Prograf Has Potential to Ease Inflammatory Immune Response in MuSK MG Patients, Study Finds

Prograf (tacrolimus) suppressed the proliferation and inflammatory responses of specific immune cells collected from patients with MuSK-antibody positive myasthenia gravis (MuSK-MG), a new study.

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.”