MRL/MP-<i>lpr/lpr</i> Mouse as a Model of Immune-Induced Sensorineural Hearing Loss

Kusakari, Chikashi; Hozawa, Koji; Kyogoku, Masahisa; Koike, Shuji; Takasaka, Tomonori

doi:10.1177/0003489492101s1017

Cited by 55 publications

(24 citation statements)

References 15 publications

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“…Moreover, the reported hearing loss associated with CII immunization has not been reproduced consistently (48). MRL/MpJ-lpr/lpr and C3H/lpr mice have been used recently in ASNHL studies because they develop spontaneous hearing loss (49)(50)(51). Their hearing deficiency, however, is due to a systemic lymphoproliferative disorder resulting from the autosomal-recessive lpr Fas deletion (52).…”

Section: Discussionmentioning

confidence: 99%

Murine autoimmune hearing loss mediated by CD4+ T cells specific for inner ear peptides

Solares¹,

Edling²,

Johnson³

et al. 2004

J. Clin. Invest.

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Autoimmune sensorineural hearing loss (ASNHL) is characterized typically by bilateral, rapidly progressive hearing loss that responds therapeutically to corticosteroid treatment. Despite its name, data implicating autoimmunity in the etiopathogenesis of ASNHL have been limited, and targeted self-antigens have not been identified. In the current study we show that the inner ear–specific proteins cochlin and β-tectorin are capable of targeting experimental autoimmune hearing loss (EAHL) in mice. Five weeks after immunization of SWXJ mice with either Coch 131–150 or β-tectorin 71–90, auditory brainstem responses (ABR) showed significant hearing loss at all frequencies tested. Flow cytometry analysis showed that each peptide selectively activated CD4+ T cells with a proinflammatory Th1-like phenotype. T cell mediation of EAHL was determined by showing significantly increased ABR thresholds 6 weeks after adoptive transfer of peptide-activated CD4+ T cells into naive SWXJ recipients. Immunocytochemical analysis showed that leukocytic infiltration of inner ear tissues coincided with onset of hearing loss. Our study provides a contemporary mouse model for clarifying our understanding of ASNHL and facilitating the development of novel effective treatments for this clinical entity. Moreover, our data provide experimental confirmation that ASNHL may be a T cell–mediated organ-specific autoimmune disorder of the inner ear

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Section: Discussionmentioning

confidence: 99%

Murine autoimmune hearing loss mediated by CD4+ T cells specific for inner ear peptides

Solares¹,

Edling²,

Johnson³

et al. 2004

J. Clin. Invest.

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“…Kusakari et al 22 have also shown that the IgG deposition and the degeneration of the stria vascularis in MRL/lpr mice at 20 weeks of age are responsible for SNHL. Therefore, it is likely that BMT prevents the development of SNHL as the result of the prevention of immune complex deposits on the stria vascularis in the cochleae.…”

Section: Discussionmentioning

confidence: 96%

“…34,35 It has also been found that MRL/lpr mice show inner ear diseases due to the development of autoantibody or immune complex deposits. [19][20][21][22] The autoantibody or immune complex deposits have been thought to be induced by auto-reactive B cells in collaboration with abnormal T cells, which have the lpr gene and the defect in the Fas gene and escape from Fas-mediated apoptosis, leading to the proliferation and activation of B cells. 36 In the present study, we treated MRL/lpr mice with CY and irradiation to eliminate the host immunocompetent cells and bone marrow cells.…”

Section: Discussionmentioning

confidence: 99%

“…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.…”

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confidence: 99%

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

Lee

Iwai

Sugiura

et al. 2000

Bone Marrow Transplant

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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...

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“…Deterioration of ABR thresholds of 20-week-old MRL/ MP-lpr/lpr mice, bred for the study of autoimmune disease [159], was prevented by daily prednisolone treatment for 10 weeks [160].…”

Section: Immune-mediated Progressive Snhlmentioning

confidence: 99%

How Useful Is Corticosteroid Treatment in Cochlear Disorders?

Lamm¹,

Arnold²

1999

Otorhinolaryngol Nova

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The scientific basis for the administration of corticosteroids classified as glucocorticoids in certain cochlear disorders, such as immune-mediated progressive and idiopathic acute sensorineural hearing loss (SNHL), Ménière’s disease and noise-induced hearing loss (NIHL), was discussed. The current knowledge on the physiological functions of endogenous glucocorticoids and the pharmacological effects of their synthetic analogs was summarized. Emphasis was placed on experimental studies on corticosteroids in the cochleovestibular system and on the therapeutic effects of glucocorticoids on SNHL, Ménière’s disease, NIHL and chronic tinnitus obtained from clinical trials. Glucocorticoids exert numerous profound effects on almost every organ system, including mechanisms involved in anti-inflammatory action and immunosuppression. However, inflammatory tissue alterations are not only elicited by bacterial, viral or other immunopathological processes but also by physically and chemically induced cellular damage, tissue ischemia and hypoxia. Regardless of whether one or more of these insults underlie SNHL, Ménière’s disease and NIHL, glucocorticoids effectively counteract subsequent inflammatory tissue damage in the auditory and vestibular system. This was confirmed in experimental studies on immune-mediated progressive SNHL, and thrombosis-induced and noise-induced cochlear ischemia, hypoxia and hearing loss. Glucocorticoid treatment results of immune-mediated progressive and acute idiopathic SNHL are promising, although placebo-controlled trials on the effect in acute idiopathic SNHL have revealed conflicting data (probably due to the small number of patients). Clinical studies on the effect of systemic glucocorticoid monotherapy on Ménière’s disease and NIHL have not yet been performed. After intratympanic application, relief of vertigo, tinnitus and preservation of hearing in Ménière’s disease was observed in previous studies; however, recently none of these effects have been confirmed in a placebo-controlled trial. Similarly, in contrast to previous reports, chronic tinnitus of various origins did not improve after repetitive glucocorticoid application onto the round window membrane using a micropump connected to an implanted microcatheter.

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MRL/MP-lpr/lpr Mouse as a Model of Immune-Induced Sensorineural Hearing Loss

Cited by 55 publications

References 15 publications

Murine autoimmune hearing loss mediated by CD4+ T cells specific for inner ear peptides

Murine autoimmune hearing loss mediated by CD4+ T cells specific for inner ear peptides

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

How Useful Is Corticosteroid Treatment in Cochlear Disorders?

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