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

I understand that further animal toxicity studies are in progress. However, over 100 patients have received intracerebral GDNF infusion by one route or another with no clinical toxicity and I can't believe that GDNF treatment won't be available again, at least in some form, in the medium term. To date, the immunogenicity of the recombinant GDNF has not proven to be of clinical significance, but could in any case be circumvented by implantation of autologous or encapsulated eukaryotic cells, genetically modified to secrete GDNF. Stimulating metabolic pathways that induce the synthesis of GDNF sounds attractive but poses problems of targeting, delivery, and specificity. I suggest that this is a less promising option, but would be happy to be proven wrong.

View all comments by Seth Love

The report by Love and colleagues in Nature Medicine provides intriguing preliminary evidence for a biological effect of GDNF in humans with Parkinson disease. The greater area of staining for tyrosine hydroxylase in the striatum on the side previously most affected by Parkinson disease suggests that GDNF stimulated neuronal sprouting and that this accounted for the increase in fluorodopa uptake seen on positron emission tomography. These observations are exciting but leave many unanswered questions. Is the change in striatal tyrosine hydroxylase and fluorodopa PET sufficient to account for the 38 percent reduction (i.e., improvement) in motor scores? Even more impressive changes in both of these parameters are seen following fetal nigral transplantation, but clinical benefit has been disappointing in double-blind placebo-controlled trials. Love and colleagues present additional results of GFAP and GAP43 immunohistochemistry; however, similar control data from normal and untreated parkinsonian brains were not provided for comparison. Finally, although the results are potentially...  Read more

The report by Love and colleagues in Nature Medicine provides intriguing preliminary evidence for a biological effect of GDNF in humans with Parkinson disease. The greater area of staining for tyrosine hydroxylase in the striatum on the side previously most affected by Parkinson disease suggests that GDNF stimulated neuronal sprouting and that this accounted for the increase in fluorodopa uptake seen on positron emission tomography. These observations are exciting but leave many unanswered questions. Is the change in striatal tyrosine hydroxylase and fluorodopa PET sufficient to account for the 38 percent reduction (i.e., improvement) in motor scores? Even more impressive changes in both of these parameters are seen following fetal nigral transplantation, but clinical benefit has been disappointing in double-blind placebo-controlled trials. Love and colleagues present additional results of GFAP and GAP43 immunohistochemistry; however, similar control data from normal and untreated parkinsonian brains were not provided for comparison. Finally, although the results are potentially important in demonstrating a biological effect of this treatment, they also raise questions about the early and bilaterally symmetrical clinical benefit reported following open-label unilateral infusion by Slevin et al., since Love’s patient showed very clear progression on the non-infused side.

The double-blind placebo-controlled trial failed to demonstrate significant efficacy of bilateral intraputamenal GDNF infusion. Importantly, this trial utilized a different catheter and somewhat different doses than were used in the patient reported by the Bristol group. It is not known whether these differences could account for the contrasting results of the open-label and double-blind studies. In addition, a similar change in fluorodopa PET to that originally reported by Gill and colleagues) was obtained in the double-blind trial despite the lack of benefit. During this trial and its open-label extension, 10 percent of patients developed blocking antibodies to GDNF, and subsequently, studies in primates demonstrated evidence for an unusual cerebellar toxicity. The clinical implications of these two findings for humans with Parkinson disease are unknown. In the face of a negative double-blind clinical trial and the development of these safety issues, Amgen chose to discontinue further use of this treatment in Parkinson disease. Subsequently, two patients from New York took the company to court demanding that continued treatment with GDNF be made available to them. The court found in favor of Amgen and the lawsuit was dismissed. Unfortunately, the current formulation of recombinant GDNF as manufactured by Amgen will probably not be used again in patients with Parkinson disease unless further basic studies can resolve these potentially important safety issues. It is hoped that other trophic factors or other methods of applying GDNF (e.g., gene therapy or cell-based therapies) will fulfill the promise of this approach in Parkinson disease. Finally, it should be emphasized that many of the problems we face in managing late-stage Parkinson disease do not stem from striatal dopamine deficiency, and therefore would not be expected to respond to even the most effective rejuvenation or replacement of the nigrostriatal dopamine system.

