Seroepidemiological study of antibodies to adult T-cell leukemia virus-associated antigen (ATLA) in free-ranging Japanese monkeys (Macaca fuscata).
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Biomedical subjects
Publications and source records attributed to Y Hinuma.
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Human cytotoxic T cells (Tc) specific for autologous adult T cell leukemia virus- (ATLV) bearing cells were induced in vitro. Peripheral blood leukocytes (PBL) from healthy donors were stimulated repeatedly with autologous ATLV-bearing T cells. In two out of four seropositive donors and one out of two seronegative donors, the responder cells showed cytotoxicity for autologous ATLV-bearing cells, but not for autologous PBL, autologous cloned T cell lines, Epstein Barr virus-transformed autologous lymphoblastoid B cell line (LCL) cells, or various ATLV-negative cell line cells. The effector cells induced were cytotoxic T cells possessing Leu-1 and Leu-2a antigens that were able to proliferate continuously in vitro with periodic restimulation by appropriate cells and supplementation with partially purified T cell growth factor (TCGF). Of three Tc lines tested, one exhibited significant cytotoxicity against allogeneic ATLV-bearing cells that shared HLA-A2 antigen with the effector cells, possibly indicating HLA-restriction of ATLV-specific Tc. HLA-restriction was also suggested by cold target inhibition of cytotoxicity. Interestingly, Tc from this individual could also kill fresh adult T cell leukemia cells that were not expressing the ATLV surface antigens. These results, together with the target specificities of other Tc lines, suggest the possibility of at least two distinct target antigens recognized by ATLV-specific Tc, with one of these antigens differing from the ones detected by serologic methods.
Mouse monoclonal antibodies, GIN-2, -7 and -14, against adult T-cell leukemia virus (ATLV) were prepared by a hybridoma procedure. These antibodies belonged to different subclasses of IgG, but they reacted similarly with both ATLV-specific polypeptides p19 and p28. In the reaction with monoclonal antibodies and various ATLV-producer cell lines, it was found that MT-2 and MT-2-related T-cell lines produced both p19 and p28, whereas MT-2-unrelated cell lines produced p19, but not p28.
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Chromosomes were studied in cultured T lymphocytes carrying adult T-cell leukemia-associated antigens (ATLA) that were obtained from five Japanese anti-ATLA seropositive healthy adults. Chromosomally abnormal cells were observed in three of the five healthy adults, and these cells were clonal in two subjects. All cells examined in one subject had rearrangements of chromosome nos. 7 and 14. Clonal cells from the second had a minute chromosome of unknown origin. A few cells in the third had nonclonal rearrangements of chromosomes. Thus, ATLA-positive T lymphocytes in some anti-ATLA seropositive healthy people have chromosome aberrations.
Patients with filariasis were commonly observed until 1961-1970 in the Goto Islands, an area where adult T-cell leukemia (ATL) is endemic. The positive rate of antibodies to ATL virus-associated antigen among persons with a high antibody titer to filarial antigen was higher than that among persons with a low antibody titer in both sexes. Thus, filarial parasites might have some promoting effects on ATL virus infection and/or ATL virus proliferation among inhabitants in the endemic areas of filariasis and ATL.
A case of adult T-cell leukemia (ATL) in a 23-yr-old Japanese man without immunoglobulin (Ig)G antibody to ATL-associated antigen (ATLA) (anti-ATLA) is presented. Comparative studies revealed that there were no differences between the present case and the anti-ATLA-positive ATL cases, except for the onset of the former at a younger age. Serologic and epidemiologic studies were performed to determine whether in this case the disease was still dependent on ATLA. As serum IgE and IgA had been persistently elevated, the serum was examined for these antibodies to ATLA. Furthermore, after the patient's serum was treated with glycine buffer to dissociate possibly existing immune complexes, it was assayed for antibodies (IgG, IgE and IgA) to ATLA. However, no antibody activity could be demonstrated. Sero-epidemiologic studies revealed that there were no anti-ATLA-positive healthy adults (ATLA-HA) in either his family or among the residents of his birthplace, whereas some ATLA-HA have been found among the residents of the birthplaces of other ATL patients. Although further investigation is necessary, it seems reasonable for the present to consider that a minor group of ATL patients independent of ATL virus may exist.
