Sensorineural hearing loss (SNHL) of unexplained etiology is a common entity with an incidence rate of 1:10,000 for which there are few effective treatments. McCabe proposed that a subset of patients presenting with sudden or rapidly progressive onset of hearing loss, vestibular involvement, or systemic immune disease, such as vasculitis, might be of autoimmune origin. Some of these patients have antibodies to inner ear antigens and show improvement of symptoms on immunosuppressive therapy but such therapy is dangerous and should be used only when clearly indicated. Thus it is important to develop animal model systems for autoimmune sensorineural hearing loss (AISNHL) which can be used to determine if antibodies to inner ear antigens do cause hearing loss, and to determine the mechanism(s) by which the hearing loss occurs. We previously developed monoclonal antibodies (mabs) to inner ear antigens and demonstrated that mice carrying high titers of the KHRI-3 mab to a prominent cochlear antigen, develop high frequency hearing loss and corresponding outer hair cell loss in the basal turn of the cochlea. Furthermore, intracochlear infusion of this antibody in Guinea pigs results in in vivo antibody binding to the supporting cells, hearing loss, and pathologic changes that include loss of outer hair cells. and supporting cells. These tests indicate that exogenously administered antibody to a cochlear antigen can induce hearing loss. We will use this system to: test the hypothesis that antibodies to inner ear antigens mediate SNHL, and we will determine the pathogenic mechanism of antibody induced hearing loss. We will affinity purify mabs raised to inner ear proteins (such as KHRI-3, -4 and 5) as well as control mabs and prepare Fab and Fab' antibody fragments. These preparations will be infused in mice and Guinea pigs in which hearing, inner ear pathology and antibody binding will be tested. Proteins identified by mabs that induce hearing loss, will be affinity purified on mab columns and used as antigen to induce AISNHL. Preliminary studies using highly purified KHRI-3 Mab has replicated earlier results obtained with crude antibody preparations supporting the hypothesis that this Mab, and not some other component of the hybridoma, is responsible for the induced hearing loss. Mabs to inner ear proteins that produce antibody- mediated auditory damage provide a useful small animal model of AISNHL. Eventually these studies should lead to better diagnosis test and therapy of AISNHL.
