This article elegantly shows the strength of transcriptome analysis for the rapid discovery of a new drug. In this study, the authors identified the therapeutic potential of modulating CD40L in ALS using an animal model.

Through transcriptome analysis, this group identified the upregulation of CD40L-related pathway in three tissues that are all relevant to motor neuron degeneration: muscle, spinal cord, and sciatic nerve. This signaling pathway related to CD40L activation became more prominent as the disease progressed; this finding justifiably led the investigators to test its implication to therapy. The therapeutic potential was tested in mSOD1 mice, and anti-CD40L was found to be effective with respect to both disease onset and progression. The authors compared the results to those observed in inflammatory diseases and, based on Mac-1 expression and T cell activation, suggested that the therapy acts in the animal model of mSOD1 as anti-inflammatory treatment; such a conclusion should be taken with caution, and more so when it comes to clinical translation.

CD40L was...  Read more

This article elegantly shows the strength of transcriptome analysis for the rapid discovery of a new drug. In this study, the authors identified the therapeutic potential of modulating CD40L in ALS using an animal model.

Through transcriptome analysis, this group identified the upregulation of CD40L-related pathway in three tissues that are all relevant to motor neuron degeneration: muscle, spinal cord, and sciatic nerve. This signaling pathway related to CD40L activation became more prominent as the disease progressed; this finding justifiably led the investigators to test its implication to therapy. The therapeutic potential was tested in mSOD1 mice, and anti-CD40L was found to be effective with respect to both disease onset and progression. The authors compared the results to those observed in inflammatory diseases and, based on Mac-1 expression and T cell activation, suggested that the therapy acts in the animal model of mSOD1 as anti-inflammatory treatment; such a conclusion should be taken with caution, and more so when it comes to clinical translation.

CD40L was originally described on T lymphocytes; its expression has since been detected on a wide variety of cells, including platelets, mast cells, macrophages, basophils, NK cells, B lymphocytes, as well as non-hematopoietic macrophages. Primarily, in its bound form, CD40L serves as a self-controlling, co-stimulatory molecule; thus, it acts as a mechanism of prevention of unnecessary lymphocyte activation and works at multiple levels. CD40L allows full immune cell activation, prevents anergy or apoptosis, induces differentiation to effector or memory status, sustains cell proliferation, and allows cell-cell crosstalk and cooperation. Therefore, neutralizing CD40L might lead to different effects at different stages of the disease. Moreover, its mechanism of action may be critically affected by the dosing, resulting in an effect suggestive of Dr. Jekyll and Mr. Hyde. This situation is very much reminiscent of minocycline in ALS, which showed similar efficacy in animal models of mSOD1 and failed in human trials. The case of minocycline might represent a general phenomenon with respect to the use of anti-inflammatory therapies in ALS. Such therapies are beneficial in inflammatory diseases such as multiple sclerosis, and, in their relevant animal model, experimental autoimmune encephalomyelitis (EAE). As opposed to ALS, these diseases are inflammatory in their etiology, whereas ALS is characterized by local inflammation, but is not considered an inflammatory disease. Moreover, elevated CD40L in mSOD1 mice might represent beneficial attempts to cope with the disease that are not sufficiently controlled. Therefore, blockage of CD40L may have a beneficial phase/effect/outcome at certain disease stages, but not in a blanket way. Thus, targeting a co-stimulatory molecule as a therapeutic approach may interrupt essential beneficial immune responses in addition to targeting the disease process.

View all comments by Michal Schwartz

Against the backdrop of sometimes disappointing results from genomewide association studies of the transcriptome (GWAS-T), the work by Lincecum and colleagues represents a triumph for this approach. The authors applied transcriptome analysis to the high-copy SOD1 transgenic mouse model of ALS. Importantly, they thoroughly investigated central and peripheral tissues from SOD1 mice at timepoints prior to, during, and after disease onset. Their GWAS-T results pointed to co-stimulatory immune and inflammatory molecules as being centrally associated with ALS-like pathology in this system, and they utilized a sophisticated statistical algorithm to arrive at the CD40-CD40L interaction as a candidate treatment target. They then treated SOD1 mice with a neutralizing CD40L antibody and found benefit by virtually any index of ALS-like disease: the biologic therapy improved body weight maintenance and survival, reduced inflammatory lesions, decreased motor neuron loss, and attenuated expression of immune co-stimulatory genes.

I read this work with enthusiasm and excitement, because over...  Read more

Against the backdrop of sometimes disappointing results from genomewide association studies of the transcriptome (GWAS-T), the work by Lincecum and colleagues represents a triumph for this approach. The authors applied transcriptome analysis to the high-copy SOD1 transgenic mouse model of ALS. Importantly, they thoroughly investigated central and peripheral tissues from SOD1 mice at timepoints prior to, during, and after disease onset. Their GWAS-T results pointed to co-stimulatory immune and inflammatory molecules as being centrally associated with ALS-like pathology in this system, and they utilized a sophisticated statistical algorithm to arrive at the CD40-CD40L interaction as a candidate treatment target. They then treated SOD1 mice with a neutralizing CD40L antibody and found benefit by virtually any index of ALS-like disease: the biologic therapy improved body weight maintenance and survival, reduced inflammatory lesions, decreased motor neuron loss, and attenuated expression of immune co-stimulatory genes.

I read this work with enthusiasm and excitement, because over a decade ago we demonstrated that pharmacologic or genetic blockade of CD40-CD40L interaction mitigated AD-like pathology in transgenic mouse models of the disease. This included reduction of: abnormal tau proteins, cerebral amyloidosis, brain inflammation including gliosis, and behavioral impairment (Tan et al., 1999; Tan et al., 2002). At that time, many in the field of AD research were unwilling to accept that the immune system played any role in the pathogenesis of AD, let alone that immune molecules could be targeted for AD treatment. It is terribly exciting that these authors have extended the concepts that we were exploring vis-à-vis CD40-CD40L in AD to another key neurodegenerative disease: ALS. I hope that the authors are able to successfully translate their findings to the clinical syndrome.

References:
Tan J, Town T, Paris D, Mori T, Suo Z, Crawford F, Mattson MP, Flavell RA, Mullan M. Microglial activation resulting from CD40-CD40L interaction after beta-amyloid stimulation. Science. 1999 Dec 17;286(5448):2352-5. Abstract

Tan J, Town T, Crawford F, Mori T, DelleDonne A, Crescentini R, Obregon D, Flavell RA, Mullan MJ. Role of CD40 ligand in amyloidosis in transgenic Alzheimer's mice. Nat Neurosci. 2002 Dec;5(12):1288-93. Abstract

View all comments by Terrence Town

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