Antibodies to adult T-cell leukemia associated antigen (ATLA) in the sera from 14 patients with Hodgkin's disease (HD) were examined by the indirect immunofluorescence method. All patients were born in the ATL-endemic area, Kagoshima and Miyazaki prefectures, of Japan. Seven of the 13 evaluable patients (54%) gave positive reactions in the anti-ATLA test. Most of the positive patients were over 40 years of age and the positive rate in males was higher than that in females. The most interesting finding in the anti-ATLA positive patients was the presence of circulating abnormal lymphocytes which are usually found in ATL patients. Histological subclassification of the positive patients had no tendency to converge into a particular subclass of HD. Although there was no definite evidence to show an etiological relationship between ATL virus and HD, several findings in this study seem to suggest that in anti-ATLA positive patients, especially in the ATL-endemic area, the anti-ATLA positive state might have some inevitable influence on the natural history of their HD.
Attempts were made to find a putative virus causally related to ATL. A retrovirus was demonstrated in a T-cell line originating from leukemic cells of a patient with adult T-cell leukemia (ATL) in and subsequent virological and serological studies suggested that the virus be etiologically related to ATL. This retrovirus was named adult T-cell leukemia virus (ATLV). This article reports the general properties of ATLV and the possible etiological relation of ATLV to ATL.
Members of three distinct classes of animal virus have been associated with naturally occurring neoplasias in man: Epstein--Barr virus (EBV), a DNA virus belonging to herpesvirus group, papillomavirus, and a novel human RNA (retro) virus, human T-cell leukemia virus or adult T-cell leukaemia (ATL) virus. We have established seven continuous cell lines from ATL patients and 0.1-7% of these cells consistently express ATL-specific antigens (ATLA). EBV-associated nuclear antigen (EBNA) is also found in more than 90% of these cells. We have cloned cells from two of these lines and show here that both ATLA and EBNA were present in the same B-cell clone carrying surface immunoglobulin (sIg).
Sera from patients with adult T-cell leukemia (ATL) or other diseases and from healthy adults, whose titers of antibodies against ATL-associated antigens (ATLA) had been determined by indirect immunofluorescence, were analysed by a procedure of immunoprecipitation followed by SDS-polyacrylamide gel electrophoresis. For this an ATL virus (ATLV)-producer cell line, MT-2, was labelled with [35S]-methionine. All 12 anti-ATLA-positive sera but none of the eight anti-ATLA-negative sera tested reacted specifically with four polypeptides with molecular weights of 70,000, 53,000, 36,000 and 24,000 daltons. Furthermore, enrichment of three polypeptides with molecular weights of 76,000, 43,000 and 28,000 daltons was observed on reaction with anti-ATLA-positive sera. In control experiments using ATLA-negative T-cell lines, Molt-4 and HPB-ALL, none of these seven polypeptides were precipitated by reaction with anti-ATLA-positive sera. All six anti-ATLA-positive sera tested were shown to react with a polypeptide with a molecular weight of 24,000 of purified ATLV.
The transmission of adult T cell leukemia virus, a human retrovirus, into fresh leukocytes from normal humans was examined. One of three virus-carrying cell lines, tested after being subjected to lethal x-irradiation, consistently transformed leukocytes from adult peripheral blood and umbilical cord blood. All the transformed cell lines expressed adult T cell leukemia virus-associated antigen, but transformed lines originating from adult and umbilical cord blood exhibited T cell and non-T, non-B cell surface natures, respectively. Efforts to transform human leukocytes with cell-free virus were unsuccessful.
