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1.
Trends Immunol ; 22(8): 424-7, 2001 Aug.
Article in English | MEDLINE | ID: mdl-11473830

ABSTRACT

The immune system confines neoplasia at various stages of tumor development. Whereas the role of cellular immunity has been investigated widely and utilized in the clinic, the importance of humoral immunity in this process has begun to emerge only in recent years. Circulating antinuclear autoantibodies (ANAs) typically found in autoimmune conditions, have also been detected in cancer patients and in healthy elderly individuals. The pathogenic role of ANAs in autoimmunity is well studied; however, little research has been carried out to elucidate the functions of ANAs in cancer patients. Experimental data favoring the antitumor activity of ANAs might support the clinical testing of monoclonal ANAs as a cancer therapy, if confirmed by further experiments.


Subject(s)
Antibodies, Antinuclear/therapeutic use , Antineoplastic Agents/therapeutic use , Aging/immunology , Animals , Antibodies, Antinuclear/immunology , Antineoplastic Agents/immunology , Humans , Neoplasms/immunology , Neoplasms/therapy , Nucleosomes/immunology
2.
Anal Biochem ; 292(2): 245-9, 2001 May 15.
Article in English | MEDLINE | ID: mdl-11355857

ABSTRACT

For many practical applications, monoclonal antibodies must be chemically modified without any significant loss in their immunoreactivity. In some situations, however, the amino acid residue crucial for antibody activity may be highly reactive toward the modifying agent, which results in antibody inactivation. The method to prevent inactivation of a modification-sensitive antinuclear monoclonal antibody by acylating agents was developed. The method is based on the hypothesis that a highly reactive amino group exists within, or in the vicinity of, the binding site of the antibody, providing crucial interaction with negatively charged moieties of DNA. It has been shown that negatively charged polymers, such as dextran sulfate or heparin, may provide temporary protection, presumably interacting noncovalently with this amino group and thus masking it. The protecting molecule can be removed later by chromatography on a protein A column, thus regenerating modified but not inactivated antibody in the free form for use in subsequent applications. In particular, we have modified antibody 2C5 with a chelating agent, diethylenetriaminepentaacetic acid (DTPA) without the loss of activity. Modified antibody was labeled with radioactive isotope, (111)In, via chelation by antibody-attached DTPA. The labeled antibody was shown to demonstrate the same specificity of binding to nucleosomes as the nonmodified antibody, so it may be used in immunoscintigraphy or biodistribution studies. The method might be useful for the modification of other modification-sensitive antibodies with other acylating chemicals, such as crosslinking agents or biotin derivatives.


Subject(s)
Antibodies, Antinuclear/immunology , Antibodies, Antinuclear/metabolism , Antibodies, Monoclonal/immunology , Antibodies, Monoclonal/metabolism , Polymers/chemistry , Polymers/metabolism , Acylation , Animals , Antibodies, Antinuclear/chemistry , Antibodies, Monoclonal/chemistry , Antibody Specificity , Chelating Agents/chemistry , Chelating Agents/metabolism , Dextran Sulfate/chemistry , Dextran Sulfate/metabolism , Heparin/chemistry , Heparin/metabolism , Indium Radioisotopes , Mice , Pentetic Acid/chemistry , Pentetic Acid/metabolism , Protein Denaturation , Static Electricity , Succinimides/chemistry , Succinimides/metabolism
3.
Cancer Detect Prev ; 22(5): 470-5, 1998.
Article in English | MEDLINE | ID: mdl-9727629

ABSTRACT

Monoclonal antibody (MoAb) 2C5, a nucleosome-specific antinuclear autoantibody (ANA) from the repertoire of aged mice, was recently reported to recognize the surface of various tumor cells but not normal cells. Surface-bound nucleosomes (NSs) were previously proven to be MoAb 2C5's target on the outer membrane of tumor cells. Furthermore, MoAb 2C5 was found to have a strong antitumor effect during the early stages of tumor development. In an attempt to further increase antitumor effect of nucleosome-specific tumorocidal monoclonal antibody against established tumors, we investigated a possible way to enhance antibody association with tumor cells. Evidence is presented here demonstrating that the in vitro treatment of tumor cells (S49 T lymphoma) resulting in a partial cell death and massive liberation of intact NSs from dead tumor cells into the culture medium was accompanied by a 50-fold increase of MoAb 2C5 binding to the surface of surviving tumor cells. Massive NS release was observed in the case of S49 T-cell treatment with dexamethasone and vincristine. However, a partial cell killing that was not accompanied with NS release (EL4 lymphoma treatment with doxorubicin) did not result in the enhanced binding of MoAb 2C5 to the surface of surviving tumor cells. The use of NS-specific tumorocidal antibodies, such as MoAb 2C5, in combination with another NS release-inducing tumor therapy, should provide an enhanced antibody-tumor binding.


