T Cells to the Rescue
During inflammation, two parts of the immune system, the "innate" and the "adaptive," work hand in hand to defend against invading pathogens. The brain is harboring its own innate immune cells called glia cells, and these cells are activated in many neurodegenerative diseases such as ALS or Alzheimer disease. The activation of the brain's own innate immune cells is a double-edged sword. It can lead to neuroprotection, and frequently does so in acute injuries such as trauma or stroke. In a more chronic setting, such as neurodegenerative disease, the innate immune activation leads mainly to a detrimental outcome. The recent publication of the Appel lab now showed that a specific type of peripheral adaptive immune cells, the CD4+ T cells, enter the central nervous system in the mouse model of ALS. Once there, they seem to reprogram the local innate immune response. This leads to a more protective environment for the motor neurons, the cell type dying off in this dreadful disease. What is so astonishing about this finding is that the CD4+ cells only...  Read more

T Cells to the Rescue
During inflammation, two parts of the immune system, the "innate" and the "adaptive," work hand in hand to defend against invading pathogens. The brain is harboring its own innate immune cells called glia cells, and these cells are activated in many neurodegenerative diseases such as ALS or Alzheimer disease. The activation of the brain's own innate immune cells is a double-edged sword. It can lead to neuroprotection, and frequently does so in acute injuries such as trauma or stroke. In a more chronic setting, such as neurodegenerative disease, the innate immune activation leads mainly to a detrimental outcome. The recent publication of the Appel lab now showed that a specific type of peripheral adaptive immune cells, the CD4+ T cells, enter the central nervous system in the mouse model of ALS. Once there, they seem to reprogram the local innate immune response. This leads to a more protective environment for the motor neurons, the cell type dying off in this dreadful disease. What is so astonishing about this finding is that the CD4+ cells only need to enter in a small number to produce a big effect. While still in early stages of discovery, this venue of research might open new ways for neuroprotection in ALS and other neurodegenerative diseases.

View all comments by Thomas Moeller

Amyotrophic lateral sclerosis (ALS) and Alzheimer’s might share important pathogenic pathways, and discoveries in one of these diseases or its animal models could therefore be important for the understanding of the other. Although considered a typical neurodegenerative disease mainly affecting motorneurons, ALS is often accompanied by T cell infiltration in the corticospinal tracts of patients. The significance of this T cell infiltration is not known. However, T cells have been demonstrated to secrete neurotrophic factors, and infusion of T cells specific for a myelin antigen has been demonstrated to protect against neurodegeneration after crush injury to the optic nerve and spinal cord (2).

In the current paper, the authors addressed the significance of CD4+ T cells in mice overexpressing mutant Cu2+/Zn2+ superoxide dismutase (mSODG93A), a widely used animal model for ALS. The mSODG93A mice develop a disease with many similarities to ALS, including T cell infiltration in the spinal cord. In this study, mSODG93A mice were bred with mice lacking recombination-activating gene...  Read more

Amyotrophic lateral sclerosis (ALS) and Alzheimer’s might share important pathogenic pathways, and discoveries in one of these diseases or its animal models could therefore be important for the understanding of the other. Although considered a typical neurodegenerative disease mainly affecting motorneurons, ALS is often accompanied by T cell infiltration in the corticospinal tracts of patients. The significance of this T cell infiltration is not known. However, T cells have been demonstrated to secrete neurotrophic factors, and infusion of T cells specific for a myelin antigen has been demonstrated to protect against neurodegeneration after crush injury to the optic nerve and spinal cord (2).

In the current paper, the authors addressed the significance of CD4+ T cells in mice overexpressing mutant Cu2+/Zn2+ superoxide dismutase (mSODG93A), a widely used animal model for ALS. The mSODG93A mice develop a disease with many similarities to ALS, including T cell infiltration in the spinal cord. In this study, mSODG93A mice were bred with mice lacking recombination-activating gene 2 (RAG2), which is needed for developing functional T cells and B cells. The mSODG93A/RAG2-/- mice developed more rapidly evolving disease than mSODG93A mice. In contrast to mSODG93A with functional lymphocytes, no T cell infiltration occurred in the spinal cords of the mSODG93A/RAG2-/- mice. In a series of elegant experiments with bone marrow transplantation, the authors showed that infiltrating CD4+ T cells are neuroprotective and responsible for prolonged disease duration and survival. Bone marrow transplantation also restored the CD4+ T cell expression of neurotrophic factors. Concordant data was obtained with bone marrow transplantation to mSODG93A mice from mice lacking chemokine receptor 2 (CCR2), which is needed for T cell attraction. The infiltrating lymphocytes were CD4+ T helper cells; no B cells were observed and CD8+ cytotoxic T cells were only observed at very late stages.

How do these highly convincing data translate to human disease? This question is open to speculation, and although it is tempting to believe that the T cell infiltration observed in ALS patients is part of a reparative response to neurodegeneration, there are currently no observations in humans indicating that immune dysregulation plays a primary role in the development of ALS. T cell infiltration during early phases of ALS is extremely difficult to address, and has so far not been studied (3). Nevertheless, T cell-based therapies with glatiramer acetate (GA), an immunomodulator widely used for the treatment of multiple sclerosis, has been investigated in preclinical and early clinical trials in ALS (4,5). This drug induces an anti-inflammatory phenotype and production of substantial amounts of brain-derived nerve growth factor (BDNF) in GA-reactive T cells (6). Although the results of this therapy in humans have so far been disappointing, the results provided by Beers et al. support that T cells may be therapeutic targets in ALS. Moreover, it provides new molecular insight into the expanding field of protective immunology, showing that the T cells are not always the bad guys.

References:
1 McGeer PL, McGeer EG. Inflammatory processes in amyotrophic lateral sclerosis. Muscle Nerve. 2002 Oct;26(4):459-70. Abstract

2. Moalem G, Leibowitz-Amit R, Yoles E, Mor F, Cohen IR, Schwartz M. Autoimmune T cells protect neurons from secondary degeneration after central nervous system axotomy. Nat Med. 1999 Jan;5(1):49-55. Abstract

3. Holmøy T. T cells in amyotrophic lateral sclerosis. Eur J Neurol. 2008 Apr;15(4):360-6. Abstract

4. Gordon PH, Doorish C, Montes J, Mosley RL, Mosely RL, Diamond B, Macarthur RB, Weimer LH, Kaufmann P, Hays AP, Rowland LP, Gendelman HE, Przedborski S, Mitsumoto H. Randomized controlled phase II trial of glatiramer acetate in ALS. Neurology. 2006 Apr 11;66(7):1117-9. Abstract

5. Habisch HJ, Schwalenstöcker B, Danzeisen R, Neuhaus O, Hartung HP, Ludolph A. Limited effects of glatiramer acetate in the high-copy number hSOD1-G93A mouse model of ALS. Exp Neurol. 2007 Aug;206(2):288-95. Abstract

6. Chen M, Valenzuela RM, Dhib-Jalbut S. Glatiramer acetate-reactive T cells produce brain-derived neurotrophic factor. J Neurol Sci. 2003 Nov 15;215(1-2):37-44. Abstract

View all comments by Trygve Holmoy

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