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Proc Natl Acad Sci U S A ; 93(17): 9102-7, 1996 Aug 20.
Artículo en Inglés | MEDLINE | ID: mdl-8799161


Allelic exclusion at the T-cell receptor alpha chain locus is incomplete resulting in the generation of T cells that express two T-cell receptors. The potential involvement of such T cells in autoimmunity has been suggested [Padovan, E., Casorati, G., Dellabona, P., Meyer, S., Brockhaus, M. & Lanzavecchia, A. (1993) Science 262, 422-424; Heath, W. R. & Miller, J. F. A. P. (1993) J. Exp. Med. 178, 1807-1811]. Here we show that expression of a second T-cell receptor can rescue T cells with autospecific receptors from thymic deletion and allow their exit into the periphery. Dual receptor T cells, created by constitutive expression of two transgenic T-cell receptors on a Rag1-/- background, are tolerant to self by maintaining low levels of autospecific receptor, but selfreactive effector function (killing) can be induced through activation via the second receptor. This opens the possibility that T cells carrying two receptors in the periphery of normal individuals contain putatively autoreactive cells that could engage in autoimmune effector functions after recognition of an unrelated environmental antigen.

Autoinmunidad/inmunología , Supresión Clonal/inmunología , Proteínas de Homeodominio , Receptores de Antígenos de Linfocitos T alfa-beta/inmunología , Autotolerancia/inmunología , Linfocitos T/inmunología , Animales , Autoinmunidad/genética , Supresión Clonal/genética , Complemento C5/genética , Cruzamientos Genéticos , Activación de Linfocitos , Ratones , Ratones Transgénicos , Proteínas/genética , Receptores de Antígenos de Linfocitos T alfa-beta/genética , Autotolerancia/genética
J Biol Chem ; 265(25): 15183-8, 1990 Sep 05.
Artículo en Inglés | MEDLINE | ID: mdl-2168404


HL60 cells have types A and B tumor necrosis factor (TNF) receptors whereas HEp2 cells have only the type B receptor (Hohmann, H.-P., Remy, R., Brockhaus, M., and van Loon, A.P.G.M. (1989) J. Biol. Chem. 264, 14927-14934). TNF-beta can be cross-linked to each of these receptors and competes with TNF-alpha for binding to both receptors. TNF-alpha and TNF-beta activate the transcription factor NF-kappa B in HL60 and HEp2 cells. Maximal activation of NF-kappa B required binding of TNF-alpha or TNF-beta to 20-25% of the total number of TNF receptors and was achieved within minutes after the addition of TNF-alpha to HL60 cells. Both TNF-alpha and TNF-beta activate NF-kappa B at 5-10-fold lower concentrations in HL60 cells compared with HEp2 cells, and this correlates well with their different affinities for binding to these cells. Thus, TNF-alpha and TNF-beta are indistinguishable with respect to the correlation between degrees of receptor binding and activation of NF-kappa B.

Proteínas de Unión al ADN/metabolismo , Linfotoxina-alfa/metabolismo , Receptores de Superficie Celular/metabolismo , Factores de Transcripción/metabolismo , Factor de Necrosis Tumoral alfa/metabolismo , Secuencia de Bases , Sitios de Unión , Unión Competitiva , Línea Celular , Humanos , Cinética , Linfotoxina-alfa/farmacología , Datos de Secuencia Molecular , FN-kappa B , Receptores del Factor de Necrosis Tumoral , Proteínas Recombinantes/metabolismo , Proteínas Recombinantes/farmacología , Células Tumorales Cultivadas/metabolismo , Factor de Necrosis Tumoral alfa/farmacología
Cancer Res ; 45(5): 2255-63, 1985 May.
Artículo en Inglés | MEDLINE | ID: mdl-3886129


