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[1292] Indoleamine 2,3-Dioxygenase Expression in Liver Biopsy Samples from Hepatitis C Infected Patients

TS Johnson, R Shahidzadeh, RR Schade, JR Lee, AL Mellor, DH Munn. Medical College of Georgia, Augusta, GA; MCG, Augusta, GA; VAMC, Augusta, GA

Background: Dysregulation of T cell responses may set the stage for chronic Hepatitis C infection. Hep C infection is commonly treated with Interferon- and ribavirin, often with poor clinical response. In mice, interferon- is a potent inducer of indoleamine 2,3-dioxygenase (IDO), which is expressed by specific dendritic cell subsets that have been shown to suppress T cell proliferation cells in an antigen-specific manner (J Immunol 175:5601). IDO-inhibitor drugs are in pre-clinical development for treatment of IDO-induced immunosuppression in cancer and chronic infection.
Design: Immunohistochemical staining for IDO was performed on 107 archival liver biopsy specimens, obtained prior to treatment, from patients with Hep C infection at the Medical College of Georgia. Biopsy grading was based on the regional involvement of portal and parenchymal areas (1+ - 4+). Biopsies from Hep C negative transplant donor candidates were used as negative controls, while tumor draining lymph nodes with IDO+ cells were used as positive controls.
Results: Three distinct patterns of IDO positivity were observed in patients with Hep C: 1) IDO+ cells in portal triads and fibrotic septae; 2) IDO+ cells marginated within sinusoids; and 3) IDO+ cells in parenchyma. Biopsies from liver transplant donors (n=10) showed 40% negative and 60% 1+. Therefore, we considered only grades 2-4+ to represent abnormal IDO enhancement. Of 107 biopsies from patients with confirmed Hep C, 61% (65/107) had abnormally elevated IDO+ cells. Within our sample, a total of 44 patients received treatment (IFNa and/or ribavirin) and had evaluable pre- and post-therapy viral load measurements. Response to therapy was defined as a 2-log reduction in viral load, or reduction below detection. 15 of 44 patients were classed as non-responders; of these, 80% showed abnormally elevated IDO+ cells (12/15). Of the patients classified as responders, 58% (17/29) showed abnormally elevated IDO.
Conclusions: IDO positive cells were increased in a majority of patients with chronic Hep C infection. We speculate that the presence of IDO+ cells may be immunosuppressive in the liver, as has been shown in models of malignancy (J Clin Invest 114:280). We further speculate that adjuvant therapy with IDO-inhibitor drugs (in preclinical development) may improve response to conventional therapy.
Category: Liver & Pancreas

Wednesday, March 28, 2007

Poster # 204, Wednesday Afternoon