Phagocyte oxidative metabolism in cyclosporine- or placebo-treated patients with insulin-dependent (type I) diabetes mellitus of recent onset.
Several lines of evidence suggest that phagocyte-mediated oxidative processes are involved in damage to pancreatic islet cells of Type I insulin-dependent diabetes mellitus (IDDM). This hypothesis, however, has not yet been explored at the clinical onset of IDDM. Similarly, the possibility that cyclosporine A (Cy-A) might exert a selective influence on these phagocyte-mediated oxidative reactions has also not yet been investigated as compared to a placebo. The present study tested both hypotheses in 32 patients with recently diagnosed IDDM who were part of the recent French multicenter randomized therapeutic trial of Cy-A. The production of reactive oxygen intermediates (ROI) by circulating polymorphonuclear (PMN) and mononuclear (MN) phagocytes was determined by luminol-dependent chemiluminescence (CL), both directly within microamounts of whole blood and in purified PMN or MN phagocyte suspensions. Lastly, CL production was measured in the absence (resting CL) and the presence of a panel of particular and soluble phagocyte membrane-stimulating agents. We found that on entry into the trial, i.e. within less than 2 months of the clinical onset of IDDM, patients had normal whole blood CL production in the absence of a stimulating agent and upon phagocytic challenge with latex or opsonised zymosan particles. By contrast, whole blood CL responses to soluble stimuli such as phorbol myristate acetate (PMA), concanavalin A (Con-A) and F Met-Leu-Phe (FMLP) were significantly higher than in the control group of 52 normal subjects (P less than 0.01). In purified PMN and MN phagocyte suspensions, both resting and stimulated CL productions were normal, regardless of the type of stimulating agent. After 3 months of treatment, whole blood CL responses to Con-A and FMLP returned to almost normal levels in patients treated with Cy-A (15 cases) but not in those receiving the placebo (17 cases); PMA-induced CL responses were also decreased, but this was found in both groups of patients. In purified phagocyte suspensions we detected no effect of Cy-A on PMN, whereas MN phagocytes from Cy-A-treated patients showed reduced CL responses to FMLP but not to other stimuli. Altogether, these results demonstrate for the first time that the capacity of circulating PMN and MN phagocytes to generate ROI is normal at the clinical onset of IDDM and suggest that circulating substances increase oxidative responses to soluble, but not particulate, stimuli.(ABSTRACT TRUNCATED AT 400 WORDS)
INSERM U25, Hôpital Necker, Paris, France.
B
B
Descamps-Latscha
A T
AT
Nguyen
G
G
Feutren
D000293:Adolescent; D000328:Adult; D003524:Cyclosporins / Q000494:pharmacology*; D003922:Diabetes Mellitus, Type 1 / Q000188:drug therapy / Q000276:immunology*; D004311:Double-Blind Method; D005260:Female; D006801:Humans; D008163:Luminescent Measurements; D008165:Luminol; D008297:Male; D015337:Multicenter Studies as Topic; D009504:Neutrophils / Q000378:metabolism; D010100:Oxygen / Q000097:blood*; D010586:Phagocytes / Q000187:drug effects / Q000378:metabolism*; D016032:Randomized Controlled Trials as Topic
D003524:Cyclosporins; D008165:Luminol; D010100:Oxygen