Incubation of human intestinal SW1116 tumor cells in serum-free medium containing butyric acid reduced their capacity to synthesize gastrointestinal carcinoma-associated (GICA) glycolipid antigen 4- to 8-fold as determined by a radioimmunobinding assay using anti-GICA monoclonal antibody:high-performance thin-layer chromatography; autoradiography; and densitometry. The structure of GICA has been described as a sialylated Lea glycolipid (J. L. Magnani, B. Nilsson, M. Brockhaus, D. Zopf, Z. Steplewski, A. Koprowski, and V. Ginsburg. J. Biol. Chem., 257: 14365-14369, 1982). Tritiated fucose incorporation into GICA was reduced per cell (7-fold), per mg protein (5-fold), and per mg lipid (4-fold). A purified organically soluble glycolipid fraction from control SW1116 cells contained more Lewis antigen than did butyrate-treated cells as determined by the high-performance thin-layer chromatography radioimmunobinding assay. Incorporation of radioactivity from [3H]fucose and guanosine diphosphate [14C]fucose into Lewis antigens in butyrate-treated cells was 2- to 3-fold lower than in control cells. HT29 cells carry the blood type of the original donor, Blood Group A. Isotope incorporation into A glycolipid antigen was reduced 2- to 8-fold upon exposure to butyrate. Commensurate with these results was a dramatic reduction in cell population-doubling rate. We propose that synthesis of these fucolipid antigens is associated more with dividing, undifferentiated tumor cell populations. The diminution in antigen levels may derive from diminished cells' capacity for fucosylation in the presence of butyrate.

Antígenos de Neoplasias/análisis , Neoplasias del Colon/inmunología , Glucolípidos/análisis , Sistema del Grupo Sanguíneo ABO , Anticuerpos Monoclonales/inmunología , Línea Celular , Técnica del Anticuerpo Fluorescente , Fucosiltransferasas/análisis , Glucolípidos/biosíntesis , Glucolípidos/inmunología , Humanos , Antígenos del Grupo Sanguíneo de Lewis/inmunología
Biochim Biophys Acta ; 834(1): 110-7, 1985 Mar 27.
Artículo en Inglés | MEDLINE | ID: mdl-3978112


A hybridoma, C-50, obtained by fusion of mouse myeloma cells with spleen cells from a mouse immunized with cells from the colorectal carcinoma cell line COLO 205, produced antibodies that detected ganglioside antigen in human adenocarcinomas in many organs. The major ganglioside antigen fraction isolated from liver metastases of a pancreatic adenocarcinoma, behaving as a homogenous band on thin-layer chromatography, consisted of three different gangliosides. One of them, A (25%), had the same carbohydrate structure as the ganglioside antigen defined by monoclonal antibody 19-9, NeuAc alpha 2-3Gal beta 1-3(Fuc alpha 1-4)GlcNAc beta 1-3Gal beta 1-4Glc-Cer(Fuc-3'-isoLM1) Magnani, J.L., Nilsson, B., Brockhaus, M., Zopf, D., Steplewski, Z., Koprowski, H. and Ginsburg, V. (1982) J. Biol. Chem. 257, 14365-14369). The major ganglioside, B (60%), was the isomeric hexasaccharide ganglioside (NeuAc alpha 2-3Gal beta 1-4(Fuc alpha 1-3)GlcNAc beta 1-3-Gal beta 1-4Glc-Cer(Fuc-3'-LM1) and the third ganglioside, C, was 6'-LM1, NeuAc alpha 2-6Gal beta 1-4GlcNAc beta 1-3Gal beta 1-4Glc-Cer (15%). Ganglioside B, isolated from human kidney, did not react with the C-50 MAb. Based on this result and on studies of COLO 205 cell induced tumours where the ganglioside antigen fraction only consisted of A, it is suggested that the C-50 MAb defines an antigen determinant present in A.

