#ECTRIMS2016 – Protein Seen as New Target in Preventing Brain Inflammation in MS

Researchers found that blocking a protein, known as integrin alpha 8, may work to prevent inflammation in the central nervous system of patients with multiple sclerosis (MS).

The results were revealed in an oral presentation, “Integrin alpha8 is a novel mediator of T lymphocyte migration across the CNS barriers,” at the 32nd Congress of the European Committee for Treatment and Research in Multiple Sclerosis (ECTRIMS), taking place in London on Sept. 14–17.

A critical component of MS pathogenesis is the migration of inflammatory immune cells (such as T-cells) from the blood into the central nervous system (CNS). The CNS tries to prevent such harmful migration through two important and tightly regulated barriers: the blood-brain barrier (BBB) and the blood-meningeal barrier (BMB).

A key protein mediating the migration of immune cells, called lymphocytes, from the peripheral blood circulation and across the CNS barriers is integrin beta1. The protein’s role in this migration, in fact, can be seen in the strong clinical efficacy of Tysabri (natalizumab), a monoclonal antibody that targets integrin alpha4beta1. (A downside of Tysabri treatment, however, is that it also targets integrin alpha4beta1 in other tissues, impairing the standard surveillance work of our immune systems. This can lead to an increased susceptibility to severe viral infections.)

Researchers aimed to find new beta1 integrin partners involved in the migration of detrimental lymphocytes across the CNS vasculature.

They found that a specific subset of T lymphocytes, the pro-inflammatory TH17 cells, express integrin alpha8, and that this protein interacts specifically with integrin beta1. The team also found that the expression of integrin alpha8 is increased in pro-inflammatory conditions in both healthy controls and MS patients.

Using methods for detecting alpha8 in tissues, researchers discovered that alpha8 is expressed on a subset of T-cells (CD3+ T cells) found throughout the brains of EAE mice, an animal MS model. Moreover, both BBB and BMB endothelial cells (ECs) contain the main binding partner of alpha8. By blocking the alpha8 binding site, the migratory ability of pro-inflammatory TH17 cells was seen to significantly decrease across an in vitro assay that mimicked ECs of the brain-blood barrier.

Next, the researchers treated the EAE mice with a compound to block alpha8, and found it was able to reduce the clinical severity, limit T-lymphocyte infiltration into the CNS, and prevent disease progression in the mouse model.

“These data highlight an important role for alpha8 in mediating pro-inflammatory T lymphocyte migration across the CNS microvasculature, suggesting that this integrin may be an effective therapeutic target to prevent disease activity and progression in MS,” the researchers concluded in their ECTRIMS’ abstract.