A nation-wide sero-epidemiologic survey of adult T-cell leukemia virus (ATLV), detected es anti-ATLA (ATLV-associated antigen), was made in Japan. Sera from adult donors in 15 different locations were screened for anti-ATLA. High incidences (6 to 37%) of antibody-positive donors were found in seven regions, one in northern Japan, and the others in southwestern regions. These areas are ATLV-endemic areas corresponding to ATL-endemic areas. Examination of sera from healthy donors aged 6 to 80 years in ATL-endemic areas showed an age-dependent increase of seropositive donors with a maximum of about 30% at 40 years of age. Anti-ATLA was found in all but two of 142 patients with ATL. Anti-ATLA-positive patients with ATL were mainly found in ATLV-endemic areas, and only a few in ATL-nonendemic areas. Six patients with cutaneous T-cell lymphoma in ATLV-nonendemic areas gave a negative reaction for anti-ATLA. The geometric mean titer of anti-ATLA of patients with ATL was higher than that of healthy donors.
Adult T-cell leukemia virus (ATLV) or ATLV-associated antigen (ATLA)-positive cell clones were isolated from peripheral blood lymphocytes of all five anti-ATLA-seropositive healthy adults tested by a limiting-dilution culture method in the presence of T-cell growth factor (TCGF) but from none of six seronegative adults similarly tested. Although ATLA-positive cells were not always detected in mass cultures of the seropositive lymphocytes, they were found consistently in T-cell cloned cultures of those lymphocytes. Continuous cultures of the ATLA-positive clones obtained were dependent on TCGF. Five clones derived from each of the five donors were maintained for greater than 4 months and, during culture, all of them acquired the ability to grow without added TCGF. The ATLA-positive clones formed rosettes with erythrocytes and expressed Leu 1, Leu 3a, and Leu 4 antigens but not Leu 2a antigen. These results indicate that anti-ATLA-seropositive healthy individuals carry ATLV in T cells circulating in their peripheral blood.
A retrovirus (ATLV) was unequivocally demonstrated in human adult T-cell leukemia (ATL) cell lines by density (1.152-1.155 g/cm3) in a sucrose gradient, reverse transcriptase activity insensitive to actinomycin D, RNA labeled with [3H]uridine, and specific proteins with molecular weights of 11,000, 14,000, 17,000, 24,000, and 45,000. Furthermore, cDNA prepared by endogenous reaction with detergent-treated virions hybridized to 35S RNA containing poly(A), which was inducible by IdUrd treatment of a T-cell line derived from leukemic cells of the ATL, and the integrated form of ATLV proviral DNA was detected in T-cell lines derived from ATL. The ATLV proviral DNA was also detected in fresh peripheral lymphocytes from all five patients with ATL tested so far but not in those from healthy adults. On the other hand, ATLV protein of Mr 42,000 was found to be at least one of the ATL-associated antigen(s) that were previously detected in ATL-leukemic cells by all sera from patients with ATL. These findings on the close association of ATLV protein and proviral DNA with ATL are direct evidence for the possible involvement of the retrovirus ATLV in leukemogenesis of human ATL.
Human lymphoblastoid cells of T and non-T--non-B lineages were examined for interferon (IFN) production induced by Sendai virus. All of the four T cell lines examined and two of the three non-T--non-B cell lines produced IFN-beta, and the third non-T--non-B cell line, HL-60, a mixture of IFN-alpha and -beta, in contrast to two B cell lines, which produced IFN-alpha
A number of human lymphoblastoid cells were examined concerning their ability to produce spontaneously liberated and virus-induced interferon (IFN). It was found that, in addition to B cells, various T and nonT-nonB lymphoblastoid cells responded well to Sendai virus infection to form IFN, the characterization of which has been recently reported (20). One B lymphoblastoid cell line from an infectious mononucleosis (IM) patient produced a large amount of IFN-alpha and might become an alternative source of IFN production. Among 68 cell lines examined, 35 cell lines liberated 10 U/ml or more of IFN spontaneously in culture fluid. The presence of Epstein-Barr virus (EBV) genome or its activation appears to have no correlation with the spontaneous liberation of IFN. Spontaneously produced IFN from three cell lines was characterized as IFN-alpha. Comparatively higher amounts of IFN were produced in cells from IM patients than those from Burkitt's lymphoma cases or healthy adults. Spontaneously produced IFN was detected more easily in cells transformed by EBV alone than in those transformed by EBV and a tumor promoter, TPA.