Evaluation of the in vitro and in vivo effects of cyclosporine on the lung T-lymphocyte alveolitis of active pulmonary sarcoidosis.
Pulmonary sarcoidosis is a granulomatous disorder characterized by the accumulation of activated helper/inducer T-lymphocytes in the lower respiratory tract, a process thought to be central to the pathogenesis of the disease. Because cyclosporine, a fungus-derived cyclic peptide, has specific inhibitory effects on T-lymphocyte activation, it should suppress activated sarcoid lung T-cells, and thus it should theoretically be an ideal therapeutic agent for sarcoidosis. This was confirmed in vitro: the addition of cyclosporine to T-cells recovered from the lungs of patients with active sarcoid suppressed the spontaneous release of interleukin-2 (IL-2) and monocyte chemotactic factor by these cells and inhibited their exaggerated spontaneous replication. In contrast, the oral administration of conventional doses (10 mg/kg/day) of cyclosporine to eight of these patients over a 6-month period was not accompanied by suppression of sarcoid lung T-cell activation. On the average, the spontaneous release of IL-2 and monocyte chemotactic factor, the proliferation of lymphocytes, and the number of helper/inducer T-cells present in the lungs of these subjects remained elevated and similar to their pretherapy values. Consistent with this lack of effect on sarcoid lung T-cell activation, no improvement in lung function was observed over the trial period. Thus, although cyclosporine is effective in vitro in suppressing the exaggerated activation of sarcoid lung T-cells, it does not do so in vivo, suggesting this agent will not be useful in the therapy of active pulmonary sarcoidosis, at least when administered in a conventional fashion.
Martinet
Y
Y
Pulmonary Branch, National Heart, Lung and Blood Institute, Bethesda, Maryland 20892.
Pinkston
P
P
Saltini
C
C
Spurzem
J
J
Müller-Quernheim
J
J
Crystal
R G
RG
D000328:Adult; D002478:Cells, Cultured; D003524:Cyclosporins / Q000494:pharmacology / Q000627:therapeutic use*; D005260:Female; D006801:Humans; D007249:Inflammation / Q000188:drug therapy; D008168:Lung / Q000187:drug effects / Q000473:pathology*; D008171:Lung Diseases / Q000188:drug therapy* / Q000473:pathology / Q000503:physiopathology; D008213:Lymphocyte Activation / Q000187:drug effects; D008297:Male; D011650:Pulmonary Alveoli / Q000187:drug effects / Q000473:pathology*; D012507:Sarcoidosis / Q000188:drug therapy* / Q000473:pathology / Q000503:physiopathology; D013601:T-Lymphocytes / Q000187:drug effects / Q000473:pathology
D003524:Cyclosporins