References:
Slevin JTGGA, Smith CD, Gash DM, Kryscio R, Young AB. Improvement of bilateral motor functions in patients with Parkinson disease through the unilateral intraputamenal infusion of glial cell line-derived neurotrophic factor. J Neurosurg. 2005 Feb;102(2):216-22. Abstract

View all comments by Anthony Lang

The findings reported by Dr. Love, while having some overlap with the tissue transplant studies, show significant differences, particularly with regard to neuronal resprouting and also to the involvement of the substantia nigra. It seems likely that GDNF does not generate new neurons but restores existing neurons and their extensive arborization. Since these existing neurons are capable of making postsynaptic connections, the dopamine can get where it needs to. Presumably, fetal tissue is unable to make synaptic connections, possibly because of a lack of signaling proteins like GDNF.

However, two enduring myths continue to surface.

First, that the double-blind trial of GDNF was "negative." It was not. While it is correct to say that it failed to meet its preset endpoints, nevertheless, unlike the tissue transplant study, there was a strong signal suggestive of drug efficacy, which is why Amgen continued to prepare for a proper phase III study even after announcing the phase II results.

Second, that there continue to be "safety issues," specifically regarding the...  Read more

The findings reported by Dr. Love, while having some overlap with the tissue transplant studies, show significant differences, particularly with regard to neuronal resprouting and also to the involvement of the substantia nigra. It seems likely that GDNF does not generate new neurons but restores existing neurons and their extensive arborization. Since these existing neurons are capable of making postsynaptic connections, the dopamine can get where it needs to. Presumably, fetal tissue is unable to make synaptic connections, possibly because of a lack of signaling proteins like GDNF.

However, two enduring myths continue to surface.

First, that the double-blind trial of GDNF was "negative." It was not. While it is correct to say that it failed to meet its preset endpoints, nevertheless, unlike the tissue transplant study, there was a strong signal suggestive of drug efficacy, which is why Amgen continued to prepare for a proper phase III study even after announcing the phase II results.

Second, that there continue to be "safety issues," specifically regarding the antibodies and the cerebellar lesions seen in four monkeys. There is now overwhelming evidence that the lesions were caused not by direct toxicity, but by abrupt withdrawal from very high concentrations of GDNF. Regarding the antibodies, these occur with the injection of just about any protein, and were expected in this study. Life-threatening complications are extremely rare. Indeed, we have it on good authority that senior officials at Amgen, who were in a position to speak authoritatively on this topic, did not consider them at all problematic.

Thus, the present formulation of GDNF is safe and also very probably effective.

View all comments by Michael Hutchinson

In the recent papers from the groups of Przedborski and Eggan, provocative evidence is reported that spinal motor neurons may die in SOD1 mutant mice because of soluble toxic factors released by SOD1 mutant astrocytes. This result is surprising because previous studies with chimeric SOD1 mutant mice have shown that expression of mutant SOD1 in microglia but not astrocytes is implicated in the neuron death. However, profound reactive astrocytosis occurs very early in mouse and human motor neuron diseases. This is true in the SOD1 mutant mice, where reactive astrocytosis is a dramatic feature of the disease, with prominent reactive astrocytosis occurring long before much motor neuron death occurs (Carlos Pardo, personal communication).

The new studies provide striking evidence that astrocyte-conditioned medium from SOD1 mutant astrocytes is toxic, as wild-type spinal motor neurons survive longer in culture when cultured alone or with wild-type astrocyte conditioned medium than with mutant astrocyte- conditioned medium. Thus, the lower survival of the spinal motor neurons...  Read more

In the recent papers from the groups of Przedborski and Eggan, provocative evidence is reported that spinal motor neurons may die in SOD1 mutant mice because of soluble toxic factors released by SOD1 mutant astrocytes. This result is surprising because previous studies with chimeric SOD1 mutant mice have shown that expression of mutant SOD1 in microglia but not astrocytes is implicated in the neuron death. However, profound reactive astrocytosis occurs very early in mouse and human motor neuron diseases. This is true in the SOD1 mutant mice, where reactive astrocytosis is a dramatic feature of the disease, with prominent reactive astrocytosis occurring long before much motor neuron death occurs (Carlos Pardo, personal communication).

