Biomedical subjects
Publications and source records attributed to G Klein.
Tumour biopsies from Burkitt lymphoma patients, as well as human nasopharyngeal carcinoma cells growing in athymic mice, contain Epstein-Barr virus DNA as covalently closed circular DNA. In addition integrated viral DNA sequences seem to be present.
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It was shown by double immunofluorescence studies that Epstein-Barr viral nuclear antigen (EBNA) was preserved in EBV-infected cells after they had entered the productive viral cycle, as signalled by the appearance of the early antigen (EA)complex. A nuclear component of the EA comples could be clearly distinguished from EBNA with regard to antigenic specificity.
We have previously shown that spleen cells from normal mice contain lymphocytes that kill certain in vitro-grown Moloney lymphoma lines in a 51Cr release test. The killing activity shows a marked dependence on the genotype of the donor mouse. In vivo rejection studies with a Moloney lymphoma line in various normal semisyngeneic F1 hybrids showed a clear positive correlation between in vitro natural cytotoxicity and in vivo rejection. Thus mice can be grouped as high- or low-reactive according to their in vitro cytolytic behavior as well as their in vivo rejection potential. A lymphoid cell without detectable T- or B-cell markers is responsible for the in vitro killing effect. The present study also shows that the in vivo growth inhibitory function is T-cell-independent. Lymphoid cells depleted of T- and B-cells and transferred together with Moloney lymphoma cells into an irradiated syngeneic recipent were highly efficient in delaying tumor growth. Furthermore, syngeneic or semisyngeneic thymecto-mized, irradiated, fetal-liver-reconstituted mice showed if anything an increased in vivo resistance to a Moloney lymphoma compared to control mice. In contrast, tumor cells histoincompatible with regard to the H-2 locus showed the expected preferential growth in the thymectomized animals. We thus conclude that the major in vivo resistance against transplantation of the syngeneic or semisyngeneic Moloney lymphoma used in this study is T-independent.
EBV-neutralizing antibody titers were determined in 11 sera derived from African Burkitt lymphoma or nasopharyngeal carcinoma patients and in the corresponding serum fractions retained above XM 100 Diaflo membranes after low pH treatment, and after recombination of the retained and passed fractions by neutralization of the acidified samples. They were compared with the corresponding antimembrane antigen (MA) titers in seven of the same sera. While all sera tested showed substantial increase of the anti-MA activity in the retained fraction, resulting in a significantly increased mean titer, EBV neutralizing activity did not change at all after identical treatment or changed only in a random fashion, resulting in stable mean titers. It is suggested that anti-MA and neutralizing antibodies are directed against at least partly different antigens on the virus.
After removal of SRBC rosette-forming T-cells from the peripheral blood, the residual, largely B-lymphocyte fraction of five infectious mononucleosis patients was found to contain 0.5-2% blast cells, positive for the EBV-determined nuclear antigen (EBNA). There was a rough parallelism between the presence of large lymphoblasts in the hematological smear, EBNS-positive large blasts in the B-cell fraction and the ability of the T-cell fraction to exert an EBV-specific lymphocytotoxicity on established cell lines in vitro. EBNA-positive B-cells and EBV-specific killer T-cells disappeared after the acute phase of the disease.
The karyotypes of cells from 10 Burkitt lymphoma (BL) biopsies, eight cell lines established from BL and nine cell lines from non-BL sources were studied by chromosome banding techniques. With the exception of the BL-derived cell lines BJAB, GC-BJAB, Maku and U-8691 all biopsies and lines of Burkitt origin contained an extra band at the distal region of the long arm of one chromosome 14. An extra band on chromosome 14 was also found in cells of one non-BL biopsy, in cells from a lymphosarcoma-derived cell line and in a long-established cell line derived from the pleural exudate of a patient with Hodgkin's disease. A distal region at the long arm of one chromosome 8 was missing in all metaphase figures of good technical quality in the same material. The size, morphology and stain-ability of the missing region corresponded fairly well to the extra region at chromosome 14. We therefore suggest that the chromosome 14 marker represents a translocation between chromosomes 8 and 14,t (8q-; 14q+). The translocation was present neither in lymphocytes of the peripheral blood of five Burkitt patients nor in five lymphoblastoid cell lines of non-BL origin. Trisomy 7 was found in two of the 10 BL biopsies, in two BL-derived cell lines, in one non-BL biopsy, in two lymphosarcoma-derived cell lines and in one cell line derived from a patient with Hodgkin's disease.
The experiments described herein were designed to determine whether part of the Ig coat of tumor cells consists of specific anti-tumor antibodies. It was demonstrated that the inoculation of polyoma virus-induced sarcoma cells (SEYF-a) into syngeneic A.BY mice stimulates the production of cytotoxic antibodies against the tumor-cell population. The level of these antibodies, which was undetectable during the first week after transplantation, increased markedly during the second week, and remained high thereafter. Following the increase in cytotoxic antibodies in the serum, a cell-bound potentially cytotoxic antibody was detected on the tumor cells by testing their sensitivity to rabbit complement. The increase in cell-bound, potentially cytotoxic antibody followed the kinetics of the increase in serum antibody during the second week after transplantation and was inversely correlated to the amount of free antigens on the cell surface. These antigens, responsible for the sensitivity of the cells to a syngeneic hyperimmune cytotoxic antiserum, became non-available for the cytotoxic antibodies during propagation of the tumor cells. Cells from a tumor propagated for 3 weeks could not compete for anti-tumor antibodies with cells propagated for 1 week. Yet it was possible to increase the antigenic capacity of cells from an old tumor by a treatment that would cause the release of tumor-associated Ig. Cytotoxic anti-SEYF-a antibodies could be dissociated from tumor cells propagated in vivo by methods causing dissociation of antigen-antibody complexes, and detected in tumor eluates.
Trinitrophenylated Moloney virus-induced YAC cells induced a higher cytotoxic antibody response and better protection against small tumor cell doses in syngeneic, low-responsive strain A mice than nonmodified YAC cells that had been inactivated by irradiation or mitomycin C treatment. The results indicated that genetically determined low responsiveness to a virally induced antigen can be overcome, at least to some extent, by coupling the immunizing cells to a strong immunogenic hapten.
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Somatic cell hybrids have been selected between three pairs of established human lymphoid cell lines producing pure lines of proliferating hybrid cells: Raji/Namalwa, Raji/Daudi, and Raji/BJAB. The hybrid cell lines have been characterized with respect to isozyme pattern, volume, and karyotype.
CBA/H and CBA/HT676 radiation chimeras were prepared by lethal irradiation and subsequent reconstitution with bone marrow of the host karyotype and thymocytes of the opposite karyotype. After T- and B-cell chimerism had been established, the animals were inoculated with SEWA or TA3Ha ascites tumor--donor cell hybrids were isolated following the explantation of TA3Ha tumor in selective HAT medium and by selecting for adherent cells from SEWA. The T6T6 chromosomal marker served to distinguish between the type of cell involved in the fusion. In all hybrids the donor component was a nonthymus-derived cell.
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Hybridization studies on high and low malignant L cell derivatives support our previous conclusions, in showing that crosses between highly tumorigenic and poorly tumorigenic lines to a marked suppression of the malignant phenotype. Malignant behaviour is not, however, suppressed when cells from one highly tumorigenic line are crossed with those of another tumorigenic line. The present results show further that these rules apply even when all the cells crossed are closely related derivatives of one cell line.