Several cytokines exhibit a high degree of temporal regulation as well as somnogenic potency (e.g., interleukin-1 [IL-1], tumor necrosis factor-alpha [TNF-alpha]). Seeking the underlying cause of obstructive sleep apnea syndrome (OSAS), we investigated whether circadian rhythms of cytokine release were altered in 10 patients with OSAS. Ten healthy volunteers served as the control population. Seven of the 10 OSAS patients were reexamined after 3 mo of therapy with nasal continuous positive airway pressure (nCPAP) mask ventilation. Circadian cytokine release (IL-1, IL-6, gamma-interferon [gamma-IFN], TNF-alpha) was investigated ex vivo by short-term culture of blood samples. The circadian rhythm of TNF-alpha release was significantly disturbed in OSAS patients: nocturnal physiologic peaks in this cytokine had almost disappeared and an additional daytime peak had developed. Circadian variations in IL-1, IL-6, and gamma-IFN, and in the immunoregulatory hormones melatonin and cortisol, did not differ from those in the controls. Because TNF-alpha is a known modulator of sleep, and nCPAP therapy did not normalize TNF rhythms, we assume that TNF-alpha could well play a pathophysiologic role in OSAS. Further studies should be directed at whether a physiopathologic and/or pathogenic link exists between TNF-alpha and OSAS.

The optimal therapy for sarcoidosis remains unclear. Most patients show a short-term response to corticosteroid therapy, but they have to face the risk of significant side effects. Because tumor necrosis factor alpha (TNF) plays a critical role in granuloma formation and sustenance as well as in the progression of sarcoidosis, we investigated pentoxifylline (POF), which exerts TNF-inhibitory activity, as a therapeutic agent in active pulmonary sarcoidosis. Twenty-three previously untreated patients with documented disease progression during the preceding 3 mo were treated with POF (25 mg/kg daily) and followed for 6 mo of therapy. Two patients were lost to follow-up, and three patients discontinued POF therapy because of gastrointestinal side effects; 18 patients were thus evaluated. Eleven patients improved, seven remained stable and, most importantly, none deteriorated. Lung function tests-DL(CO), Pa(O2) and Pa(O2)[exercise]-were significantly improved in the patient group as a whole and increased in a highly significant manner in those who improved. Three patients with corticosteroid-resistant disease progression were additionally treated with a combination of corticosteroids with POF. In all three patients the combination therapy resulted in an immediate complete decrease of disease activity, even after tapering prednisone to 7.5 mg daily or tapering off corticosteroids. These promising results suggest that POF may improve therapeutic regimens in pulmonary sarcoidosis either by sparing or replacing corticosteroids.

The ancient drug colchicine has repeatedly been proposed as a novel drug for therapy of pulmonary fibrosis. The present study was undertaken to add to the knowledge on colchicine's antiinflammatory and antifibrotic properties and thus help determine its actual rank in the treatment of pulmonary fibrosis. In vitro cell culture experiments with stimulated and unstimulated normal donor peripheral blood mononuclear cells (PMNC) and a human lung fibroblast cell line (WI-38) were used to determine the effects of colchicine on PMNC cytokine release (interleukin-6 and tumor necrosis factor-alpha) as well as on fibroblast proliferation and collagen synthesis rates. Reverse transcriptase polymerase chain amplifications of alpha 1 (III) collagen were done to detect collagen messenger ribonucleic acid (mRNA) expression. Colchicine did not significantly modulate tumor necrosis factor-alpha (TNF-alpha) and interleukin-6 (IL-6) release of PMNC. Colchicine inhibited fibroblast proliferation and total collagen synthesis significantly at concentrations obtainable in serum in vivo. Transcription of the alpha 1 (III) collagen gene into mRNA continued under colchicine. We conclude that colchicine is a potent in vitro inhibitor of fibroblast functions in terms of proliferation and collagen synthesis. The mechanism of collagen inhibition is more likely an inhibition of cellular collagen secretion than a switch off of collagen mRNA transcription. On the other hand, although colchicine is known to inhibit many leukocyte functions, it is a poor inhibitor of cytokines known to be important for fibrogenesis (e.g. IL-6, TNF-alpha, IL-1, platelet-derived growth factor, and transforming growth factor-beta). This makes colchicine, at least from a theoretical standpoint and as concluded from in vitro studies, a preferable candidate for a combined therapeutic strategy.

Summary Control of mycobacterial infection by the cellular immune system relies both on antigen‐presenting cells and on T lymphocytes. The quality of an effective cellular immune response is dependent on functional signal transduction residing in the cytoplasmic tails of the T‐cell receptor CD3 components. In order to investigate potential effects of mycobacteria on T‐cell receptor signalling, we examined the protein expression of T‐cell signal transduction molecules (CD3ζ, ZAP‐70, p59fyn, p56l ck). In Western blots of peripheral blood mononuclear cells of Mycobacterium tuberculosis infected patients, only the CD3ζ‐chain showed a marked reduction in protein expression. To investigate the situation in situ, immunoenzymatic and immunofluorescence stainings for CD3ε and CD3ζ expression were performed on sections of normal lymphoid tissue, M. leprae infected and sarcoid tissue. CD3ε and CD3ζ expression were similar with respect to intensity, localization and the number of cells stained in normal lymphoid tissue and in sarcoid granulomas. In contrast, the granulomas of M. leprae infected tissues showed a significantly reduced expression of CD3ζ compared to CD3ε. Using double immunofluorescence analysis, virtually no CD3ζ expression could be detected in comparison to the CD3ε expression in the lesions. Apparently, mycobacteria are capable of significantly reducing CD3ζ‐chain expression, which may be restored by cytokines. IL‐2‐enhanced ζ‐chain expression and T‐cell effector functions, defined by interferon‐γ release, in M. tuberculosis‐specific and human leucocyte antigen‐DR restricted CD4+ T cells isolated from granuloma lesions from patients with pulmonary tuberculosis. Because CD3ζ is essential for CD3 signalling and for eliciting T‐cell effector functions, reduced CD3ζ protein expression could result in altered signal transduction and inefficient T‐cell effector functions. Alternatively, reduced CD3ζ‐chain expression may protect T cells from repetitive TCR stimulation associated with anergy or apoptosis.

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