Monoclonal antibody induced hearing loss.
Monoclonal antibodies KHRI-3 and KHRI-5 identify antigens expressed on inner ear supporting cells and auditory hair cells respectively. To determine if these antibodies affect inner ear function groups of syngeneic Balb/c mice were inoculated with hybridomas KHRI-3, KHRI-5 and other Ig-secreting hybridomas. Hybridomas UM-A9, UM-7F11, the non-secreting SP2/0 myeloma and mice with no hybridoma were used as controls. Animals were tested for auditory brainstem responses (ABR) for frequencies of 4, 8, 16 and 24 kHz, before the inoculation of the hybridomas and at intervals of 6 to 10 days thereafter or daily once tumors became palpable. In normal mice there were no changes in ABR thresholds over the course of the experiment. Other control animals showed little change in ABR even when the growth of the hybridoma or myeloma tumors were far advanced. Of the KHRI-5 hybridoma bearing animals only one of seven animals exhibited threshold shifts greater than 15 dB. In contrast, most mice bearing the KHRI-3 hybridoma exhibited high frequency threshold shifts of 40-50 dB that coincided temporally with the growth of the hybridoma, the presence of circulating KHRI-3 antibody, and greatly increased immunoglobulin titers. Ears from KHRI-3-bearing mice that developed high frequency hearing loss also had a novel type of lesion in the basal turn of the cochlea that was characterized by loss of outer hair cells and absence of typical supporting cell scars. Such changes were not found in control hybridoma-bearing mice. These findings suggest that KHRI-3 antibody has an effect on hearing that is secondary to damage to the organ of Corti and loss of outer hair cells. Our results have important implications for antibody-mediated mechanisms of hearing loss and provide an animal model in which to study this phenomenon.
Nair
T S
TS
Cell Biology Laboratory, Kresge Hearing Research Institute, University of Michigan, Ann Arbor 48109-0506, USA.
Raphael
Y
Y
Dolan
D F
DF
Parrett
T J
TJ
Perlman
L S
LS
Brahmbhatt
V R
VR
Wang
Y
Y
Hou
X
X
Ganjei
G
G
Nuttall
A L
AL
D000161:Acoustic Stimulation; D000818:Animals; D000911:Antibodies, Monoclonal / Q000097:blood / Q000633:toxicity*; D000937:Antigen-Antibody Reactions; D001309:Auditory Threshold / Q000187:drug effects; D003051:Cochlea / Q000166:cytology / Q000187:drug effects / Q000276:immunology; D004797:Enzyme-Linked Immunosorbent Assay; D016057:Evoked Potentials, Auditory, Brain Stem / Q000187:drug effects*; D005786:Gene Expression Regulation / Q000187:drug effects* / Q000235:genetics; D006198:Hair Cells, Auditory / Q000187:drug effects / Q000276:immunology; D034381:Hearing Loss / Q000139:chemically induced* / Q000235:genetics; D006825:Hybridomas; D051379:Mice; D008807:Mice, Inbred BALB C; D009101:Multiple Myeloma / Q000473:pathology; D009925:Organ of Corti / Q000187:drug effects / Q000276:immunology / Q000473:pathology; D013047:Specific Pathogen-Free Organisms; D013050:Spectrometry, Fluorescence; D014407:Tumor Cells, Cultured
D000911:Antibodies, Monoclonal