Rapamycin alleviates inflammation and muscle weakness, while altering the Treg/Th17 balance in a rat model of myasthenia gravis

Abstract

Myasthenia gravis (MG) is an autoimmune disease commonly treated with immunosuppressants. We evaluated the novel immunosuppressant, rapamycin (RAPA), in a rat model of experimental autoimmune MG (EAMG). Mortality rates in the RAPA (12%) were significantly down compared with the EAMG (88%) or cyclophosphamide (CTX) (68%) intervention groups. Muscular weakness decreased after both RAPA and CTX treatment. However, Lennon scores were lower (1.74 ± 0.49, 3.39 ± 0.21, and 3.81 ± 0.22 in RAPA, CTX, and EAMG groups, respectively), and body weights (203.12 ± 4.13 g, 179.23 ± 2.13 g, and 180.13 ± 5.13 g in RAPA, CTX, and EAMG groups, respectively) were significantly higher, only in the RAPA group. The proportion of regulatory T cells (Treg) significantly increased, while that of Th17 cells significantly decreased in the RAPA group compared with the EAMG group. In comparison, CTX intervention resulted in increased Th17 but significantly decreased Tregs. Hence, RAPA can be more effectively used in comparison with CTX to treat MG, with an efficacy higher than that of CTX. In addition, our results suggest RAPA’s efficacy in alleviating symptoms of MG stems from its ability to correct the Treg/Th17 imbalance observed in MG.

AEB-071 Ameliorates Muscle Weakness by Altering Helper T Lymphocytes in an Experimental Autoimmune Myasthenia Gravis Rat Model

“…Imbalances in helper T cells and T reg lymphocytes induce MG [ 26 ]. In this study we observed an increased proportion of T h 1, T h 2, and T h 17 lymphocytes in EAMG and decreased T reg lymphocyte numbers, in agreement with previous reports [ 3 ]. Dysregulated numbers of CD4 + helper T cells have been linked to a loss of immune balance [ 26 , 27 ] as reported in multiple sclerosis, systemic lupus erythematosus, and MG [ 26 – 28 ].…”

“…Despite extensive research in the field, the exact pathogenesis of MG remains unclear [ 2 ]. MG leads to cellular immune abnormalities mediated by CD4 + T lymphocytes [ 3 ]. Native CD4 + helper T lymphocytes (T h 1, T h 2, and T h 17 subsets) [ 4 ] are elevated in MG [ 5 ] and are correlated with higher AChR antibody titers [ 6 ].…”

Gut Microbiota as Regulators of Th17/Treg Balance in Patients With Myasthenia Gravis

“…Anti-IL-6 monoclonal antibody has been reported to show good efficacy in patients with EAMG. Additionally, other studies have shown that rapamycin and artemisinin lessen motor symptoms in EAMG rats, with an ability of correcting Treg/Th17 imbalances ( 51 , 52 ). Rapamycin is the most common inhibitor targeting mTOR, which inhibits the differentiation of Th17 cells ( 53 ) and induces the proliferation of Treg cells ( 54 ) by inhibiting the mTOR signaling pathway.…”

Effects of Mitophagy on Regulatory T Cell Function in Patients With Myasthenia Gravis

“…Similarly, Rapa significantly improved symptoms in MG animal model rats (42). The mortality of rats after Rapa treatment was lower than that in rats administered the traditional immunosuppressant cyclophosphamide.…”