Immune activation in ALS is multifaceted, with both beneficial and harmful aspects. Therefore, we think specific pathways should be targeted instead of the whole response. One cautionary tale is the clinical trial of minocycline, which blocks microglia activation. It resulted in surprising acceleration of disease progression in patients.

In the spinal cord, the motor neuron cell body is affected by microglia, the resident immune cell of the central nervous system (CNS). A large part of the microglia response may be beneficial to motor neurons. We found that microglia secrete protective factors, including insulin-like growth factor 1 and progranulin. At the same time, we have found that there is also an important peripheral immune component involving adaptive immune cells such as T cells and NK cells, humoral immunity (complement and antibodies), and innate immunity including circulating monocytes, which enter the peripheral nerves to become inflammatory macrophages. We believe these nerve-infiltrating macrophages may be inhibitory to motor axon growth that would in turn be...  Read more

Immune activation in ALS is multifaceted, with both beneficial and harmful aspects. Therefore, we think specific pathways should be targeted instead of the whole response. One cautionary tale is the clinical trial of minocycline, which blocks microglia activation. It resulted in surprising acceleration of disease progression in patients.

In the spinal cord, the motor neuron cell body is affected by microglia, the resident immune cell of the central nervous system (CNS). A large part of the microglia response may be beneficial to motor neurons. We found that microglia secrete protective factors, including insulin-like growth factor 1 and progranulin. At the same time, we have found that there is also an important peripheral immune component involving adaptive immune cells such as T cells and NK cells, humoral immunity (complement and antibodies), and innate immunity including circulating monocytes, which enter the peripheral nerves to become inflammatory macrophages. We believe these nerve-infiltrating macrophages may be inhibitory to motor axon growth that would in turn be harmful to motor neurons.

Gilenya blocks S1P receptors, which are involved in lymphocyte migration from lymph nodes into the CNS. The drug has a beneficial effect in multiple sclerosis. What is interesting is that Gilenya also has an effect on monocyte-endothelial cell adhesion. It would be interesting to know if blocking S1P receptors prevents monocyte/macrophage entry into peripheral nerve tissues during ALS neurodegeneration. We hypothesize this action may be protective. If Gilenya is purely blocking T cells from entering the CNS, we would be careful as Dr. Stan Appel's and our work has shown that, at least in ALS mice, T cells are mainly neuroprotective. It would be interesting to see their preclinical data to determine which cell types are most affected in Gilenya treatment. Of course, the other very important point to keep in mind is that mutant SOD1 mice are not ALS patients, and therefore the type of immune response in patients may also differ from what we see in inbred mice.

Overall, I am excited that ALSTDI and others are bringing neuroimmune interactions to the forefront of possible mechanisms involved in ALS, especially in the arena of therapeutic development. This will be the first trial specifically targeting peripheral immune cells, so I eagerly await their results to see the effects. I believe this will be an important element affecting motor neuron survival, especially in the symptomatic phase of disease.

View all comments by Isaac Chiu