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1.
Cancer Immunol Immunother ; 50(3): 125-33, 2001 May.
Article in English | MEDLINE | ID: mdl-11419179

ABSTRACT

The T-cell-specific receptor, CTLA-4, has been demonstrated to be a potent negative regulator of lymphocyte activation, the functional significance of which has been demonstrated in murine tumor models using blocking antibodies. However, the mechanism(s) involved in enhancing tumor regression has not been identified. In this study, we determined whether IFN gamma was playing a role in this activity. In vitro, anti-CTLA-4 enhanced IFN gamma production by lymph node cells obtained from tumor-bearing mice (351 pg/ml vs 77 pg/ml). Additionally, fibrosarcoma-challenged animals treated with anti-CTLA-4 had elevated levels of the IFN-inducible enzyme 2-5-OAS in draining lymph nodes (850 pM vs 260 pM for controls) and an increased amount of IFN gamma in tumor lysates (at day 7, 620 pg/100 micrograms vs 160 pg/100 micrograms in controls). The importance of IFN gamma was demonstrated by the ability of neutralizing antibodies to completely abrogate the anti-tumor effects of anti-CTLA-4. Moreover, fibrosarcoma cells were shown to be exquisitely sensitive to IFN gamma-mediated class I upregulation and histological examination of tumors from anti-CTLA-4-treated mice revealed a trend toward increased tumor cell apoptosis and decreased angiogenesis. These studies have demonstrated that one mechanism for the anti-tumor effects of anti-CTLA-4 relates to its ability to augment IFN gamma production, resulting in an increased expression of class I on the tumor, enhanced apoptosis, and a decrease in blood vessel growth.


Subject(s)
Antigens, Differentiation/metabolism , Immunoconjugates , Interferon-gamma/metabolism , 2',5'-Oligoadenylate Synthetase/metabolism , Abatacept , Animals , Antigens, CD , Antigens, Differentiation/blood , Antigens, Differentiation/immunology , Apoptosis , CTLA-4 Antigen , Cancer Vaccines , Dose-Response Relationship, Drug , Female , Fibrosarcoma/therapy , Flow Cytometry , Immunoglobulin G/metabolism , Immunosuppressive Agents/pharmacology , Immunotherapy , Interferon-gamma/biosynthesis , Lymph Nodes/cytology , Mice , Mice, Inbred BALB C , Mice, Inbred C57BL , Mitosis , Neoplasm Transplantation , Neoplasms, Experimental/prevention & control , Neoplasms, Experimental/therapy , Platelet Endothelial Cell Adhesion Molecule-1/biosynthesis , Time Factors , Up-Regulation
2.
Mol Immunol ; 32(14-15): 1131-41, 1995 Oct.
Article in English | MEDLINE | ID: mdl-8544862

ABSTRACT

We have designed and expressed in bacteria a recombinant fetal form of human myelin basic protein (21.5 kDa isoform; rhMBP21.5), a candidate autoantigen in multiple sclerosis. An exon 2 insertion, carboxy-terminal histidine tag and preferred bacterial codons differentiate the MBP21.5 gene from that encoding the adult, brain-derived form of human MBP (18.5 kDa isoform; hMBP18.5). MBPs were expressed at high levels in E. coli and extracted from whole cells by simultaneous acid solubilization and mechanical disruption. A nearly two-fold increase in recombinant protein was detected in strains harboring MBP genes with bacterial preferred codons compared to genes containing human codons. The recombinant molecules were purified in two steps, first by reversed-phase chromatographic separation and then by metal affinity chromatography. Dimeric forms of recombinant MBP21.5 were detected under physiological conditions, however, substitution of a serine for the single cysteine at amino acid residue 81 resulted in only monomer formation. All forms of recombinant MBPs induced proliferative responses of human T lymphocytes specific for epitopes in MBP18.5 kDa. In contrast, human T cell lines that recognize an exon 2-encoded epitope of MBP responded to the 21.5 kDa isoform of MBP, but not the 18.5 kDa isoform.


Subject(s)
Myelin Basic Protein/immunology , Myelin Basic Protein/isolation & purification , Recombinant Proteins/immunology , Recombinant Proteins/isolation & purification , Adult , Amino Acid Sequence , Base Sequence , Embryonic and Fetal Development/immunology , Exons/immunology , Genetic Vectors , Humans , Isomerism , Molecular Sequence Data , Molecular Weight , Myelin Basic Protein/genetics , Recombinant Proteins/genetics
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