Prevention of autoimmune hearing loss in MRL/lpr mice by bone marrow transplantation

Abstract

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...

Prevention of accelerated presbycusis by bone marrow transplantation in senescence-accelerated mice

“…4 We have previously shown that autoimmune mechanisms participate in the development of the sensori-neural hearing loss in MRL/lpr mice. 12,13 We have also demonstrated that T cells in the systemic circulation infiltrate the inner ear and proliferate locally as a consequence of the immune response. 20 On the other hand, it has been shown that macrophages support the regeneration of the central and peripheral nervous system; 21,22 the cells secrete interleukin-1 (IL-1) 23 and mediate the release of nerve growth factor (NGF) in a variety of tissues, including Schwann cells.…”

“…12 We have also demonstrated that the hearing loss and cochlear pathology are derived from defects in the bone marrow cells; BMT can be used to prevent the development of the sensori-neural hearing loss. 13 If senescence is accelerated by the dysfunctions of immunocompetent cells, the normalization of the immune system by allogeneic BMT should prevent accelerated senescence. Therefore, we examine whether allogeneic BMT can prevent the accelerated impairment of both immune functions and hearing.…”

Prevention of Hearing Loss by Alteration of the Systemic Immune System

“…SHL and immune dysfunction. Several factors including inflammaging, immune dysfunction, oxidative stress, genetic abnormality, ototoxic drugs, and noise exposure lead to AHL as a consequence of deterioration in the SG, hair cells, and striavascularis of the cochlea [12]- [18].…”

Prevention of Hearing Loss by Alteration of the Systemic Immune System

“…We performed allogeneic bone marrow transplantation (BMT) in which MRL/lpr recipient mice received bone marrow cells from young C57BL/6 mice which are non-autoimmune prone and show slow manifestation of presbycusis [12,13]. The BMT procedures consist of systemic irradiation with 9-10 Gy to delete immunocompetent cells, including bone marrow cells, in recipients and then inoculating bone marrow cells from C57BL/6 donor mice.…”

“…Thus, cochlear function and pathology are affected by, or coordinated with, the systemic environment including the immune system. We have also studied preventive treatments for progressive bilateral SHL caused by disturbances in systemic immunity with autoimmune diseases or aging, but not caused by genetic abnormalities or acoustic trauma [11][12][13][14][15][16][17][18].…”