These results provide early evidence of Prograf’s potential in treating this type of MG.
The study, “Tacrolimus inhibits Th1 and Th17 responses in MuSK-antibody positive myasthenia gravis patients,” appeared in the journal Experimental Neurology.
MG is characterized by the production of autoantibodies against molecules a patient’s body produces, including muscle-specific tyrosine kinase (MuSK), an essential protein for the formation and maintenance of neuromuscular junctions — the site where nerve cells and muscles communicate. This results in muscle weakness and possibly also in muscle atrophy (shrinkage).
In patients, immune CD4+ T-cells show increased inflammatory responses via the T helper (Th) cell subsets Th1 and Th17, which are involved in B-cell maturation. Of note, B-cells produce antibodies. Th17 cells have also been implicated in other autoimmune diseases, including multiple sclerosis and rheumatoid arthritis.
Astellas Pharma’s Prograf is an immunosuppressant therapy that inhibits T-cell activation and proliferation, used to help prevent organ rejection after a transplant. It’s also used in the treatment of MG patients with anti-acetylcholine receptor (AChR) autoantibodies. Studies in transplant patients show inhibition of Th1 and Th17 responses, but no research has been conducted to characterize Prograf’s effects in people with MuSK-MG.
A research team from China and the U.S. addressed this gap, as well as Prograf’s inhibition of CD8+ T-cells. (CD4 and CD8 are two molecules found on the surface of specific T-cell populations.)
The researchers analyzed CD4+ and CD8+ T-cell proliferation and production of inflammatory-mediator molecules called cytokines, following a three- or-seven-day in vitro (lab) culture of peripheral blood mononuclear cells (PBMCs) — which comprise T-cells, B-cells, monocytes, and macrophages — with or without Prograf.
PMBCs were obtained from 31 MuSK-MG patients (mean age, 44). All had evident symptoms of this MG for more than a year prior to the blood collection. They were being treated with prednisone, azathioprine, CellCept (mycophenolate mofetil, by Genentech) or a combination immunosuppressant treatment.
Both doses of Prograf were seen to markedly suppress CD4+ and CD8+ T-cell proliferation on day three. The two doses also significantly suppressed Th1 and Th17 responses, as evidenced by a lower frequency of CD4+ T-cells producing cytokines interferon (IFN)-gamma, interleukin (IL)-2, and IL-17, previously identified as the pathogenic (disease-causing) subset of Th17 cells.
The frequencies of CD8+ T-cells with IFN-gamma and IL-2 — known for their robust pro-inflammatory effects — were also lower. And Prograf treatment blocked Th17 cells producing IL-17 and IFN-gamma, both pro-inflammatory molecules.
Data further showed that Prograf (10 ng/mL for three days) suppressed follicular Th cell (Tfh) and regulatory Th (Treg) cell subsets. Of note, while Tfh cells are crucial for the survival, development and function of B-cells, Tregs dampen excessive immune responses.
“Overall, the current study demonstrates tacrolimus’ [Prograf’s] ability to suppress proinflammatory Th1 and Th17 responses in MuSK-MG at concentrations that have been used to treat AChR-MG,” the scientists wrote.
They note that clinical trials are needed to assess Prograf’s risk-benefit profile in these patients, but believe their findings “provide preliminary support for tacrolimus [Prograf] as a potential alternative immunosuppressive therapy for MuSK-MG.”
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