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.

Thymus involvement in early‐onset myasthenia gravis

“…The clear implication of the thymus in MG is also demonstrated using immunodeficient mice that are grafted with thymic biopsies from MG patients. Indeed, almost all the animals display human anti‐AChR Abs in their serum, and 50% of them develop MG‐like symptoms in correlation with the loss of AChR at the muscle endplates …”

An imbalance between regulatory T cells and T helper 17 cells in acetylcholine receptor–positive myasthenia gravis patients

“…developed a humanized preclinical model that recapitulates the features of human MG. In this model, subcutaneous transplantation of thymus fragments from MG patients in NOD/ scid gamma mice induces MG symptoms that include fatigability and the presence of anti‐AChR antibodies . Additionally, in this model, the thymic fragments from MG patients conserve their inflammatory status, with overexpression of IL‐6, IL‐17, TNF‐α, and IFN‐γ .…”

“…In this model, subcutaneous transplantation of thymus fragments from MG patients in NOD/ scid gamma mice induces MG symptoms that include fatigability and the presence of anti‐AChR antibodies . Additionally, in this model, the thymic fragments from MG patients conserve their inflammatory status, with overexpression of IL‐6, IL‐17, TNF‐α, and IFN‐γ . This humanized MG mouse model may be relevant for determining the importance of different T cell subsets, especially T H 17 cells, in the disease course and for evaluating therapies targeting molecules of the IL‐17/IL‐23 pathway.…”

Pathophysiological mechanisms of autoimmunity

“…These thymic B cells can produce antibodies to AChR, as assessed by titration in culture supernatants of thymic cells or in the sera of immunodeficient mice grafted with MG thymic tissue . Importantly, anti‐AChR antibodies produced by MG thymic B cells are pathogenic, since grafts of MG thymic fragments could result in myasthenic symptoms in immunodeficient mice …”

“…30,31 Importantly, anti-AChR antibodies produced by MG thymic B cells are pathogenic, since grafts of MG thymic fragments could result in myasthenic symptoms in immunodeficient mice. 32 The increased number of B cells in the MG thymus is associated with increased expression of BAFF, a factor supporting survival and differentiation of B cells. 33 Increased serum levels of BAFF are found in MG as well as in several other AIDs.…”