Summary:A substrain of the senescence-accelerated mouse (SAM), the SAMP1 mouse, is an animal model for accelerated senescence including the age-related acceleration of both immunological dysfunction and hearing loss caused by the impairment of spiral ganglion cells. In the present study, we examine whether the accelerated presbycusis can be prevented by allogeneic BMT. Young SAMP1 (H-2 k ) mice were irradiated with 9 Gy and then reconstituted with bone marrow cells from normal BALB/c (H-2 d ) mice. Allogeneic BMT was found to prevent the development of immunological dysfunction, hearing loss, and apoptosis of spinal ganglion cells in SAMP1 mice. These findings indicate that some types of accelerated presbycusis do not result from defects in the cochlea, but do from defects in the hematopoietic stem cells (HSC) and immunocompetent cells derived from the HSC. If this is the case, either allogeneic BMT, which replaces abnormal HSC with normal HSC and reconstructs a normal immune system in the recipients, or autologous BMT using genetically modified bone marrow cells, could become a new strategy for the treatment of presbycusis. Bone Marrow Transplantation (2001) 28, 323-328. Keywords: presbycusis; spiral ganglion cell; bone marrow transplantation; T lymphocyte; apoptosis There has been no strategy for the prevention and treatment of presbycusis. There is a widespread presumption based on clinical observations that presbycusis is an inherited disorder, and that genetic factors may influence both the rate and severity of the hearing loss. 1,2 However, the genetic factors are still unclear, since more than one pathologic process may be acting upon the auditory system, 1 and environmental factors are also involved. 3 Among animal models of presbycusis, the SAMP1 mouse is most suitable by virtue of its progressive hearing loss with an onset at an early age, as well as accelerated senescence in an inherited pattern. 4,5 Molecular studies, such as transfer experiments of the Akv-1 gene 4 and apoA-II gene, 6 are in progress. Age-accelerated somatic mutations were also found in the hypoxanthine phosphoribosyl transferase (Hprt) locus of splenic lymphocytes. 7 This mouse strain shows an early occurrence of accelerated dysfunctions of immunocompetent cells, particularly T cells, 4,8 followed by accelerated hearing impairment, 5 the loss of physical activity, alopecia, periophthalmic lesions, and increased lordokyphosis of the spine, as well as spontaneous age-associated amyloidosis and shortened lifespan. 9,10 Early production of autoantibodies against DNA, thymocytes and collagen type II and the early deposition of immune complexes in the glomeruli of the kidney have been demonstrated in these mice. 11 Since age-related changes in the immune system appear relatively early in life, it is suggested that immune impairment may be a cause of age-related disease. 4 We have previously shown that the dysfunctions of immunocompetent cells, but not abnormalities in the cochlea, cause the development of autoimmune sensori-neural hearin...

Summary:We examined the effects of bone marrow transplantation (BMT) on immune-mediated inner ear diseases in MRL/Mp-lpr/lpr (MRL/lpr) mice, which manifest not only lupus nephritis but also sensorineural hearing loss (SNHL) at the age of 20 weeks. These mice were treated with cyclophosphamide (CY) and irradiation (5 Gy × 2), followed by the transplantation of bones plus bone marrow cells from allogeneic normal C57BL/6 mice at the age of 12 weeks. Hematolymphoid cells were reconstituted with donor-derived cells 3 months after BMT. Thus-treated MRL/lpr mice showed neither lupus nephritis nor SNHL even 24 weeks after BMT. No pathological findings were observed in either glomeruli or cochleae. These findings suggest that BMT can be used to prevent the development of autoimmune SNHL in MRL/lpr mice. Bone Marrow Transplantation (2000) 26, 887-892. Keywords: MRL/lpr mouse; autoimmune hearing loss; bone marrow transplantation It has become widely recognized that autoimmune mechanisms are involved in inner ear diseases 1-3 such as steroidresponsive sensorineural hearing loss (SNHL) 4 and Méni-ère's disease, 5 as first proposed by McCabe in 1979. 1 Inner ear dysfunction causes various audiovestibular symptoms such as SNHL, tinnitus and vertigo. The presence of SNHL as a part of or in combination with systemic autimmune diseases such as systemic lupus erythematosus (SLE), 6-8 rheumatoid arthritis (RA), 9-12 Behçet's disease, 13,14 Cogan's syndrome, 15,16 and ulcerative colitis 17,18 has been reported.MRL/lpr mice were found to spontaneously develop SNHL as well as SLE by autoimmune mechanisms. The mice carrying the lymphoproliferation (lpr) mutation have defects in the Fas gene, and a defect in negative selection of self-reactive T cells in the thymus. In cooperation with abnormal T cells, auto-reactive B cells produce autoantibodies or immune complexes which are deposited in the lesions of both the stria vascularis of the cochlea and the basement membranes of the glomeruli. [19][20][21][22] It has recently been reported that SNHL in MRL/lpr mice can be improved by steroid therapy and the levels of serum immune complexes were found to be reduced after steroid therapy. 23 We have also reported that the SNHL and cochlear pathology can be transferred to normal mice by the injection of lymphocytes from MRL/lpr mice. 24 In addition, we have demonstrated that autoimmune diseases are induced by abnormal hemopoietic stem cells (HSCs). When normal mice are reconstituted with bone marrow cells or HSCs from animals with autoimmune diseases such as SLE, 25 diabetes mellitus 26 and focal and segmental glomerular sclerosis, 27 the autoimmune diseases are transferred to the normal mice. In addition, we have found that BMT can be used to treat these autoimmune diseases. 28,29 In the present study, we show that autoimmune SNHL in MRL/lpr mice can be prevented by allogeneic BMT. Materials and methods AnimalsMRL/lpr mice (H-2K k ) were purchased from SLC Japan (Shizuoka, Japan). C57BL/6 (B6) (H-2K b ) mice were purchased from CLEA Japan (Osa...