3. Koziel MJ, Dudley D, Wong JT, et al. Intrahepatic cytotoxic T lymphocytes specific for hepatitis C virus in persons with chronic hepatitis. J Immunol 1992;149:3339 –3344. 4. de Vries JE, de Waal Malefyt R. Interleukin 10. Austin, Texas: Molecular Biology Intelligence Unit, R. G. Landes Co., 1995. 5. Reitamo S, Remitz A, Tamai K, et al. Interleukin 10 modulates type 1 collagen and matrix metalloprotease gene expression in cultured human skin fibroblasts. J Clin Invest 1994;94:2489 – 2492. 6. van Montfrans C, van de Ende A, Fedorak RN, et al. Anti- and proinflammatory effects of interleukin-10 in mild to moderate Crohn’s disease (abstr). Gastroenterology 1999;116:G3370. 7. Schreiber S, Fedorak RN, Nielsen OH, et al. A safety and efficacy study of recombinant human interleukin-10 (rHuIL-10) treatment in 329 patients with chronic active Crohn’s disease (CACD) (abstr). Gastroenterology 1998;114:G4423. 8. Desreumaux P, Brandt E, Gambiez L, et al. Distinct cytokine patterns in early and chronic ileal lesions of Crohn’s disease. Gastroenterology 1997;113:118 –126. 9. Louis H, Van Laethem JL, Wu W, et al. Interleukin-10 controls neutrophilic infiltration, hepatocyte proliferation, and liver fibrosis induced by carbon tetrachloride in mice. Hepatology 1998;8: 1607–1615. 10. Jones CA, Cayabyab RG, Kwong KYC, et al. Undetectable inter- leukin (IL)-10 and persistent IL-8 expression early in hyaline membrane disease: a possible developmental basis for the pre- disposition to chronic lung inflammation in preterm newborns. Pediatr Res 1996;39:966 –975. Supported by grants from Schering, France. doi:10.1053/gast.2000.20105 Reply. We agree with the hypothesis of Dharancy and colleagues that a defect in intrahepatic IL-10 expression may contribute to hepatic inflammation and fibrosis in patients with chronic HCV. In fact, our article referenced the study by Napoli et al. 1 that first reported the down-regulation of intrahepatic IL-10 mRNA in pa- tients with HCV. The down-regulation of IL-10 and the up-regula- tion of intrahepatic Th1-like cytokines (IL-2, interferon [IFN]-) that characterize progressive liver injury in HCV formed the basis of our hypothesis-driven therapeutic trial. We have also reported on the physiologic production of IL-10 and other serum cytokines. In general there was a marked reduction in circulating proinflammatory cytokines (tumor necrosis factor ) and an increase in HCV antigen-driven production of IL-10. Fortunately, we did not observe increases in liver enzyme levels or hepatic inflam- mation, which might reflect the proinflammatory effect of IL-10 that Dharancy et al. suggest. Of interest, IL-10 was not detectable in the serum in most of our patients before initiation of therapy. We are now in the process of examining intrahepatic levels of IL-10 and other inflammatory/fibrosis markers from the pre– and post–liver biopsy specimens with oligonucleotide microarray techniques. We hope that this information will allow us to directly address the impact that intrahepatic IL-10 and other cytokines had in decreasing hepatic inflammation and fibrosis. Last, Dharancy et al. refer to the interaction between IL-10 and the response to antiviral therapy. In theory, the potential immune-mod- ulating benefit of IL-10 may compromise the effectiveness of antiviral therapy. It has recently been reported that heterogeneity in the promoter region of the IL-10 gene has a role in determining the initial response of chronic hepatitis C to IFN- therapy. 2 Patients who have polymorphisms in the IL-10 gene promoter associated with high IL-10 production have a poor response to IFN-. These patients may actually benefit from treatment strategies designed to enhance a Th1 response and suppress the Th2 response. We await further investigation by Dr. Dharancy and others to help clarify the role of this important cytokine. DAVID R. NELSON, M.D. GARY L. DAVIS, M.D. Section of Hepatobiliary Diseases University of Florida Gainesville, Florida 1. Napoli J, Bishop A, McGuinness PH, et al. Progressive liver injury in chronic hepatitis C infection correlates with increased intrahepatic expression of Th1-associated cytokines. Hepatology 1996;24: 759 –765. 2. Edwards-Smith CJ, Jonsson JR, Purdie DM, et al. Interleukin-10 promoter polymorphism predicts initial response of chronic hepa- titis C to interferon alfa. Hepatology 1999;30:526 –530. Interleukin 10: The Magic Bullet for Liver Fibrosis? Dear Sir: We read with interest the report of Nelson et al. 1 on the anti- fibrotic effect of IL-10 in patients with chronic hepatitis C. Twenty- two patients received subcutaneous IL-10 for 90 days, and pretreat- ment and posttreatment biopsy specimens were compared using the Ishak scoring system for inflammation and fibrosis. The authors found that inflammation decreased from 4.3 to 2.7 and fibrosis from 3.6 to 2.6 points (of a maximum of 6) (both P  0.001). Pharmacologic treatment that can prevent progression of liver fibrosis or even induce removal of already deposited excess extracel- lular matrix (fibrolysis) is urgently needed for patients with chronic liver diseases. This applies particularly to the patients with chronic hepatitis C who do not respond to a combination therapy of IFN- and ribavirin, the best treatment currently available. Therefore, an increasing number of researchers and pharmacologic companies focus on the development of antifibrotic drugs. In this context, the reduc- tion of histologic liver fibrosis that reached significance in a group of only 22 patients who were treated for only 90 days, as observed by Nelson et al., is most remarkable and deserves commenting. Liver fibrosis, especially when caused by hepatitis C, is usually slowly progressive, leading to cirrhosis (5– 6 points of the used Ishak score) in roughly one third of patients within 15–25 years, whereas other patients are likely not to progress at all or to progress to cirrhosis at a very slow pace (50 years). 2 As expected, none of the 22 patients progressed during the 90 days of the Nelson study, but 10 patients had a reduction of the fibrosis score of 1 point, and 2 patients each reductions of an astonishing 2 and 3 points. Considering the difficulty of removing excess hepatic connective tissue in experimen- tal models of chronic liver injury, 3 even with innovative treatment strategies, most experts in fibrosis research would likely agree to ask the following questions: (1) Could sampling error (a well-recognized problem with precirrhotic or cirrhotic livers, i.e., those scoring 5 or 6 points) have occurred? We would like to know the initial fibrosis scores of the patients who regressed by 2 or even 3 points. (2) Is the semiquantitative assessment that was used in the study reliable for assessing small differences in connective tissue content? This is im- portant because IL-10 suppressed inflammation, and a decrease in the portal, periportal, and septal inflammatory infiltrate may lead to less edematous and thus expanded fibrotic areas, without net loss of connective tissue. For this reason several large ongoing studies cur- rently use either quantitative image analysis for the Sirius red– 1412 CORRESPONDENCE GASTROENTEROLOGY Vol. 119, No. 5