Administration of bone marrow stromal cells ameliorates experimental autoimmune myasthenia gravis by altering the balance of Th1/Th2/Th17/Treg cell subsets through the secretion of TGF-beta.

Bone marrow stromal cells (BMSCs) are strong candidates for cell therapy against human autoimmune diseases. Intravenous administration of syngenic BMSCs to EAMG-model rats effectively ameliorated the disease, partially through a TGF-beta-dependent mechanism. The proliferative ability of T or B cells from EAMG rats was inhibited by BMSCs at proper cocultured ratios. And the imbalance of Th1, Th2, Th17 and Treg cell subsets accompanied with the development of EAMG was corrected by the administration of BMSCs. These results provide further insights into the pathogenesis of MG, EAMG, and other immune-mediated diseases, and support a potential role for BMSCs in their treatment.

Modulation of immune responses and suppression of experimental autoimmune myasthenia gravis by surgical denervation of the spleen.

Critical interactions between the nervous system and the immune system during experimental autoimmune myasthenia gravis (EAMG) were examined in an animal model for human MG after immunization of adult female Lewis rats with Torpedo acetylcholine receptor (AChR) and complete Freund's adjuvant. Immunized rats depicted marked clinical severity of the disease. Using enzyme-linked immunospot (ELISPOT) assay and in situ hybridization techniques, immune responses in these animals were examined and showed elevated numbers of anti-AChR IgG secreting B cells and AChR reactive interferon (IFN)-gamma-secreting cells, enhanced mRNA expression of the proinflammatory cytokines IFN-gamma and tumour necrosis factor (TNF)-alpha as Th1 subset and the anti-inflammatory cytokines interleukin (IL)-4 and IL-10 as a Th2 subset, and transforming growth factor (TGF)-beta as a Th3 cytokine. Corticosterone and prostaglandin E(2) (PGE(2)) levels were measured by radioimmunoassay and illustrated increased production after immunization. Surgical denervation of the spleen reduced significantly the clinical severity of the disease, suppressed the numbers of IgG and IFN-gamma-secreting cells, down-regulated the mRNA expression for cytokines and reduced corticosterone and PGE(2) production. As controls, sham-operated rats were used and showed results as the EAMG non-denervated control rats. The data present herein, and for the first time, substantial effects of the nervous system on immune responses that may influence the outcome of EAMG. These effects were not dependent on cytokine inhibitory mediators such as prostaglandins or stress hormones. IL-10 and TGF-beta, the two potent immunosuppressive cytokines, were also suppressed, indicating a general suppression by splenic denervation. More investigations are initiated at our laboratories to understand the evident neural control over the immune system during challenges leading to the break of tolerance and development of autoimmunity, which may assist in innovative therapeutic approaches.