Posttransplantation cyclosporine-induced lymphoproliferative disorders: clinical and radiologic manifestations

Fifteen allograft transplant recipients acquired lymphoproliferative disorders after immunosuppressive therapy with cyclosporine and steroids. Many of these lymphoproliferative disorders regressed or disappeared completely after reduction of cyclosporine dose. This disease has several aspects that distinguish it from usual posttransplantation lymphomas that occur with regimens that do not contain cyclosporine. The time course from transplantation to onset of lymphoma is relatively short, with an average of approximately 8 months. Organs show a wide spectrum of abnormalities typical of other immunosuppression-associated lymphomas, but there is unique sparing of the central nervous system. The tumor is also unique in that it responds to a decrease in the cyclosporine dose.     

In vivo suppression of restenosis in balloon-injured rat carotid artery by adenovirus-mediated gene transfer of the cell surface-directed plasmin inhibitor ATF.BPTI

Injury-induced neointimal development results from migration and proliferation of vascular smooth muscle cells (SMC). Cell migration requires controlled proteolytic degradation of extracellular matrix surrounding the cell. Plasmin is a major contributor to this process by degrading various matrix proteins directly, or indirectly by activating matrix metalloproteinases. This makes it an attractive target for inhibition by gene transfer. An adenoviral vector, Ad.ATF.BPTI, was constructed encoding a hybrid protein, which consists of the aminoterminal fragment (ATF) of urokinase-type plasminogen activator (u-PA) linked to bovine pancreas trypsin inhibitor (BPTI), a potent inhibitor of plasmin. This hybrid protein binds to the u-PA receptor, thereby inhibiting plasmin activity at the cell surface, and was found to be a potent inhibitor of cell migration in vitro. Local infection with Ad.ATF.BPTI of balloon-injured rat carotid artery resulted in detectable expression of ATF.BPTI mRNA and protein in the vessel wall. Morphometric analysis of arterial cross-sections revealed that delivery of Ad.ATF.BPTI to the carotid artery wall at the time of balloon injury inhibited neointima formation by 53% (P < 0.01) at 14 days and 19% (P = NS) at 28 days after injury when compared with control vector-infected arteries. Intima/media ratios were decreased by 60% (P < 0.01) and 35% (P < 0.05) at 14 and 28 days, respectively, when compared with control vector-infected arteries. Furthermore, a small but significant increase in medial area was found in the Ad.ATF.BPTI-treated arteries at 28 days (P < 0.05). These results show that local infection of the vessel wall with Ad.ATF.BPTI reduces neointima formation, presumably by inhibiting SMC migration, thereby offering a novel therapeutic approach to inhibiting neointima development.     

Low-grade malignant lymphoma, hepatitis C virus infection, and mixed cryoglobulinemia

Because a close relationship has been established between mixed cryoglobulinemia and hepatitis C virus (HCV) infection, the clinical, histologic, and virologic findings of 31 patients affected by mixed cryoglobulinemia have been determined. HCV infection was investigated by the presence of anti-HCV antibodies and by polymerase chain reaction (PCR) amplification of the 5' untranslated region (5'UTR), and the genotype of HCV was also determined according to Okamoto et al (J Gen Virol 73:673, 1992). A bone marrow (BM) biopsy was performed in all patients, and liver and kidney biopsies were performed when indicated. The prevalence of anti-HCV antibodies was high (83.9%); polymerase chain reaction amplification of the 5' untranslated region was positive in 26 subjects (83.9%), and Core region amplification in 26 of 27 subjects (96.2%). A high prevalence of genotype II was found (76.6%). Chronic liver disease was present in 15 (48%) patients. BM biopsy specimens showed the presence of low-grade non-Hodgkin's lymphomas in 12 cases (38.7%), whereas, in 11 patients (35.5%), the BM infiltration was not monoclonal (reactive). Mixed cryoglobulinemia is closely associated with HCV infection. Apparently, only 1 patient was not infected by the virus. Several HCV genotypes are involved in the pathogenesis of mixed cryoglobulinemia. The disease is associated with a high prevalence of low-grade non-Hodgkin's lymphomas.