 45-2081 suggest that inhibitors of TNF may have potential as therapeutics for inflammatory diseases in the lung.

Interleukin-10 is an important cytokine that is involved in regulation of pro-inflammatory cytokines and T-cell responses. Interleukin-10 has been studied extensively in various preclinical and clinical models of inflammation. The most remarkable and consistently reproducible quality of IL-10 is its ability to downregulate macrophage functions. This includes inhibiting the production of pro-inflammatory cytokines such TNF-alpha, Interleukin-1, Interleukin-6 and antigen presentation by these professional antigen presenting cells. Additionally, Interleukin-10 also has effects on various other cell types of hematopoietic origin such as B-cells, neutrophils, and most importantly T-cells. Interleukin-10 has shown efficacy in several models of autoimmune disease. The present article deals with the effect of Interleukin-10 in animal models of inflammatory bowel disease and the results of phase I clinical trials in normal human volunteers and chronic active Crohn's disease patients.

CPA was well tolerated at all dose levels (10-150 mg) following single oral dose administration to healthy male volunteers. There was no relationship between the intensity, duration and number of adverse events reported and the dose of CPA. There was a dose-related increase in exposure as measured by AUC0-infinity and Cmax. Administration of 10 mg CPA following food resulted in a delayed tmax, and a significant decrease in Cmax but not AUC0-infinity.

The first morning session of the Eighth International Conference of the Inflammation Research Association was titled 'Targets in Cytokine Activation'. It encompassed four areas of research that may be considered as either current or future targets. Probably the best established target of the four is interleukin-1 beta converting enzyme (ICE) and Winnie Wong from BASF Bioresearch Corporation presented an overview of work in this field. This was followed by a newly emerging target called TACE (TNF-alpha converting enzyme) in a presentation from Douglas Cerretti of Immunex. The final two presentations covered work with chemoattractant receptors (Craig Gerard, Harvard) and mice where the inducible NO synthase gene had been deleted (John Mudgett, Merck).