May 28, 2015
MS Society-funded research uncovers a promising new therapeutic target for preventing immune cell invasion of the brain
Many different types of immune cells are thought to contribute to the development of multiple sclerosis (MS). While some have firmly established roles, others are still hotly debated. One of these mysterious types is a group of immune cells called CD8+ T lymphocytes (T cells). While present in MS lesions, their function – whether as proinflammatory agents or immune suppressors – is unclear. Recent evidence points towards a disease-causing role for CD8+ T cells; however, researchers are still trying to determine how these cells cross the blood-brain barrier (BBB) to access the central nervous system and cause inflammation.
A group at Université de Montréal led by MS Society-funded research Dr. Alexandre Prat investigated whether a protein on the surface of CD8+ T cells called melanoma cell adhesion molecule (MCAM) facilitates the entry of these harmful immune cells into the central nervous system. Their work was published in the journal Annals of Neurology.
The researchers first established whether CD8+ T cells possess MCAM on their surface in post mortem brains of individuals with relapsing-remitting MS. They also measured the percentage of MCAM-positive CD8+ T cells in the blood of MS donors.
The researchers next used a number of cell culture experiments to determine how MCAM affected the behavior of CD8+ T cells. They tested whether MCAM-containing CD8+ T cells were 1) better at passing through cells of the BBB, 2) toxic to oligodendrocytes (cells that produce the myelin that wraps around nerve fibres and is attacked during MS) and, 3) releasing molecules that are pro-inflammatory and toxic to other cells.
The researchers then explored whether MCAM-positive CD8+ T cells contributed to the development of an MS-like disease in animals. To this end, mice were injected with either MCAM-positive or MCAM-depleted CD8+ T cells that were pre-programmed to attack myelin. In both cases mice developed an MS-like disease, and its severity (assessed by measuring tail and limb disability) was compared between the two groups.
To test the potential benefit of blocking the binding of MCAM to the BBB, the researchers administered a blocking molecule to mice with a progressive MS–like disease. The mice were divided into two groups: one group was given the molecule before the onset of disease symptoms; the other after disease onset.
MCAM-expressing CD8+ T cells were identified in the brains of individuals with relapsing remitting MS, both in and around active lesions. Levels also spiked in the blood of relapsing-remitting MS donors during a relapse period.
In cell culture, MCAM-positive CD8+ T cells bound to and penetrated cells of the BBB with more efficiency than MCAM-negative cells, were toxic to myelin-producing oligodendrocytes, and produced a number of pro-inflammatory and cell-toxic molecules.
MS-like symptoms were slower to develop and less severe in mice injected with MCAM-depleted CD8+ T cells. Likewise, an MCAM-blocking molecule reduced disease severity in mice with an MS-like disease. An important observation was that the MCAM-blocking molecule was effective whether administered before or after disease onset.
This study demonstrates that MCAM can be found on pro-inflammatory CD8+ T cells and allows them to pass through cells of the BBB, drive inflammation and destroy myelin-producing oligodendrocytes. There also appears to be a strong correlation between the presence of MCAM and the severity of MS symptoms, making the results from the MCAM-blocking experiments extremely encouraging.
MCAM is also found on pro-inflammatory CD4+ T cells, another group of immune cells known to play a role in the development of MS. Blocking MCAM would therefore potentially limit the ability of both pro-inflammatory CD4+ and CD8+ T cells to cross the BBB and cause disease within the brain.
Blocking MCAM also reduced disease severity in mice with an MS-like disease, regardless of whether the therapeutic blocking molecule was given before or after the onset of symptoms. As noted by the authors, these results suggest that MCAM-blocking molecules could provide a novel therapeutic to control long-term disability in MS, possibly halting disease progress from the very first symptoms. Further testing will be needed, however, if we are to begin translating therapeutics from mice to humans.
Larochelle C et al. (2015). Melanoma cell adhesion-molecule positive CD8 T lymphocytes mediate central nervous system inflammation. Annals of Neurology. DOI:10.1002.