Animal Models To Study NMO and TM

Clinicians and scientists use a variety of tools to study rare diseases. Collecting data and specimens from patients is critical to understanding TM and NMO, but to understand the basic biology of a condition, scientists commonly use animal models of the disease. To date, there are no accepted animal models of idiopathic transverse myelitis (TM) or neuromyelitis optica (NMO). For decades, however, there has been an experimental model of multiple sclerosis called experimental autoimmune encephalomyelitis (EAE). This model is imperfect and does not completely replicate MS, but has been useful for a variety of experiments. In humans, MS, TM and NMO are thought to be caused by an immune system that targets the brain, optic nerve or spinal cord by accident. In EAE, a mouse’s immune system is primed to target the brain, optic nerve or spinal cord.  In humans, different parts of the immune system (for example B-cells and T-cells) play critical but variable roles in the pathogenesis of MS, TM and NMO.

EAE can be triggered by immunizing mice with myelin antigens¹. Antigens¹ are anything that triggers the immune system to produce antibodies² against it. The antigens¹ that target myelin used in EAE include myelin basic protein (MBP), proteolipid protein (PLP), and myelin oligodendrocyte glycoprotein (MOG). EAE causes demyelination in the brains and spinal cords of animals. Traditionally, studies have indicated that T-helper cells³ are a key component in EAE, but it is unclear the role B-cells⁴ play in EAE. In mice, when stimulated, there tends to be activation of T-cells or B-cells, but there is usually not a strong activation of both simultaneously.

In their 2006 article, Bettelli et al described a mouse model that triggered EAE in a majority (59%) of mice with B-cells⁴ and T-cells³ that were MOG-specific. In this model, unlike others, BOTH strongly primed B and T cells were generated in the mouse simultaneously. To get this mouse model, mice expressing T-cells³ that target the myelin antigen MOG were crossed (bred) with mice that have B cells⁴ that produce antibodies against the myelin antigen MOG. These crossed mice developed EAE on average 44.1 days after birth and the mortality rate was 10%. Furthermore, this mouse model showed more inflammatory lesions that were concentrated in the spinal cord and optic nerves. These mice had inflammatory lesions in the spinal cord and optic nerve, but not the brain, which mimics the lesion pattern seen in Neuromyelitis Optica (NMO). In this mouse model T-cells³ and B-cells⁴ cooperated to create this NMO-like disease. The MOG-specific T-cells³ helped produce a large amount of a MOG-specific antibody², and the MOG-specific B-cells⁴ helped the T-cells³ propagate and activate.

The authors stated that the combination of the increased production of the antibodies² and the MOG-specific T-cell³ response might have created the EAE in the mice. It is also unclear why these mice developed an NMO-like lesion distribution, but the authors noted that there was more MOG RNA in the optic nerve than in the spinal cord, and more MOG RNA in the spinal cord than the brain, which may account for why lesions are located in the optic nerve and spinal cord in this model.

This article describes a phenotype in a mouse that looked eerily similar to NMO, but was not based on anti-Aquaporin 4 pathology (the proposed model of disease in NMO). Since its publication there have been articles documenting an NMO-like phenotype in humans with anti-MOG antibodies. Thus, while this mouse model may not be applicable to patients with anti-AQP4 antibodies, it may be useful to model an NMO-like disease that is based on a different antigen. What this model reminds us about is the ability of two different patients (or animals in this case) to have very similar conditions, but different causes. This will be true for NMO, TM and even MS. Animal models are useful for numerous things. Developing a reliable model for TM will be helpful in advancing the field.

Definitions (from NIH)

1. Antigen- An antigen is any substance that causes your immune system to produce antibodies against it. An antigen may be a foreign substance from the environment, such as chemicals, bacteria, viruses, or pollen. An antigen may also be formed inside the body, as with bacterial toxins or tissue cells.

2. Antibodies- An antibody is a protein produced by the body’s immune system when it detects harmful substances, called antigens. Examples of antigens include microorganisms (bacteria, fungi, parasites, and viruses) and chemicals. Antibodies may be produced when the immune system mistakenly considers healthy tissue a harmful substance (autoimmune disorder).

3. T cell- T cells are a type of lymphocyte. Lymphocytes are white blood cells. T cells help the body fight diseases or harmful substances by attacking cells that have been tagged with antibodies. 

4. B cell- B cells are a type of lymphocyte. They make up part of the immune system. B cells work chiefly by secreting substances called antibodies into the body’s fluids.

Original publication: Bettelli E, Baeten D, Jäger A, Sobel RA, Kuchroo VK. Myelin oligodendrocyte glycoprotein–specific T and B cells cooperate to induce a Devic-like disease in mice. J Clin Invest. 2006;116(9): 2393-402.