The new studies provide striking evidence that astrocyte-conditioned medium from SOD1 mutant astrocytes is toxic, as wild-type spinal motor neurons survive longer in culture when cultured alone or with wild-type astrocyte conditioned medium than with mutant astrocyte- conditioned medium. Thus, the lower survival of the spinal motor neurons cannot be attributed to less production of neurotrophic factors by the mutant astrocytes. Together, these in-vitro and in-vivo findings directly implicate reactive astrocytes in the pathophysiology of spinal motor neuron death in the SOD1 mutant mice. One caveat is that in the in-vitro studies, the astrocytes that were studied were obtained from neonatal spinal cords long before any reactive gliosis actually occurs. However, neonatal astrocytes in culture have a similar phenotype to reactive astrocytes in vivo, and may in fact be comparable.

So how can these new observations of Przedborski and Eggan be reconciled with previous studies that found that chimeric SOD1 mutant mice with mutant SOD1 in microglia but not astrocytes is implicated in the neuron death? For one thing, it is unclear if mutant microglia were actually present in the astrocyte cultures used in these new studies. Steps were taken to minimize microglial contamination, but because astrocytes secrete high levels of microglial mitogens such as colony stimulating factor-1 (CSF1), microglia almost always heavily contaminate neonatal astrocyte cultures prepared by the commonly used methods of McCarthy and DeVellis. It would be good to repeat the study using more stringent methods of microglial elimination, such as immunopanning, and it would be important to confirm by immunostaining that microglia are in fact absent from the astrocyte-conditioned medium at the time it is harvested. It is also possible that mutant astrocytes release factors in culture that are toxic to motor neurons but that these factors are not actually secreted in vivo or are not toxic to the neurons in vivo. The only way to find out for sure, of course, will be to identify this toxic astrocyte factor. At the present time, it is difficult to think of a model that reconciles the previous in-vivo observations implicating mutant microglia with the present in-vitro observations implicating mutant astrocytes.

Assuming astrocytes make a toxic factor, what could be its nature? The possibility that it is glutamate has already been ruled out, as have been the obvious cytokine candidates. Moreover, the motor neurons undergo apoptosis. One possibility is that it is a factor that binds to, inhibits, or proteolyzes required trophic factors or culture substrates present in the culture medium that are required for long-term motor neuron survival.

Another possibility is that the toxic astrocytes alter the pH of the culture medium or lower antioxidant levels, which are both crucial parameters for good neuronal survival. Alternatively, a toxic factor could be released, such as a cytokine of some sort or an excitotoxin. Glutamate agonists have not been ruled out. For instance, homocysteine is an NMDA agonist that is exclusively made by astrocytes; other possibilities are aspartate and N-acetyl-aspartylglutamate, which all act on NMDA receptors. In addition, astrocytes have previously been shown to secrete high levels of NMDA potentiators such as L-glycine or D-serine, and it is possible that the mutant astrocytes secrete higher levels of these. Glutamate excitotoxicity can lead to apoptosis, so it would be important in future experiments to test whether the toxic astrocyte factor can be blocked by APV or other NMDA receptor blockers, as so far only kainate and AMPA receptor blockers have been tested.

A very interesting new paper by Don Cleveland’s group provides evidence, using laser capture studies of mRNA expression, that spinal motor neurons in the SOD mutant mice have elevated levels of several complement proteins. This raises the possibility that there is complement-induced toxicity. However, microglia and serum, which are both rich sources of the complete set of complement proteins required for the complement cascade to function, were not present in the motor neuron cultures; therefore, this seems an unlikely possibility. Moreover, complement-mediated toxicity would be expected to cause lysis and not necessarily apoptosis (though mild toxic insults are well documented to lead to apoptosis in neurons). Interestingly, the new Cleveland work also provides evidence for a strong upregulation of the serine biosynthetic pathway. Astrocytes have previously been shown to preferentially use the serine synthetic pathway, whereas neurons do not (a result we have recently confirmed by gene profiling of purified neural cell populations; Cahoy and Barres, unpublished observations). It is possible that SOD1 mutant neurons upregulate these pathways as they die, but a more likely possibility is that there was some contamination by reactive glial genes in these studies, a possibility that is suggested by the presence of other upregulated well-described astrocyte genes such as CD44 and aquaporin 4. This latter possibility again raises the possibility that the toxic factor being released by mutant astrocytes is D-serine or L-glycine.