Adenocarcinoma/análisis , Anticuerpos Monoclonales , Antígenos de Neoplasias/análisis , Gangliósidos/análisis , Neoplasias Pancreáticas/análisis , Anciano , Animales , Secuencia de Carbohidratos , Cromatografía en Capa Delgada , Humanos , Neoplasias Hepáticas/secundario , Masculino , Ratones , Ratones Desnudos
Arch Biochem Biophys ; 233(1): 161-8, 1984 Aug 15.
Artículo en Inglés | MEDLINE | ID: mdl-6465894


Monoclonal antibodies directed against human cancer cells were prepared by the murine hybridoma technique. These antibodies detect Lewis blood group antigens as determined by indirect solid-phase radioimmunoassay, hapten inhibition studies, and chromatogram binding assay. One monoclonal antibody is specific for the Lea terminal carbohydrate of Gal beta 1----3Glc NAc(4----1 alpha Fuc) beta 1----3LacCer. Five monoclonal antibodies react with the Leb terminal carbohydrate sequence of Fuc alpha 1----2Gal beta 1----3GlcNAc(4----1 alpha Fuc) beta 1----3LacCer, and four of these antibodies are highly specific for this glycolipid and do not react with other similar di- and monofucosylated glycolipids. One of the anti-Leb antibodies cross-reacts with blood group H glycolipid and has binding properties similar to those of the previously described antibody NS-10-17 [M. Brockhaus, J. L. Magnani, M. Blaszczyk, Z. Steplewski, H. Koprowski, K.-A. Karlsson, G. Larson, and V. Ginsburg (1981) J. Biol. Chem. 256, 13223-13225]. Two antibodies react with both the Lea and Leb antigens, though both bind preferentially to Leb.

Anticuerpos Monoclonales , Anticuerpos Antineoplásicos , Neoplasias del Colon/inmunología , Antígenos del Grupo Sanguíneo de Lewis/inmunología , Conformación de Carbohidratos , Secuencia de Carbohidratos , Línea Celular , Humanos , Neoplasias/inmunología , Neoplasias Pancreáticas/inmunología , Radioinmunoensayo , Neoplasias del Recto/inmunología , Neoplasias Gástricas/inmunología
J Biol Chem ; 258(7): 4091-7, 1983 Apr 10.
Artículo en Inglés | MEDLINE | ID: mdl-6833243


Solid phase radioimmunoassay and a chromatogram binding assay were used to characterize the binding specificities of five monoclonal antibodies generated from mice immunized with human tumor cell lines when tested against various glycolipids. Four antibodies derived from mice immunized with pancreatic carcinoma cells detected specifically the human blood group B determinant, Gal alpha 1 leads to 3Gal (2 comes from 1 alpha Fuc). These antibodies preferred type 2 (Gal beta 1 leads to 4GlcNAc) glycolipids. No reactivity was detected with a rat B determinant based on GalNAc. An antibody derived following immunization with a rectal carcinoma cell line was shown to have binding properties identical with those of an antibody that reacts specifically with the stage-specific embryonic mouse antigen (SSEA-1), bearing the determinant Gal beta 1 leads to 4GlcNAc (3 comes from 1 alpha Fuc) (Gooi, H. C., Feizi, T., Kapadia, A., Knowles, B. B., Solter, D., and Evans, M. J. (1981) Nature 292, 156-158). Thin layer chromatography was used to detect the binding of a monoclonal anti-tumor antibody recently shown to react with a sialylated Lea glycolipid (Magnani, J. L., Nilsson, B., Brockhaus, M., Zopf, D., Steplewski, Z., Koprowski, H., and Ginsburg, V. (1982) Fed. Proc 41, 898) and an anti-Leb antibody (Brockhaus, M., Magnani, J. L., Blaszczyk, M., Steplewski, Z., Koprowski, H., Karlsson, K.-A., Larson, G., and Ginsburg, V. (1981) J. Biol. Chem. 256, 13223-13225) to mixtures of glycolipids from normal and tumor tissues.

Adenocarcinoma/inmunología , Anticuerpos Monoclonales , Antígenos de Neoplasias/análisis , Antígenos de Grupos Sanguíneos/inmunología , Neoplasias del Colon/inmunología , Glicoesfingolípidos/análisis , Neoplasias del Recto/inmunología , Animales , Complejo Antígeno-Anticuerpo , Conformación de Carbohidratos , Secuencia de Carbohidratos , Línea Celular , Humanos , Ratones , Radioinmunoensayo