MONOCYTE FUNCTION IN IDDM PATIENTS AND HEALTHY-INDIVIDUALS

Interleukin 1β(IL‐1β) and tumour necrosis factor alpha (TNF‐α) may be pathogenetically important in insulin‐dependent diabetes mellitus (IDDM), which is associated with genes of the HLA region. Since a regulatory role of HLA region genes on monokine production may exist, we looked for an association between the monokine and prostaglandin E2 (PGE2) responses of monocytes (Mo) from 20 healthy males (18–50 years) with HLA‐DR types relevant for IDDM susceptibility and resistance (DR 1,2, DR 1,3, DR 1,4, DR 3,4). Monokine assays were established and evaluated and the secretions of IL‐1β, TNF‐α, and PGE2 measured in Mo cultures (2 h, 6 h, 20 h) prepared by endotoxin‐free techniques and stimulated by low‐dose E. coli lipopolysaccharides (LPS). There were no significant associations between Mo responses and HLA‐DR phenotype. Likewise, Mo from DR2 (n=5) and DR4 (n= 5) homozygous healthy males demonstrated no significant differences in monokine and PGE2 responses of Mo. In the HLA class III region a diallelic TNF‐β gene Ncol polymorphism consisting of alleles of 5.5 kb and 10.5 kb was recently described and associated with susceptibility to autoimmune diseases including IDDM. We report that IL‐1β and TNF‐α responses of Mo from TNF‐β 10.5 kb homozygous healthy individuals were significantly higher than for TNF‐β 5.5/10.5 kb heterozygotes. IL‐1β and TNF‐α responses of Mo from males (18–35 years) with newly diagnosed (n= 10) and long‐standing IDDM (n= 10) and from age‐ and HLA‐DR‐matched healthy males (n= 10) were studied. LPS, gamma interferon (IFN), and TNF‐α‐stimulated Mo cultures were investigated. No significant differences were found between Mo responses of IDDM patients and controls. IFN (1000 U/ml) in the presence of LPS significantly potentiated LPS‐stimulated Mo TNF‐α secretion and reduced the levels of IL‐β immunoreactivity in Mo lysates. IFN and TNF‐α did not have any effects on LPS‐stimulated Mo secretion of IL‐1 β immunoreactivity. We conclude that Mo IL‐1β and TNF‐α production is normal in patients with recent‐onset and long‐standing IDDM. The interindividual differences in monokine responses may be accounted for by the diallelic human TNF‐β gene polymorphism rather than by HLA class II genes. This observation may be important for understanding the association of certain H LA haplotypes with autoimmune phenomena and disease. Copyright © 1990, Wiley Blackwell. All rights reserved