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Antibody-mediated tumor cytotoxicity of microglia
A Sutter1, A Hekmat, G A Luckenbach
1Department of Immunopharmacology, E. Merck, Darmstadt, FRG.
Abstract:
The status of microglial cells as potent effector cells in antibody-mediated tumor cytotoxicity (ADCC) could be established. Microglia (greater than or equal to 99.9% pure) derived from brain cortices of newborn mice were shown to lyse human tumor cell lines expressing different levels of epidermal growth factor (EGF) receptors in the presence of MAb 425, a monoclonal murine anti-primate EGF receptor antibody. MAb 425 mediates microglial ADCC (MiADCC) at concentrations as low as 10(-11) M. Antibody ligands binding unilaterally to either EGF receptors on target cells or Fc receptors on microglia have little effect on MiADCC. At 10(-10) M MAb 425, a 10(3)-fold excess of MAb 425 F(ab')2 fragments or irrelevant antibodies of identical isotype did not block MAb-425-induced MiADCC. Formation of effector-target cell contacts seems to be critical for MiADCC and MiADCC could not be inhibited by anti-tumor necrosis factor-alpha antibodies. In addition to its stimulatory effect on MiADCC, MAb 425 bound to EGF receptors exerted a microgliotrophic effect. Factor(s) derived from astrocytes enhance MiADCC.
Insights
Microglia can kill human tumor cells through antibody-mediated tumor cytotoxicity (ADCC) when activated by specific antibodies targeting EGF receptors. This microglial ADCC (MiADCC) is efficient and crucial for effector-target cell contact.
Area of Science:
- Neuroimmunology
- Cancer Biology
- Cellular Immunology
Background:
- Microglial cells are key immune cells in the central nervous system.
- Antibody-mediated tumor cytotoxicity (ADCC) is a therapeutic mechanism involving immune cells.
- The role of microglia in ADCC against tumors was not fully established.
Purpose of the Study:
- To investigate the potential of microglial cells as effector cells in antibody-mediated tumor cytotoxicity (ADCC).
- To characterize the efficacy and requirements of microglial ADCC (MiADCC) against human tumor cells expressing EGF receptors.
Main Methods:
- Primary mouse microglia (≥99.9% purity) were isolated from newborn mouse cortices.
- Microglia were tested for their ability to lyse human tumor cell lines in the presence of MAb 425, an anti-EGF receptor antibody.
- Experiments involved varying antibody concentrations and using antibody fragments or irrelevant antibodies to assess specificity and blocking effects.
Main Results:
- Microglia demonstrated potent antibody-mediated tumor cytotoxicity (ADCC) against human tumor cells expressing EGF receptors.
- Microglial ADCC (MiADCC) was mediated by MAb 425 at very low concentrations (10^-11 M).
- Effector-target cell contact was critical for MiADCC, which was not inhibited by anti-TNF-alpha antibodies; MAb 425 also showed a microgliotrophic effect.
Conclusions:
- Microglial cells are effective effector cells in antibody-mediated tumor cytotoxicity (ADCC).
- Microglial ADCC (MiADCC) is a specific and potent anti-tumor mechanism that can be enhanced by astrocyte-derived factors.
- Targeting EGF receptors on tumors with antibodies can activate microglia for cancer therapy.