Detection of TT Virus in Lymph Node Biopsies of B-Cell Lymphoma and Hodgkin's Disease, and its Association with EBV Infection

By means of representational difference analysis, a viral clone (N22) of 500 nucleotides was isolated from serum of a patient (TT) with posttransfusion hepatitis of unknown etiology. The N22 clone showed a poor homology to any reported sequences. Oligonucleotide primers were deduced from the N22 sequence for detecting it by polymerase chain reaction. N22 sequence in serum banded at a sucrose density of 1.26 g/cm3, indicating its association with a viral particle which was designated TT virus (TTV). Since nucleic acids of TTV were sensitive to DNase I, it would be a DNA virus. TTV DNA was detected in sera from three of the five patients with posttransfusion non-A to G hepatitis, including the index case (TT). TTV DNA titers closely correlated with aminotransferase levels in the three patients. These results indicate that TTV would be a novel DNA virus with a possible capacity to induce posttransfusion non-A to G hepatitis. Copyright 1997 Academic Press.

Lymphoma associated with Epstein-Barr virus (EBV) is a complication of bone marrow transplantation that responds poorly to standard forms of therapy. The lymphoma is usually of donor origin. We hypothesized that treatment with infusions of donor leukocytes, which contain cytotoxic T cells presensitized to EBV, might be an effective treatment. We studied five patients in whom EBV-associated lymphoproliferative disorders developed after they received a T-cell-depleted allogeneic bone marrow transplant. Biopsy specimens were immunophenotyped, subjected to the polymerase chain reaction to determine the origin of the lymphoma (donor or host) and to detect the presence of EBV, and analyzed by Southern blotting for the presence of the clonal EBV genome and immunoglobulin-gene rearrangement. Patients were treated with infusions of unirradiated donor leukocytes at doses calculated to provide approximately 1.0 x 10(6) CD3+ T cells per kilogram of body weight. Histopathological examination of biopsy specimens from all five patients demonstrated monomorphic, malignant lymphomas of B-cell origin. Each of the four specimens that could be evaluated was of donor-cell origin. Evidence of clonality was found in two of the three samples adequate for study. EBV DNA was detected by the polymerase chain reaction in all five samples. In all five patients there were complete pathological or clinical responses. The responses were first documented histologically within 8 to 21 days after infusion. Clinical remissions were achieved within 14 to 30 days after the infusions and were sustained without further therapy in the three surviving patients for 10, 16, and 16 months. In a small number of patients, infusions of unirradiated donor leukocytes were an effective treatment for EBV-associated lymphoproliferative disease that arose after allogeneic bone marrow transplantation.