Ethnicity and cytokine production gauge response of patients with hepatitis C to interferon-alpha therapy.
Interferon is the primary treatment for hepatitis C virus (HCV). However, the long-term success rate is low particularly for African Americans relative to Caucasians and may be due to differential immune abilities. This study compared cytokine production from PHA-stimulated peripheral blood from 25 healthy and 40 HCV-infected African Americans and Caucasians. HCV patients were designated as IFN responders or nonresponders based on outcome after therapy. Ethnicity and genotype were associated with IFN response. IFN responders were 100% Caucasian, whereas nonresponders were 67% Caucasian and 33% African American (P = 0.01). Genotype 1 was present in 100% nonresponders and 50% responders (P < 0.05). Age, sex, liver histology, ALT, and viral titers were equivalent (ns). Cytokine production from healthy individuals showed ethnic variation in cytokine levels. Healthy African Americans produced greater amounts of IL-2 (P = 0.06), TNF-alpha (P = 0.06) and less IL-10 (P = 0.05) than healthy Caucasians. In contrast, IFN-gamma and TGF-beta levels were equivalent. Pretherapy cytokine production among HCV patients showed a similar pattern of ethnic variation. African American nonresponders produced more IL-2 (P = 0.06) and TNF-alpha (P = 0.02) than Caucasian nonresponders. Cytokine levels among Caucasian and African American nonresponders were equivalent (P = ns) to ethnically matched healthy individuals whereas Caucasian responders produced subnormal levels of IL-10 (P < 0.05) and TGF-beta (P < 0.05). Since all African Americans failed IFN therapy, cytokine production could not be compared with therapeutic outcome. However, comparison of cytokine production among Caucasians showed that responders produced less IL-10 (P < 0.001) and more TGF-beta (P = 0.06) than nonresponders and predicted Caucasian nonresponders with 83% sensitivity and 96% specificity. HCV genotype was not relevant to cytokine production (P = ns). Distribution of cytokine genetic polymorphisms (TNF-alpha, TNF-beta, IL-10, TGF-beta) was equivalent in all ethnic groups and did not predict clinical nonresponders. In summary, it appears that ethnicity may contribute to variable immune responses and therapeutic outcome. The cytokine profile among African Americans suggests a more robust immune response, which may complicate therapy with IFN. In contrast, the subnormal cytokine production among Caucasian responders may be more permissive to IFN therapy. Pretherapy cytokine production may allow prediction of drug resistance among Caucasians.
Kimball
P
P
Department of Surgery, Medical College of Virginia at the Virginia Commonwealth University, Richmond, VA 23838, USA. pkimball@gems.vcu.edu
Elswick
R K
RK
Shiffman
M
M
D000328:Adult; D000998:Antiviral Agents / Q000494:pharmacology / Q000627:therapeutic use*; D044383:Black People; D016207:Cytokines / Q000096:biosynthesis* / Q000235:genetics; D024882:Drug Resistance, Viral; D005260:Female; D016174:Hepacivirus / Q000187:drug effects; D006526:Hepatitis C / Q000188:drug therapy* / Q000208:ethnology / Q000276:immunology / Q000821:virology; D006801:Humans; D016898:Interferon-alpha / Q000494:pharmacology / Q000627:therapeutic use*; D007963:Leukocytes, Mononuclear / Q000276:immunology; D008213:Lymphocyte Activation; D008297:Male; D011110:Polymorphism, Genetic; D016896:Treatment Outcome; D044465:White People; D001741:Black or African American
D000998:Antiviral Agents; D016207:Cytokines; D016898:Interferon-alpha