title: Preconditioned mesenchymal stem cells treat myasthenia gravis in a humanized preclinical model.
abstract: Myasthenia gravis (MG) with anti-acetylcholine receptor (AChR) Abs is an autoimmune disease characterized by severe defects in immune regulation and thymic inflammation. Because mesenchymal stem cells (MSCs) display immunomodulatory features, we investigated whether and how in vitro-preconditioned human MSCs (cMSCs) could treat MG disease. We developed a new humanized preclinical model by subcutaneously grafting thymic MG fragments into immunodeficient NSG mice (NSG-MG model). Ninety percent of the animals displayed human anti-AChR Abs in the serum, and 50% of the animals displayed MG-like symptoms that correlated with the loss of AChR at the muscle endplates. Interestingly, each mouse experiment recapitulated the MG features of each patient. We next demonstrated that cMSCs markedly improved MG, reducing the level of anti-AChR Abs in the serum and restoring AChR expression at the muscle endplate. Resting MSCs had a smaller effect. Finally, we showed that the underlying mechanisms involved (a) the inhibition of cell proliferation, (b) the inhibition of B cell-related and costimulatory molecules, and (c) the activation of the complement regulator DAF/CD55. In conclusion, this study shows that a preconditioning step promotes the therapeutic effects of MSCs via combined mechanisms, making cMSCs a promising strategy for treating MG and potentially other autoimmune diseases.
authors.affiliation: Sorbonne Universités, UPMC Univ Paris 06, Paris, France.|INSERM U974, Paris, France.|AIM, Institute of Myology, Paris, France.
authors.forename: Muriel
authors.initials: M
authors.lastname: Sudres
authors.affiliation: Sorbonne Universités, UPMC Univ Paris 06, Paris, France.|INSERM U974, Paris, France.|AIM, Institute of Myology, Paris, France.
authors.forename: Marie
authors.initials: M
authors.lastname: Maurer
authors.affiliation: Sorbonne Universités, UPMC Univ Paris 06, Paris, France.|INSERM U974, Paris, France.|AIM, Institute of Myology, Paris, France.
authors.forename: Marieke
authors.initials: M
authors.lastname: Robinet
authors.affiliation: Sorbonne Universités, UPMC Univ Paris 06, Paris, France.|INSERM U974, Paris, France.|AIM, Institute of Myology, Paris, France.
authors.forename: Jacky
authors.initials: J
authors.lastname: Bismuth
authors.affiliation: Sorbonne Universités, UPMC Univ Paris 06, Paris, France.|INSERM U974, Paris, France.|AIM, Institute of Myology, Paris, France.
authors.forename: Frédérique
authors.initials: F
authors.lastname: Truffault
authors.affiliation: Sorbonne Universités, UPMC Univ Paris 06, Paris, France.|INSERM U974, Paris, France.|AIM, Institute of Myology, Paris, France.
authors.forename: Diane
authors.initials: D
authors.lastname: Girard
authors.affiliation: Sorbonne Universités, UPMC Univ Paris 06, Paris, France.|INSERM U974, Paris, France.|AIM, Institute of Myology, Paris, France.
authors.forename: Nadine
authors.initials: N
authors.lastname: Dragin
authors.affiliation: Sorbonne Universités, UPMC Univ Paris 06, Paris, France.|INSERM U974, Paris, France.|AIM, Institute of Myology, Paris, France.
authors.forename: Mohamed
authors.initials: M
authors.lastname: Attia
authors.affiliation: Centre Chirurgical Marie Lannelongue, Le Plessis Robinson, France.
authors.forename: Elie
authors.initials: E
authors.lastname: Fadel
authors.affiliation: Hôpital Civil de Strasbourg, Strasbourg, France.
authors.forename: Nicola
authors.initials: N
authors.lastname: Santelmo
authors.affiliation: Department of Neurology, Agnes Ginges Center for human Neurogenetics, Hadassah Hebrew University Medical Center, Jerusalem, Israel.
authors.forename: Camille
authors.initials: C
authors.lastname: Sicsic
authors.affiliation: Department of Neurology, Agnes Ginges Center for human Neurogenetics, Hadassah Hebrew University Medical Center, Jerusalem, Israel.
authors.forename: Talma
authors.initials: T
authors.lastname: Brenner
authors.affiliation: Sorbonne Universités, UPMC Univ Paris 06, Paris, France.|INSERM U974, Paris, France.|AIM, Institute of Myology, Paris, France.
authors.forename: Sonia
authors.initials: S
authors.lastname: Berrih-Aknin
mesh_terms: D000293:Adolescent; D000328:Adult; D000818:Animals; D000911:Antibodies, Monoclonal / Q000097:blood; D001402:B-Lymphocytes / Q000276:immunology*; D002648:Child; D004195:Disease Models, Animal; D005260:Female; D064593:Heterografts; D006801:Humans; D008297:Male; D045164:Mesenchymal Stem Cell Transplantation / Q000379:methods*; D059630:Mesenchymal Stem Cells / Q000166:cytology*; D051379:Mice; D016688:Mice, Inbred NOD; D016513:Mice, SCID; D020720:Myasthenia Gravis, Autoimmune, Experimental / Q000628:therapy*; D011950:Receptors, Cholinergic / Q000276:immunology*; D055815:Young Adult
chemical_list: D000911:Antibodies, Monoclonal; D011950:Receptors, Cholinergic