[Malignant lymphomas in primates and the principles of their morphological diagnosis (on a baboon model of malignant lymphomas)].

114 baboons with non-Hodgkin lymphoma (NHL) were examined, by using the morphoimmunological phenotyping technique. According to the Kiel classification, 14 types of non-Hodgkin lymphomas of high and low malignancy are identified and described. These include 8 T-cell lymphomas and six B-cell NHL. Some morphoimmunological characteristics were found. The morphological cell atypia coincided with the abnormal immunotype of tumor cells. The nosological type of hemoblastosis in the baboons is characterized by the development of mainly malignant lymphomas.

[Development of a method for creating a colony of Macaca mulatta, free of herpes B virus infection]. / Razrabotka metoda po sozdaniiu kolonii Macaca mulatta, svobodnoi ot gerpes v virusnoi infektsii.

To form the colony of monkeys, free of herpes B virus, the serological study was made with the aim of finding out the carriers of this virus. 482 rhesus macaques (Macaca mulatta) from the Adler monkey house were examined for the presence of antibodies to herpes B virus by the method of point immunoblotting with the use of Herpes virus simiae as antigen. The contamination of monkeys in different open-air cages varied from 12.5% to 92%. In different age groups, it was 27% in nonpubescent monkeys (49 out of 182 animals), 55% in adolescent monkeys (55 out of 99), 73% in pubescent monkeys (131 out of 179) and 95% in monkeys over 15 years (21 out of 22 animals). 9 groups of rhesus macaques (comprising altogether 81 animals), free of herpes B virus, were selected. The monkeys were repeatedly tested within a year; after that 10-17% of formerly seronegative monkeys were rejected and removed from the selected group. After the third testing 2.5% more of the animals were found to have seroconversion. The colony of rhesus macaques thus created exists at present. The animals are subjected to constant serological observation.

[Morpho-immunologic phenotypes of T-cell non-Hodgkin's malignant lymphoma in baboons and their connection with with T-lymphotropic retrovirus STLV-1]. / Morfoimmunologicheskie fenotipy T-kletochnykh nekhodzhinskikh zlokachestvennykh limfom pavianov i ikh sviaz' s T-limfotropnym retrovirusom STLV-1.

8 cytological types were detected among 58 cases of T-NHL of Papio hamadryas according to human updated Kiel classification (1988). 5 of them were of low grade (lymphocytic, prolymphocytic, T-zone, angioimmunoblastic, small cell pleomorphic) and 3-of high grade (medium and large cell pleomorphic, immunoblastic, large cell anaplastic CD30/Ki-1+). There are differences in a tumor structure and generalization in baboon and human lymphomas in spite of significant similarities. STLV-1 presence (antibodies in blood and virus genome fragments in the lymphoma cell DNA) detected by PCR-amplification in 7 investigated types of baboon T-NHL. CD4+ immune phenotypes were predominant in T-cell baboon lymphomas, while CD8+ phenotypes were rare. Abnormal phenotypes in some cases were also detected in the three-color FACS-analyses.

[Large-cell anaplastic malignant CD30/Ki-1-positive T-type lymphoma, associated with STLV-1 virus (baboon malignant lymphoma model]. / Krupnokletochnye anaplasticheskie zlokachestvennye CD30/Ki-1-pozitivnye limfomy T-tipa, assotsiirovannye s virusom STLV-1 (na modeli zlokachestvennykh limfom pavianov.

Large-cell anaplastic malignant lymphoma of T-type (T-LCAL) as an original form among human non-Hodgkin's malignant lymphomas in Updated Kiel Classification (1988) was defined. In human pathology T-LCAL presents a considerable diagnostic difficulties and is not associated with HTLV except some cutaneous forms. Comparative examination was carried out in 5 cases of baboon T-LCAL as a part of long-term investigation of the lymphoma outbreak in Sukhumi monkey stock. In tumor-bearing baboons routine morphological methods, immuno-morphological phenotyping of lymphoma cells with panel of MoAT and polyclonal antibodies to T- and B-lymphoid cell antigens and antigens of cell activation, including CD30 antigen, in cell suspension and on cryostate sections were used. STLV-provirus integration in DNA of lymphoma cells in PCR was determined. Diagnostically important morphological features of baboon and human T-LCAL include pronounced anaplasia and anisocytosis of CD30-positive large blast cells, tumour cell tendency to infiltrate sinuses and vascular walls. The presence of T-cell markers (CD2, CD3, CD4, CD8 in our cases) and antigens of cell activation (CD25, HLA-DR) were found. In DNA of baboon lymph node lymphomas (also in the cases without skin involvement) env- and tax-fragments of STLV-1 provirus were detected.

Morphological characteristics of malignant T-cell lymphomas in baboons.

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.

Baboon T cell lymphomas expressing the B cell-associated surface proteins CD40 and Bgp95.

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.

[Comparative study of lymph node gangliosides and blood serum of normal and T-lymphotrophic baboons]. / Sravnitel'noe izuchenie gangliozidov limfaticheskikh uzlov i syvorotki krovi pavianov-gamadrilov v norme i pri T-kletochnykh limfomakh.

The gangliosides from the lymph nodes and blood sera of normal and T-lymphomic baboons were studied. In lymph nodes the major gangliosides were identified as GM3 and GD3, those in blood sera--as GM3, GM1 and GD3. Gangliosides GM3 and GD3 contained N-acetyl as well as N-glycoloyl neuraminic acids. In gangliosides isolated from lymph nodes and blood sera of T-lymphomic baboons the levels of N-glycoloyl neuraminic acid markedly exceeded that in normal tissues. In tumour lymph nodes the GM3/GD3 ratio was shifted towards GD3.

