Studies of connective tissue mast cell-mediated cytotoxicity.
Although mast cells have been implicated in mediating antitumor activity, the kinetics, mechanism(s), and suspectibility of different tumors to mast cell-mediated cytotoxicity have not been defined. Rat connective tissue mast cells (CTMC) of greater than or equal to 99% purity were investigated in vitro and found to express maximal spontaneous cytotoxicity against the mouse fibrosarcoma cell line WEHI-164 (56.0% +/- 2.1 SEM), the ultraviolet B (UVB)-induced, cutaneous fibrosarcoma 5C25 (34.7% +/- 3.4 SEM), and the human renal cell tumor Currie (26.8% +/- 2.0 SEM) at an effector to target (E:T) ratio of 80:1. Kinetic studies of CTMC-mediated cytotoxicity demonstrated significant detectable lysis against these tumors within 8 h, which was maximal by 16 h. Binding experiments showed that CTMC formed conjugates with all three lytic-sensitive targets; however, CTMC also attached to the lytic-resistant target YAC-1, indicating that conjugate formation alone is not sufficient for mast cell-mediated cytotoxicity. At two different concentrations, mast cell granules (MCG) lysed WEHI-164 (36.5% +/- 6.8 SEM) and 5C25 (34.4% +/- 6.9 SEM), but were only slightly cytotoxic (5.7% +/- 2.9 SEM) against Currie. A potential role for tumor necrosis factor-alpha (TNF-alpha) in CTMC-mediated cytotoxicity also was investigated. Polyclonal antibodies to TNF-alpha greatly reduced CTMC and TNF-mediated lysis of WEHI-164, but only partially inhibited CTMC killing of the slightly TNF-sensitive 5C25 tumors, and had no effect on CTMC cytolysis of Currie. Thus, this study demonstrates that CTMC mediate cytotoxicity in vitro by both TNF-associated and TNF-independent mechanisms. We conclude that CTMC are capable of mediating antitumor activity and that this effect may be important for tumor surveillance in the skin and other sites.
Department of Dermatology, University of Pittsburgh, Pennsylvania 15213.
M D
MD
Tharp
C
C
Kasper
D
D
Thiele
M R
MR
Charley
D A
DA
Kennerly
T J
TJ
Sullivan
D002460:Cell Line; D003238:Connective Tissue / Q000276:immunology*; D003239:Connective Tissue Cells; D003594:Cytoplasmic Granules / Q000276:immunology; D003601:Cytotoxicity Tests, Immunologic; D003602:Cytotoxicity, Immunologic; D006801:Humans; D007700:Kinetics; D008407:Mast Cells / Q000276:immunology*; D014407:Tumor Cells, Cultured; D014409:Tumor Necrosis Factor-alpha / Q000276:immunology
D014409:Tumor Necrosis Factor-alpha