Immunosuppression of experimental autoimmune myasthenia gravis by mycophenolate mofetil

Janssen, Sofie; Phernambucq, Marko; Martínez‐Martínez, Pilar; Baets, Marc H. De; Losen, Mario

doi:10.1016/j.jneuroim.2008.05.029

Cited by 16 publications

(15 citation statements)

References 52 publications

(86 reference statements)

Supporting

Mentioning

Contrasting

Order By: Relevance

“…The average levels of anti-AChR autoantibodies in this study were high, comparable to a previous study using the same protocol with 20 mg tAChR (36,37) and much higher than another study using 10 mg tAChR (33), ranging between 3 and 80 nM even in the 8w-Bz groups. Because 1 nM serum anti-muscle AChR antibodies can already reduce the amount of total muscle AChR by 50% in rats (33), the limited improvement of muscle strength in this study is understandable. It is therefore conceivable that if we could have used EAMG animals with a lower titer, the effects of bortezomib would have been more pronounced.…”

Section: Discussionsupporting

confidence: 83%

“…4B). The variability of autoantibody levels between animals is typical for the EAMG model, but it should be borne in mind that already a titer of 1 nM autoantibodies is sufficient to cause substantial damage to the NMJ (33). As expected, no anti-AChR Ab titers could be detected in sham/CFA-immunized animals (control group; data not shown).…”

Section: Bortezomib Reduces Autoantibody Titers In Eamgsupporting

confidence: 59%

“…44), for example, cyclophosphamide (45), pixantrone (46), linomide (47), azathioprine, and hydrocortisone (48). Also, mycophenolate mofetil efficiently reduces autoantibodies in a rat model of EAMG (33). This study now indicates that bortezomib might be useful to complement these drugs for the treatment of MG since it can additionally target plasma cells that produce autoantibodies.…”

Section: Discussionmentioning

confidence: 67%

“…The resistance against curare was used as an indirect, albeit nonlinear, measure for the safety factor of neuromuscular transmission and thus for the performance of neuromuscular transmission (33,34).…”

Section: Electromyographymentioning

confidence: 99%

See 3 more Smart Citations

Proteasome Inhibition with Bortezomib Depletes Plasma Cells and Autoantibodies in Experimental Autoimmune Myasthenia Gravis

Gomez

Vrolix

Martínez‐Martínez

et al. 2011

The Journal of Immunology

Self Cite

124

100

View full text Add to dashboard Cite

Bortezomib, an inhibitor of proteasomes, has been reported to reduce autoantibody titers and to improve clinical condition in mice suffering from lupus-like disease. Bortezomib depletes both short- and long-lived plasma cells; the latter normally survive the standard immunosuppressant treatments targeting T and B cells. These findings encouraged us to test whether bortezomib is effective for alleviating the symptoms in the experimental autoimmune myasthenia gravis (EAMG) model for myasthenia gravis, a disease that is characterized by autoantibodies against the acetylcholine receptor (AChR) of skeletal muscle. Lewis rats were immunized with saline (control, n = 36) or Torpedo AChR (EAMG, n = 54) in CFA in the first week of an experimental period of 8 wk. After immunization, rats received twice a week s.c. injections of bortezomib (0.2 mg/kg in saline) or saline injections. Bortezomib induced apoptosis in bone marrow cells and reduced the amount of plasma cells in the bone marrow by up to 81%. In the EAMG animals, bortezomib efficiently reduced the rise of anti-AChR autoantibody titers, prevented ultrastructural damage of the postsynaptic membrane, improved neuromuscular transmission, and decreased myasthenic symptoms. This study thus underscores the potential of the therapeutic use of proteasome inhibitors to target plasma cells in Ab-mediated autoimmune diseases.

show abstract

Section: Discussionsupporting

confidence: 83%

Section: Bortezomib Reduces Autoantibody Titers In Eamgsupporting

confidence: 59%

Section: Discussionmentioning

confidence: 67%

Section: Electromyographymentioning

confidence: 99%

See 2 more Smart Citations

Proteasome Inhibition with Bortezomib Depletes Plasma Cells and Autoantibodies in Experimental Autoimmune Myasthenia Gravis

Gomez

Vrolix

Martínez‐Martínez

et al. 2011

The Journal of Immunology

Self Cite

124

100

View full text Add to dashboard Cite

show abstract

“…Up to 3 μg of curare in EAMG animals and up to 16.5 μg of curare in control animals were used (c.f. Janssen et al, 2008;Seybold et al, 1976). The simultaneous recording of the CMAP during repetitive stimulation of both tibialis anterior muscles was used for measuring the lowest curare dose to produce a reproducible decremental response in each leg.…”

Section: Electromyography (Emg)mentioning

confidence: 99%

Silencing rapsyn in vivo decreases acetylcholine receptors and augments sodium channels and secondary postsynaptic membrane folding

Martínez‐Martínez

Phernambucq

Steinbusch

et al. 2009

Neurobiology of Disease

Self Cite

View full text Add to dashboard Cite

The receptor-associated protein of the synapse (rapsyn) is required for anchoring and stabilizing the nicotinic acetylcholine receptor (AChR) in the postsynaptic membrane of the neuromuscular junction (NMJ) during development. Here we studied the role of rapsyn in the maintenance of the adult NMJ by reducing rapsyn expression levels with short hairpin RNA (shRNA). Silencing rapsyn led to the average reduction of the protein levels of rapsyn (31% loss) and AChR (36% loss) at the NMJ within 2 weeks, corresponding to previously reported half life of these proteins. On the other hand, the sodium channel protein expression was augmented (66%) in rapsyn-silenced muscles. Unexpectedly, at the ultrastructural level a significant increase in the amount of secondary folds of the postsynaptic membrane in silenced muscles was observed. The neuromuscular transmission in rapsyn-silenced muscles was mildly impaired. The results suggest that the adult NMJ can rapidly produce postsynaptic folds to compensate for AChR and rapsyn loss.

show abstract

Recommendations for myasthenia gravis clinical trials

Benatar¹,

Sanders²,

Burns³

et al. 2012

Muscle and Nerve

128

View full text Add to dashboard Cite

The recommendations for clinical research standards published in 2000 by a task force of the Medical Scientific Advisory Board (MSAB) of the Myasthenia Gravis Foundation of America (MGFA) were largely successful in introducing greater uniformity in the recording and reporting of MG clinical trials. Recognizing that changes in clinical trial design and implementation may increase the likelihood that new therapies are developed for MG, the MGFA MSAB Task Force here presents updated recommendations for the design and implementation of clinical trials in MG, including (a) the use of a quantitative measure, such as the MG-Composite, that is weighted for clinical significance and incorporates patient reported outcomes; (b) consideration of nontrial strategies; and (c) development of biomarkers that support mechanistic studies of pharmacotherapies. The hope is that these updated task force recommendations will expedite the development and acceptance of more effective and less noxious therapies for MG.

show abstract

Immunosuppression of experimental autoimmune myasthenia gravis by mycophenolate mofetil

Cited by 16 publications

References 52 publications

Proteasome Inhibition with Bortezomib Depletes Plasma Cells and Autoantibodies in Experimental Autoimmune Myasthenia Gravis

Proteasome Inhibition with Bortezomib Depletes Plasma Cells and Autoantibodies in Experimental Autoimmune Myasthenia Gravis

Silencing rapsyn in vivo decreases acetylcholine receptors and augments sodium channels and secondary postsynaptic membrane folding

Recommendations for myasthenia gravis clinical trials

Contact Info

Product

Resources

About