New Primate Model Can Shed Light on Mechanisms Underlying Myelin Loss

A new primate model uncovered by researchers can help scientists understand the immune and inflammatory processes underlying the development of multiple sclerosis (MS) in humans, a study reports.

It was already known that Japanese macaques — also called snow monkeys — can spontaneously develop encephalomyelitis (JME), a disorder that results in the progressive destruction of myelin. The myelin, the fatty protective sheath that wraps around nerve fibers, is destroyed in the macaques in a process known as demyelination, much like occurs with MS in humans.

Yet, after examining the animals’ lesions, investigators have now discovered two types of immune T-cells that were primed to attack myelin sheath components. These T-cells also have been identified as drivers of inflammation in MS.

“These novel findings draw further parallels between JME and MS, and demonstrate that JME can serve as an outstanding [primate] model to investigate mechanisms that lead to an IDD [inflammatory demyelinating disease],” the investigators wrote.

Their findings were reported in the study, “Myelin‐specific T cells in animals with Japanese macaque encephalomyelitis,” published in the journal Annals of Clinical and Translational Neurology.

MS is an autoimmune disease caused by the immune system wrongly attacking the myelin sheath in nerve fibers. In humans, this process is thought to be driven by different types of immune cells that have been identified in MS lesions, including antibody-producing B-cells and several subtypes of killer T-cells.

Yet, the exact mechanisms underlying inflammation and myelin destruction by the body’s immune system are still poorly understood.

Over the years, scientists have sought to investigate these mechanisms by studying animal models. The mouse model of encephalomyelitis — experimental autoimmune encephalomyelitis, or EAE — is the most widely used MS model and has been one of the major contributors in the field.

However, the facts that these animals do not spontaneously develop EAE and have limited genetic diversity have made it difficult at times for scientists to draw parallels between EAE and MS.

“New animal models that mimic the pathophysiology [disease mechanisms] of MS will greatly aid in understanding how MS is initiated and will accelerate the development of novel MS therapies,” the investigators wrote.

“One model that could facilitate this is the spontaneous Japanese macaque encephalomyelitis (JME) model,” they wrote.

These animals, which were discovered by chance at the Oregon National Primate Research Center (ONPRC), can spontaneously develop a demyelinating disorder that bears some similarities with MS.

Previous studies also have linked JME with a viral infection by a new gamma‐herpesvirus, known as the Japanese macaque rhadinovirus (JMRV). This fact may be another similarity with MS in humans, since certain viral infections also have been proposed to act as potential disease triggers.

Moreover, this observation also opened the possibility of using these animals to develop and test new antiviral therapies that could be particularly useful to treat those with newly diagnosed MS.

“If we found a unique virus that we believed was causing MS, then you could in theory come up with a vaccine against that virus,” Dennis Bourdette, MD, study’s co-author and professor emeritus and former chair of neurology at the Oregon Health & Science University (OHSU) School of Medicine, said in a press release.

Yet, some aspects of JME, particularly its acute nature, has led some investigators to argue these animals were better suited to model other demyelinating disorders.

Now, a group of investigators at OHSU reported evidence that further highlighted the similarities of JME and MS, cementing the idea that these animals could be a promising primate model of MS.

The team isolated immune cells from demyelinating lesions in the animals’ central nervous system (CNS; composed by the brain and spinal cord), and found two distinct populations of killer T-cells, known as CD4-positive and CD8-positive T-cells. Such designations mean the T-cells have CD4 or CD8 receptors on their surface. Importantly, these cells also have been identified as drivers of inflammation in MS patients.

Researchers also discovered these immune T-cells had been primed to attack different myelin sheath components, namely the myelin oligodendrocyte glycoprotein (MOG), the myelin basic protein (MBP), and the proteolipid protein (PLP).

Moreover, the team found some of the epitopes — small protein fragments, also known as antigens — directing these cells to attack different myelin components were identical to those found in human patients, drawing yet another parallel between JME and MS.

In their final experiments, the researchers compared protein sequences from the JMRV to myelin antigens. The point of this experiment was to investigate if immune cells primed to attack viral sequences also could be attacking myelin components by mistake, due to their high degree of similarity.

The data revealed that although there were some similarities in some of the sequences, the small peptide portions that were found to be identical failed to activate immune cells and trigger an immune response, suggesting “JME and possibly MS are triggered by mechanisms involving myelin damage and not myelin epitope mimicry.”

The researchers said that future studies should focus on investigating the “triggers that precipitate JME development and progression, as understanding how disease initiates could lead to discovery of mechanisms driving MS.”