Combined therapy with interferon and low-dose ribavirin in posttransplantation recurrent hepatitis C: a pragmatic study.

Recurrent hepatitis C is a common problem after liver transplantation that can progress to liver cirrhosis of the graft. Preliminary reports of combination treatment with interferon (IFN) and ribavirin have been promising, but long-term follow-up data are not yet available. We report our experience with 1 year of combination therapy with IFN (3 million units thrice weekly) and low-dose ribavirin (600 mg/d), followed by long-term ribavirin monotherapy in 18 patients with moderate to severe recurrent hepatitis C and a median follow-up of 32 months after the completion of combined therapy. All patients were followed up clinically and histologically at regular intervals. Overall, in an intention-to-treat analysis, 15 patients had normal alanine aminotransferase levels (biochemical end-treatment response [ETR], 83%), and 8 patients were also hepatitis C virus RNA negative in serum (virological ETR, 44%) at the end of combined treatment. At last follow-up after the completion of combined therapy (median, 32 months; range, 18 to 73 months), 13 patients were biochemical responders (biochemical long term-sustained response [LT-SR], 72%), and 5 patients also maintained viral clearance (virological LT-SR, 27%). Comparison of liver biopsy specimens before and after 12 months of combined therapy showed improvement in grading scores of at least two points in the majority of the patients (73%). Notably, a trend toward fibrotic progression was only noted in nonresponders. Regarding side effects, despite the low dose of ribavirn, almost half the patients developed hemolytic anemia requiring dose reductions. In addition, long-term ribavirin monotherapy was not associated with iron accumulation. We conclude that combined therapy with low-dose ribavirin followed by long-term ribavirin monotherapy can be recommended because it favorably modifies the natural history of recurrent hepatitis C in most patients and possibly halts histological disease progression without causing iron accumulation.

Cell surface antigens of chemically induced fibrosarcomas: detection by a monoclonal antibody of a tumor-restricted Mr 12,000 protein gag antigen encoded by a dual-tropic murine leukemia virus.

Fusion products of spleen cells of W/FuDp rats immunized with a methylcholanthrene-induced BALB/c sarcoma, CA-2, and mouse myeloma cells were screened in an attempt to identify a monoclonal antibody defining the individually distinct tumor-specific transplantation antigen of CA-2. A hybridoma, MP/69/04, was isolated which produces an IgG2a monoclonal antibody that recognized a tumor-restricted antigen of CA-2. In direct binding assay, MP/69/04 reacted only with 2 of 15 methylcholanthrene induced BALB/c sarcomas tested. Thymus, spleen, lymph nodes, bone marrow, brain, adult lung fibroblasts, newborn muscle fibroblasts and 3T3 cells were negative. Absorption tests revealed, however, expression of the MP/69/04 determinant on 8 of the 12 murine leukemia virus (MuLV) producer BALB/c sarcoma tested. The antigen was not detected on any of the three non-producer sarcomas tested nor on a wide range of normal tissues and cell lines. An N-dualtropic MuLV was isolated from CA-2, and cell lines susceptible to infection by this virus were shown to express the MP/69/04 epitope. By Western blotting, the MP/69/04 epitope was identified as being expressed on the MuLV structural protein with a molecular weight of 12,000, present in CA-2 cells and in the purified CA-2 MuLV. These results indicate the MP/69/04 antigen is not a unique tumor-specific transplantation antigen but is a gag product of a recombinant retrovirus which is expressed on the cell surface of many MuLV + methylcholanthrene-induced BALB/c fibrosarcomas.

In vitro detection of cell-mediated immunity to individual tumor-specific antigens of chemically induced BALB/c fibrosarcomas.

In this study we have analyzed the in vitro cell-mediated cytotoxicity of immune peritoneal exudate cells (PEC), elicited in syngeneic mice against the MCA-induced, TSTA-bearing BALB/c fibrosarcoma CA-2, GI-17 and C-3. The 4 h 51Cr-release assay showed the immune PEC effectors to be specifically cytotoxic to fibrosarcoma used for the immunization, but not to other syngeneic MCA-induced tumors or normal fibroblasts. Cold target inhibition experiments on CA-2 cells confirmed the specificity of the reaction. When PEC, lymph-node and spleen cells from BALB/c anti-CA-2 mice were compared for anti-tumor activity, only PEC were found to kill tumor cells significantly. PEC effectors did not have a significant level of NK or NC activities since they were unable to destroy YAC-1 or WEHI-164 tumor cells. PEC anti-CA-2 were analyzed for the expression of T-cell markers by anti-Thy 1.2, anti-Ly 1.2 and Ly 2.2 monoclonal antibodies. Anti-tumor specific effector cells were identified as mature T cells since they were not adherent to plastic and showed Thy 1.2+, Ly 1.2- and Ly 2.2+ phenotypes. In addition, anti-H-2Kd but not anti-H-2Dd alloantiserum added to target cells, blocked CA-2 tumor lysis, thus supporting the conclusion that the T-cell response against TSTA is H-2 restricted.