|Budget Amount *help
¥3,000,000 (Direct Cost : ¥3,000,000)
Fiscal Year 1999 : ¥1,500,000 (Direct Cost : ¥1,500,000)
Fiscal Year 1998 : ¥1,500,000 (Direct Cost : ¥1,500,000)
One hundred and ten Japanese patients with sarcoidosis and one hundred and sixty-one control subjects were genotyped for three biallelic polymorphisms in the promoter region of TNF-α gene and a Nco I polymorphism located in the first intron of the TNF-β gene. Frequencies of genotypes and alleles, and prognosis were assessed by logistic regression analysis or chi square analysis and the Cox proportional hazards model, respectively. There were no significant differences in the frequency of polymorphisms between patients and controls, thus indicating that none of the polymorphisms are markers for the susceptibility to sarcoidosis. However, the TNF-β gene polymorphism was associated with the clinical course of sarcoidosis in that patients with the allele TNFBィイD1*ィエD11 had a significantly more prolonged clinical course than those without the allele (probability for remission; 0.48). When the analysis was restricted to those without systemic corticosteroid therapy, the differences among the
three genotypes (TNFBィイD1*ィエD11/1, TNFB*1/2, TNFB*2/2) were more overt (probability of remission; 0.33, 0.46, 1.00, respectively. When the analysis was restricted to those who could be followed for more than 60 months, similar results were found. In conclusion, the TNFB*1 allele was shown to be a marker for clinical course in patients with sarcoidosis.
We next examined the cytokine production by blood lymphocytes stimulating them in vitro. The production of TNF-α in TNF-β genotypes TNFB*1/1, TNFB*1/2, TNFB*2/2 were 180 (mean)【minus-plus】100 (SD),206【minus-plus】126, and 268【minus-plus】223 pg/ml by stimulation with PHA, respectively, and 159【minus-plus】58、345【minus-plus】166、296【minus-plus】139 pg/ml by stimulation with anti-CD3 and anti-CD28 antibodies. The production of TNF-β were 520 (mean)【minus-plus】370 (SD), 325【minus-plus】145, and 298【minus-plus】100 pg/ml by stimulation with PHA, respectively, and 242【minus-plus】134, 481【minus-plus】320, 444【minus-plus】149 pg/ml by stimulation with anti-CD3 and anti-CD28 antibodies. There no significant differences in any of these cytokine levels, however, there was a tendency toward decreased production of TNF-α and TNF-β in subjects with the genotype TNFB*1/1 when lympcytes were stimulated with anti-CD3 and anti-CD28 antibodies. Less