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FRI0415 Human skeletal muscle xenografts to model sporadic inclusion body myositis
  1. K. Britson1,
  2. K. Russell2,
  3. K. Wagner3,
  4. L.W. Ostrow4,
  5. T.E. Lloyd5
  1. 1Graduate Program in Cellular and Molecular Medicine, Johns Hopkins University School of Medicine, Baltimore
  2. 2Thomas Jefferson University, Philadelphia
  3. 3Kennedy Krieger Institute
  4. 4Department of Neurology and Pathology
  5. 5Departments of Neurology and Neuroscience, Johns Hopkins University School of Medicine, Baltimore, USA


Background Sporadic inclusion body myositis (IBM) is the most common acquired muscle disease in adults over the age of 50, yet the underlying cause of the disease is unknown, and there are no disease-modifying therapies1. The robust endomysial inflammation in addition to an increased association of IBM with specific HLA haplotypes and other autoimmune diseases suggests that IBM is primarily an autoimmune disease3. However, an association with ageing, a lack of response to immunotherapy, and presence of pathological features such as ubiquitinated protein aggregates seen in neurodegenerative diseases suggest the immune response may be secondary to myodegeneration. Thus, the relationship between inflammation, inclusions, and myodegeneration in IBM is poorly understood.

Objectives Fundamental obstacles to therapeutic development for IBM include the limited understanding of disease pathogenesis as well as a lack of animal models. It is our objective to address these deficiencies by developing a novel mouse xenograft model of IBM.

Methods In this xenograft model, human muscle biopsy specimens are transplanted into immunodeficient mice. The human myofibers cut during the biopsy procedure degenerate, but new muscle fibres regenerate from the patient’s satellite cells. This newly regenerated muscle is revascularized and innervated by the mouse host2. Xenografts are collected at various post-operative timepoints ranging from three to eleven months and cryosectioned to carry out histochemical and immunohistochemical analysis.

Results Our preliminary data show that IBM xenografts develop pathologic features of the human disease.

At 4 months, collections of xenografts from a patient with healthy muscle, a dermatomyositis patient, and an IBM patient display successful regeneration. Regeneration appears less robust in IBM xenografts and is inversely associated with number of human CD3 +cells and sarcoplasmic MHC-I upregulation. A proportion of the CD8 +T cells within the IBM xenografts are proliferative at 4 months, and this is significantly reduced at 6 months (Fisher exact test, p<0.0001). In addition, at 8.5 months, the IBM xenograft shows rare fibres containing p62 positive punta.

Conclusions This xenograft model will allow us to investigate the interactions between human muscle and immune system in a mouse host. We are using this model for mechanistic studies and preclinical therapeutic testing in IBM.

References [1] Dalakas MC. The New England journal of medicine2015;373:393–394. doi:10.1056/NEJMc1506827

[2] Zhang Y, et al. Human molecular genetics2014;23:3180–3188. doi:10.1093/hmg/ddu028

[3] Benveniste O, et al. Acta Neuropathol2015;129:611–624. doi:10.1007/s00401-015-1384-5

[4] Schmidt J, Dalakas MC. Expert review of clinical immunology2013;9:1125–1133. doi:10.1586/1744666X.2013.842467

Disclosure of Interest None declared

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