[Non-Hodgkin's malignant lymphomas in primates (immunodiagnostic principles in T-cell lymphomas)]. / Nekhodzhkinskie zlokachestvennye limformy v otriade primatov (printsipy immunodiagnostiki T-kletochnykh limfom).

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.

[Modelling of malignant lymphoma in rabbits using primate oncogenic viruses. Preliminary report]. / Modelirovanie zlokachestvennoi limfomy na krolikakh s pomoshch'iu onkogennykh virusov primatov. Predvaritel'noe soobshchenie.

Inoculation of rabbits with permanent B-cell line cultures obtained from Stumptailed Macaques M. arctoides (MAL) which contain lymphotropic herpesvirus and C-type particles has led to the development of generalized lymphomas. The lymphoma cells had rabbit karyotype and did not contain surface an cytoplasmic immunoglobulins. Permanent suspension of lymphoid cell line independent of growth factors was obtained from rabbit lymphoma. The serum of a rabbit with lymphoma transmitted from another rabbit with MAL-induced lymphoma did not react with virus-negative human Raji cells when tested in immunofluorescence. But this serum reacted positively with cytoplasmic antigens of simian 594S-F9 cells (producing lymphotropic herpesvirus and two types of retroviruses, namely, endogenous C-type and HTLV-I-like) and human C91-PL cells (producing HTLV-I). The results obtained demonstrated high oncogenicity of the viruses produced by simian permanent cellular MAL lines for rabbits.

[B-cell and T-cell immunoblastic lymphomas of baboons]. / B- i T-kletochnye immunoblastnye limfomy pavianov.

The results of morphological study of B- and T-cellular immunoblast baboon lymphomas are presented. Differences are found both in the structure of tumour cells and in the histostructure of tumours as a whole. The tumor cells of B-immunoblastic lymphomas expressed mainly IgM. The tumour cells of certain T-immunoblastic lymphomas being investigated by means of monoclonal OKT4 antibodies had a surface phenotype peculiar to T-helper cells.

Search for CEA-like molecules in polymorphonuclear leukocytes of non-human primates using monoclonal antibodies.

The monoclonal anti-CEA antibody ZIK-A42-A/C1 which reacts with NCA of human polymorphonuclear leukocytes was found to bind also to polymorphonuclear blood leukocytes of the following non-human primates tested: hamadryas baboon (Papio hamadryas), stump-tailed monkey (Macaca arctoides), pig-tailed monkey (Macaca nemestrina), and rhesus monkey (Macaca mulata). No binding was observed to mononuclear blood leukocytes. It was concluded that non-human primates contain CEA-like substances in their polymorphonuclear leukocytes as humans do and that these substances carry some identical epitopes.

[Leukemogenesis and bone marrow hematopoietic disorders in baboons with immunoblastic malignant lymphomas of B- and T-cell types]. / Leikemizatsiia i narusheniia kostnomozgovogo krovetvoreniia u pavianov pri immunoblastnykh zlokachestvennykh limfomakh B- i T-kletochnogo tipa.

Leukemization in baboon B- and T-cell immunoblastomas was investigated. Immunologic identification of tumor was carried out using standard immunological and cytochemical tests, e. g. identification of several types of E-rosette forming lymphocytes, surface and cytoplasmic immunoglobulin-carrying lymphocytes and assay of such acid hydrolases as acid phosphatase, acid alpha-naphthyl acetate esterase and beta-glucuronidase in lymphoid cells. Leukemization of immunoblastomas with bone marrow infiltration by tumor immunoblasts and the appearance of the latter in peripheral blood were observed rather frequently--in 7 of 10 cases of B-cell and in all 4 cases of T-cell immunoblastoma. Immunoblastoma progression was accompanied by a rise in lymphoid element level in peripheral blood and a lesser increase in bone marrow. At terminal stage, both patterns of immunoblastoma sometimes involved the development of leukemoid reactions of a myeloid type and disturbances in bone marrow hematopoiesis which manifested themselves by mild anemia and a slightly pronounced failure to produce platelets.

[Etiological aspects of leukemias in primates including man]. / Nekotorye aspekty étiologii leikozov primatov, vkliuchaia cheloveka.

Attempts have been made to induce viral leukemia in monkeys (Papio hamadryas and Macaca arctoides) by inoculating them with blood from humans with different types of leukemias. In hamadryas baboons, the disease spread horizontally. By today 218 P. hamadryas and 5 M. arctoides monkeys had died of malignant lymphoma. The following viruses have been isolated from sick monkeys: lymphotropic baboon herpes virus (HVP), endogenous baboon C type viruses--xenotropic (BILN), and ecotropic (EVPG). C type oncovirus called "plasmic", which differs immunologically from the endogenous one, was also detected in the blood of sick animals. Altogether 165 sera from baboons, different species of macacas and chimpanzee were examined by the immunofluorescent technique for antibodies to HTLV virus isolated recently from sick humans with T cell leukemia/lymphoma. Antibodies to HTLV virus were detected only in monkeys (P. hamadryas and M. arctoides) with malignant lymphomas or in those which had been in close contact with them. Possible origin of simian HTLV-like virus is discussed. It originates either from leukemic patients or there is a family of primate HTLV like viruses related to the occurrence of leukemia.

Immunological investigation of the prelymphoma period in baboons of the Sukhumi monkey stock.

In the "pre-lymphoma" period, some high-risk baboons develop changes in their immunity which is expressed, in particular, in the imbalnace of T-lymphocyte subpopulations, that is, increase in the number of cells of T gamma subpopulation which are carriers of suppressive functions in man. As a reflection of immunological disturbances, increase in the level of antibodies against HVP, apparently as a result of HVP activation, is observed in baboons in the "pre-lymphoma" period.