[Modeling hepatitis A in monkeys (results and prospects)].
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Biomedical subjects
Publications and source records attributed to B A Lapin.
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Fifteen cases of generalized peripheral T-cell non-Hodgkin's lymphoma in baboons were phenotyped immunologically and morphologically. Using the updated Kiel classification the cases included low-grade and high-grade lymphomas and low-grade lymphomas that had transformed into high-grade lymphomas. In the low-grade group there were seven cases of lymphocytic type, partly corresponding to chronic lymphocytic leukaemia of T type and to T-zone lymphoma in man. In addition there were four cases of prolymphocytic-lymphocytic type, which show large nodules ("proliferation centres") and which have no equivalent in the Kiel classification. In four cases there was a progression to an immunoblastic lymphoma and in one case to a large cell anaplastic lymphoma. In addition, three cases of large cell anaplastic lymphoma without a low-grade component were found. Both the immunoblastic lymphomas and the large cell anaplastic lymphomas corresponded well with the same types in the Kiel classification. The cases of large cell anaplastic lymphoma were also CD30 positive. Most of these lymphomas were CD4 positive, but there were rare cases that were either CD8 positive, showed both CD4 and CD8 positivity or had lost both antigens. Antigens associated with cell activation were often revealed. All but one baboon had antibodies in the blood against the retrovirus STLV-1 (simian T-cell leukaemia virus 1), which is very similar to human T-cell leukaemia virus 1 (HTLV-1) in man. Despite this virological resemblance, the morphology of these T-cell lymphomas does not resemble that of the HTLV-1-positive Japanese T-cell lymphomas but is like that of the HTLV-1-negative European cases.
Papio hamadryas baboons in the Sukhumi colony develop enzootic outbreaks of malignant lymphomas with an incidence of about 1.5% per year among adults of the high-risk stock. We investigated the surface phenotypes of cells from normal and lymphomatous animals using antibodies against human lymphocyte antigens. We found that more than 80% of the lymphomas that developed during the last 3 years were characterized histologically to be of the peripheral T cell type. Generally, the lymphomatous cells also expressed high levels of MHC class II DR protein, CD18 (LFA-1 beta chain), and CD45RO. Surprisingly, these cells also expressed on their surface two proteins previously characterized as being relatively B cell-restricted: CD40 and Bgp95. These proteins were never found on the peripheral blood T cells from normal animals. The expression of these two gene products was confirmed by RNA blotting and immunoprecipitation. In most cases, the two B cell-associated proteins were expressed on the predominant T cell subsets; we found both B cell proteins on CD4+, CD8+ as well as on the CD4/8 double-positive cells when these subsets were expressed at high levels. About 90% of these animals are seropositive for Herpesvirus papio and human T cell leukemia virus-1 (HTLV-1) before developing outright lymphomas. In all of the lymphoma samples, HTLV-1 tax DNA sequences were detected by PCR amplification. Whether or not HTLV-1 or the Herpesvirus papio gene products influence the surface expression of CD40 and Bgp95 remains to be determined.
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The prolonged (up to 2 years) complex observation of 11 rhesus macaques (Macaca mulatta) with spontaneous hepatitis A and 14 rhesus macaques with experimental hepatitis A developing after their intravenous and/or oral infection with human hepatitis A virus (HAV). Both natural and experimental infection took a chronic course (15-18 months). In 13 monkeys showing morphological changes in the liver during the whole period of the disease elevated enzyme levels in the blood and virus shedding in feces were periodically observed. Only one monkey had acute hepatitis A which lasted 1.5 months. In 11 monkeys the disease took an undulating course with 1-2 relapses when virological, biochemical and morphological signs of the disease could be detected. Seroconversion was observed in all monkeys. Anti-HAV IgM antibodies were retained for not more than 6-7 months and total anti-HAV antibodies, during the whole period of observation. Relapses were found to induce no antibody formation. Evidence on the prolonged (up to 12-16 months) persistence of HAV in primates was obtained for the first time.
