A novel class of antitumor antibodies: nucleosome-restricted antinuclear autoantibodies (ANA) from healthy aged nonautoimmune mice.
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.
Iakoubov
L Z
LZ
Center for Imaging and Pharmaceutical Research, Massachusetts General Hospital, Charlestown 02129-2060, USA.
Torchilin
V P
VP
D000375:Aging / Q000276:immunology; D000595:Amino Acid Sequence; D000818:Animals; D000974:Antibodies, Antinuclear / Q000494:pharmacology*; D000911:Antibodies, Monoclonal / Q000494:pharmacology; D000918:Antibody Specificity; D000920:Antibody-Dependent Cell Cytotoxicity / Q000276:immunology; D000951:Antigens, Neoplasm / Q000276:immunology; D000970:Antineoplastic Agents / Q000494:pharmacology*; D001324:Autoantigens / Q000276:immunology; D005260:Female; D016399:Lymphoma, T-Cell / Q000276:immunology / Q000628:therapy; D008546:Melanoma, Experimental / Q000276:immunology / Q000628:therapy; D051379:Mice; D008810:Mice, Inbred C57BL; D008969:Molecular Sequence Data; D009707:Nucleosomes / Q000276:immunology*
D000974:Antibodies, Antinuclear; D000911:Antibodies, Monoclonal; D000951:Antigens, Neoplasm; D000970:Antineoplastic Agents; D001324:Autoantigens; D009707:Nucleosomes