Intranasal protein limits disability in models of MS

Dr. Jacqueline Quandt at the Djavad Mowafaghian Centre for Brain Health.

Can a protein applied to the inside of the nose reduce inflammation in the central nervous system?

New research from Dr. Jacqueline Quandt’s laboratory suggests that intranasal administration of E-selectin, a type of protein that is expressed by blood vessel cells in an attempt to recruit immune cells, can bolster an immunosuppressive response in the body and calm inflammation in the brain in models of multiple sclerosis (MS).

In a paper published today in the journal Frontiers in Molecular Neuroscience, Dr. Quandt and collaborators at the National Institutes of Health (NIH) show that administering E-selectin intranasally, rather than as an infusion or a pill, reduced damage in the brain and spinal cord associated with autoimmune “attacks” like those thought to drive MS disability progression. Intranasal administration of E-selectin has been used in models of stroke, vascular cognitive dementia, and atherosclerosis, but this is the first time it has been used to mitigate inflammation in a model of MS.

“Applying the treatment intranasally activates an immunosuppressive response in the body whenever and presumably wherever E-selectin is seen, which occurs most often when there is acute inflammation in tissue; however, the process doesn’t act by shutting down E-selectin-mediated immune cell recruitment completely,” says Dr. Quandt. “That could be rather risky, and may have side effects similar to what we have seen in MS patients with other attempts to fully eliminate immune cell activity or recruitment. We have to remember that immune responses are key to protecting against bacteria or viruses and that our goal in diseases such as MS is primarily to modify immune responses without fully eliminating them, wherever possible. Inflammation is typically a healthy response to injury as it mediates repair.”

“When we see just about any protein entering the body through the nasal or oral mucosa, our body doesn’t typically give the message to fight it—otherwise we would react to almost everything we breathe in or eat. Instead, years of research have shown that giving a protein this way instead generates a more ‘regulatory’ type of immune response,” explains Dr. Quandt.

“As a result, when we administer E-selectin mucosally, we generate T-cells that are specific and proliferate in response to E-selectin, but as they do they produce immunosuppressive cytokines which have the potential to limit inflammation and thereby reduce tissue damage in the brain.”

T-cells are white blood cells that typically mediate the responses that drive both antibody and cell-mediated killing of specific bacteria or viruses. Inflammation occurs as a response to infection or injury, but when we don’t eliminate pathogens effectively in a short period of time, inflammation becomes chronic.

Chronic inflammation is thought to be a primary driver in many chronic diseases including several autoimmune disorders; it can cause damage to healthy tissues and, in MS, to axons, neurons and other important cells in the brain. When E-selectin is introduced through nasal tissue, the body learns to tolerate the protein and instead of trying to destroy it, when we see it again we instead produce factors that reduce inflammation. The phenomenon is called “immune tolerance” and plays a critical role in tempering immune responses.

MS is an autoimmune disorder in which the body’s immune system attacks myelin, the insulating layer around nerves in the brain and spinal cord, causing deterioration of motor and cognitive function. By moderating the immune system and reducing autoimmune attacks, the researchers believe they can prevent or slow disability progression and calm inflammation that would otherwise damage healthy tissue. E-selectin has been shown to be increased in serum of MS patients as they undergo an attack or relapse, particularly in patients experiencing the especially aggressive form of disease known as primary progressive MS.

“This is an approach that has been tested and found effective in a range of preclinical models,” says Dr. Quandt. “We’re hoping that this more refined approach to limiting inflammation will be effective in halting neurodegeneration and disability progression in MS.”

Dr. Hallenbeck's laboratory has long studied the cellular regulation of ischemic tolerance and inflammatory and immune mechanisms in the initiation and progression of stroke.

“Given our original discoveries showing the efficacy of this approach in stroke models, it has been particularly exciting to see the expanding promise of E-selectin tolerization in other vascular and inflammatory disorders of the nervous system," said Dr. Hallenbeck. "This promise only increases as we further our understanding  of the breadth of mechanisms that ultimately may afford future clinical benefits."