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The aim of this work was to study genomes of B-lymphotropic oncogenic herpesviruses of Macaca arctoides (HVMA), Papio hamadryas (HVP) and Cercopithecus aethiops (HVGM). Blot-hybridization detected inter- and intraspecific genome heterogeneity of investigated viruses in restriction sites EcoR1, Pst1 and Hind111. Virus-specific sequences in two-cell lines obtained from HVMA-induced rabbit tumours can prove HVMA a role in malignant tumour induction in rabbits.
The association of simian T-cell leukemia virus with baboons malignant lymphoma was studied. Proviral DNA integrated in cells of lymphoid organs was detected in 19 of 21 sick animals examined. Only 4 of 10 monkeys from high risk colony without clinical manifestations had virus-specific sequences in their cellular DNAs. As a rule, S(H)TLV-I-infected cells monoclonally proliferated both in lymphomatous and healthy baboons. The restriction patterns with EcoRI, HindIII, PstI, BamHI of S(H)TLV-I provirus were similar but not identical to those of prototype HTLV-I and STLV-I isolates.
The focus of this paper is characterization of Hepatitis A experimental model obtained for the first time in rhesus monkeys (M. mulatta) infected with fecal isolate from a patient with Hepatitis A (HAV-H1). Monkeys were susceptible to oral and intravenous routes of HAV inoculation. The disease could be reproduced regularly in 4 passages as a result of which HAV strain continuously pathogenic for M. mulatta has been established. All 17 infected monkeys developed Hepatitis A with characteristic (except jaundice) patterns: shedding of virus with the stool, elevations of serum alanine aminotransferase level, appearance of IgM anti-HAV, morphological changes developed in the liver. Our data have demonstrated that the course of experimental Hepatitis A infection in M. mulatta is similar (in many respects) to that observed in man.
Morphological and immunological phenotyping was carried out on 20 cases of peripheral baboon T-cell non-Hodgkin's malignant lymphomas (NHL) observed in a Sukhumi monkey colony. Morphologically, the lymphomas were prolymphocytic, immunoblastic, or rarely lymphoblastic types. For immunophenotyping studies, the panel of 29 monoclonal antibodies (MAb) to human or mouse leukocytic antigens were used (18 CD clusters). Three polyclonal sera to human IgG and light chains kappa and lambda were also taken in experiments. The investigated NHLs and CD4+CD8- (12 cases) or CD4-CB8+ (5 cases) phenotypes. In some cases loss of pan T-cell antigens or unusual antigen expression--loss (one case) or coexpression (two cases) of T-subset antigens--or the presence of abnormal lymphoid antigens have been revealed. In most studies, baboon T-cell NHLs tumor cells belonged to activated T-cells because they expressed Ia-like antigens and IL2R at high levels. There was no correlation between the discovered immunophenotype and the morphological pattern of malignant lymphomas.
Histological, cytochemical and ultrastructural investigation of immunologically typed B-cell non-Hodgkin's malignant lymphomas (NHL) of primates (model system on baboons) revealed 15 cases of malignant lymphomas originating from germinal centre cells of lymph nodes follicles. By the tumour cell type centroblastic (CB), centroblastic/centrocytic (CB/CC) and centrocytic (CB), malignant lymphomas were distinguished (according to Kiel classification). In case of CB NHL, tumours, as a rule, are of nodular type. Tumours, in which centrocytic infiltration predominates, are characterized by diffuse type of growth in lymphoid and nonlymphoid organs. Generalized process affects mainly lymph nodes and to considerably lower degree involves spleen and nonlymphoid parenchymatous organs.
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Ten pig-tailed monkeys (Macaca nemestrina) were subjected to 60Co radiation at a dose of 6.0-6.5 Gy and a dose rate of 1.2 Gy/min. Acute radiation sickness has developed in the monkeys causing their death on the 16-20 day. In spite of this, the initial reaction was weakly expressed and according to its manifestation it was impossible to evaluate severity and possible outcome of the lesion. At an early stage of the disease (6-24 hours) insufficient was uranin fluorescence in blood plasma, but more informative were the changes in adhesive properties of leukocytes the dynamics of lymphocytes (lymphopenia), reticulocytes (reticulocytopenia) and shifts in reticulograms (increased per cent of juvenile forms).
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