Subject(s)
Antibodies, Antinuclear/pharmacology , Antibodies, Monoclonal/pharmacology , Nucleosomes/immunology , Animals , Antineoplastic Agents, Phytogenic/pharmacology , Apoptosis , Chromatin/metabolism , Dexamethasone/pharmacology , Humans , Mice , Nucleosomes/drug effects , Nucleosomes/metabolism , Tumor Cells, Cultured , Vincristine/pharmacology
4.
Oncol Res ; 9(8): 439-46, 1997.
Article in English | MEDLINE | ID: mdl-9436197

ABSTRACT

Antinuclear autoantibodies (ANAs) of healthy aged mice were recently found to specifically interact with the surface of various tumor vs. normal cells. We characterize the specificity of three monoclonal ANAs from healthy aged Balb/c mice by indirect immunofluorescent staining of fixed Hep-2 cells, ELISA assays, and Western blotting analysis. Two of these monoclonal antibodies, 2C5 and 1G3, exhibited specificity for nucleosomes. Subsequent flow cytometry experiments demonstrated that the 2C5 antibody recognizes nucleosomes on the surface of mouse EL4 T-lymphoma cells because antibody binding could be eliminated by pretreatment of these cells with DNase or heparin and approximately 10-fold increased after preincubation of cells with nucleosomes. The injection of monoclonal antibody 2C5 into ANA-negative young mice 1 day before tumor cell inoculation and on days 1, 3, and 5 thereafter significantly suppressed tumor development and increased survival. The antitumor activity of the 2C5 antibody is demonstrated for two syngeneic mouse tumor models, EL4 T-lymphoma and B16 melanoma. In vitro analyses revealed antibody-dependent cellular cytotoxicity (ADCC) as one antitumor mechanism of the 2C5 antibody. Based on these results, we postulate a beneficial role of antinucleosome autoantibodies as tumor-protective agents for an aging host or for antibody-mediated cancer therapy, and further speculate that the presence of such antibodies represents a so far unrecognized mechanism of immune surveillance against tumors.


Subject(s)
Antibodies, Antinuclear/pharmacology , Antineoplastic Agents/pharmacology , Nucleosomes/immunology , Aging/immunology , Amino Acid Sequence , Animals , Antibodies, Monoclonal/pharmacology , Antibody Specificity , Antibody-Dependent Cell Cytotoxicity/immunology , Antigens, Neoplasm/immunology , Autoantigens/immunology , Female , Lymphoma, T-Cell/immunology , Lymphoma, T-Cell/therapy , Melanoma, Experimental/immunology , Melanoma, Experimental/therapy , Mice , Mice, Inbred C57BL , Molecular Sequence Data
5.
Int Immunol ; 7(11): 1763-9, 1995 Nov.
Article in English | MEDLINE | ID: mdl-8580074

ABSTRACT

A population of CD4+ cells has been identified in the murine female genital tract (FGT). Phenotypic studies of FGT CD4+ cells demonstrate that they express CD3 and that the majority of these cells are alpha beta TCR+Thy-1+. Most of the Thy-1+CD4+alpha beta TCR+ cells resemble memory T cells based on their expression of CD44, L-selectin and CD45RB antigens. The vast majority of Thy-1+CD4+alpha beta TCR+ FGT cells are CD5+ and all of them are B220-. Systemic stimuli including infection with Trypanosoma brucei brucei, injection with anti-CD3 epsilon, or bacterial superantigens staphylococcal enterotoxin A or B cause a rapid accumulation of CD4+ cells in the FGT exceeding that observed for CD4+ cells in spleen and lymph nodes (LN). Expansion of the FGT CD4+ cells, which are phenotypically distinct from the splenic and LN CD4+ T cells, is due to local proliferation rather than an influx of cells from the circulation. The CD4+ population in the FGT of adult nu/nu mice is dramatically reduced, indicating its thymic dependency. In lpr/lpr mice, FGT CD4 cells do not display changes characteristic of splenic or LN CD4 cells in the same animals. These findings demonstrate that the CD4+ cells of the murine FGT are thymic dependent, but that they constitute a T cell lineage that phenotypically and, probably functionally, is distinct from other peripheral CD4+ T cell populations.


Subject(s)
CD4-Positive T-Lymphocytes/classification , Genitalia, Female/immunology , Lymphocyte Activation , Receptors, Antigen, T-Cell, alpha-beta/analysis , Animals , CD4-Positive T-Lymphocytes/chemistry , Cell Differentiation/immunology , Female , Immunophenotyping , Lymph Nodes/cytology , Mice , Mice, Inbred AKR , Mice, Inbred BALB C , Mice, Inbred CBA , Mice, Inbred DBA , Mice, Mutant Strains , Mice, Nude , Spleen/cytology , Superantigens/immunology
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