Reversing autoreactivity in multiple sclerosis

There currently is no cure for MS. However, findings from a new study provide strong support for a promising advance toward that goal: the ability to reverse — and in many cases, completely alleviate — MS-like symptoms in mice.

The study appears in the journal Science Advances.

For an unknown reason in people with MS, some of the body’s first line of defense against foreign invaders — immune cells known as CD4+ T cells — fail to recognize that myelin (the fatty material surrounding and protecting nerve cells) is a normal part of the human system. If these wayward, or effector T cells, become dominant, they may provoke inflammation that damages or destroys the myelin sheath, which in turn, can severely disrupt or curtail transmission of nerve impulses from all parts of the body to the brain.

“We developed a method for ‘tipping the balance’ of the T cells reaching the central nervous system from effectors to regulatory T cells, or T regs, that modulate the immune system and have been shown to prevent autoimmune reactions,” says a co-senior author.

“Using this therapy on mice bred to exhibit symptoms modeling those seen in humans with MS, we found we could enhance the growth of T regs while simultaneously reducing the number of effectors, resulting in reversal of the MS-like symptoms in 100% of the mice, and even more exciting, achieving a full recovery in 38% — in other words, more than a third were cured of their disease.”

The researchers achieved these intriguing results by using  biodegradable polymeric microparticles — tiny bioengineered polymer spheres — to deliver three key therapeutic agents: (1) a fusion of two proteins: interleukin-2 (IL-2), which stimulates T cell production and growth, and an antibody that blocks certain binding sites on IL-2 to optimize the ones relevant to T reg expansion; (2) a major histocompatibility complex (MHC) class II molecule with a myelin peptide (protein fragment) “presented” on its surface to immunologically select myelin-specific (and therefore, protective of the nerve cell covering) T regs rather than other T cell types; and (3) rapamycin, an immunosuppressant drug that helps lower the number of effector T cells.

“We inject the loaded microparticles near lymphatic tissues to stimulate the production and growth of T regs and facilitate their travel to the central nervous system via the lymphatic system,” says another co-senior and corresponding author. “Our study findings showed that in all of our mice, the T regs stopped the autoimmune activity of the effectors against myelin, prevented further damage to the nerves and gave them the time needed to recover.”

Furthermore, the author says, the MS-like mouse disease, experimental autoimmune encephalomyelitis, was completely cured in more than a third (38%) of the animals.

“First in line will be a mouse version of type 1 diabetes,” says another co-senior author. “To engage and grow T regs specific for the insulin-producing cells in the pancreas damaged or threatened by that disease’s autoimmune activity, we’ll exchange the myelin peptide we used in the MHC-peptide portion of the MS therapy with one from those cells.”

“The belief is that by simply changing the presented peptide each time, we can target our therapy to tackle a wide variety of autoimmune diseases,” adds the author. “We hope to have a cache of potential therapies ready to go before moving forward to safety and efficacy studies in mice, followed hopefully by human trials.”