Whatever the case, these new papers call attention to the important but still poorly understood roles of neuron-glial interactions in the pathophysiology of neurodegenerative disease.

View all comments by Ben Barres

These two papers by Nagai et al. (2007) and Di Giorgio et al. (2007) independently provide strong evidence that glial cells, and perhaps specifically astrocytes, bearing SOD1 mutations are responsible for degeneration and death of motor neurons in embryonic stem cell (ESC)-based co-cultures of primary neurons and glial cells. Motor neurons bearing SOD1 mutation did not degenerate in the absence of mutant glial cells.

While these elegant findings provide important insights into the interdependency between neurons and glial cells, and provide key data concerning the pathogenesis of human ALS associated with SOD1 mutation, their relevance to sporadic and other non-SOD1 related forms of human ALS is uncertain. Increasingly, it is becoming recognized that SOD1- associated ALS, and non-SOD1 forms of ALS may be driven through different pathogenetic cascade mechanisms. In SOD1 ALS, the accumulated protein within the conglomerated ubiquitinated inclusion bodies is mutated SOD1. In other, non-SOD1 forms of familial ALS, and sporadic ALS, the filamentous or skein-like ubiquitinated...  Read more

These two papers by Nagai et al. (2007) and Di Giorgio et al. (2007) independently provide strong evidence that glial cells, and perhaps specifically astrocytes, bearing SOD1 mutations are responsible for degeneration and death of motor neurons in embryonic stem cell (ESC)-based co-cultures of primary neurons and glial cells. Motor neurons bearing SOD1 mutation did not degenerate in the absence of mutant glial cells.

While these elegant findings provide important insights into the interdependency between neurons and glial cells, and provide key data concerning the pathogenesis of human ALS associated with SOD1 mutation, their relevance to sporadic and other non-SOD1 related forms of human ALS is uncertain. Increasingly, it is becoming recognized that SOD1- associated ALS, and non-SOD1 forms of ALS may be driven through different pathogenetic cascade mechanisms. In SOD1 ALS, the accumulated protein within the conglomerated ubiquitinated inclusion bodies is mutated SOD1. In other, non-SOD1 forms of familial ALS, and sporadic ALS, the filamentous or skein-like ubiquitinated inclusions contain the TAR DNA binding protein, TDP-43 (Neumann et al., 2006; Davidson et al., 2007). Pertinently, the inclusions in SOD1-associated ALS are not TDP-43 immunoreactive (Tan et al., 2007). These latter morphological and immunohistochemical data reinforce the concept that SOD1 and non-SOD1 ALS are separate disorders even though they share a common clinical phenotype. The data, moreover, imply that a role for glial cells, as described in the work of Nagai et al., (2007) and Di Giorgio et al. (2007), may not pertain in the more common forms of ALS that are not associated with SOD1 mutation.

Nonetheless, a potential role for glial cells in non-SOD1 ALS could, perhaps, be tested in ESC-based studies using the Q342X stop codon mutation in the intraflagellar transport protein 74 (IFT74) gene, which has been associated in one family with a frontotemporal dementia and motor neuron disease (FTD+MND) clinical phenotype (Momeni et al., 2006). One patient from this family with this mutation showed ubiquitinated pathological changes within cerebral cortex and brain stem and spinal cord detectable by TDP-43 immunohistochemistry (Cairns et al., 2007). These were typical of those seen in FTD+MND, and in ALS alone (Neumann et al., 2006; Davidson et al., 2007).

References:
Cairns NJ et al (2007) Amer J Pathol (in press).

Davidson Y, Kelley T, Mackenzie IR, Pickering-Brown S, Du Plessis D, Neary D, Snowden JS, Mann DM. Ubiquitinated pathological lesions in frontotemporal lobar degeneration contain the TAR DNA-binding protein, TDP-43. Acta Neuropathol (Berl). 2007 May;113(5):521-33. Epub 2007 Jan 12. Abstract

Di Giorgio FP, Carrasco MA, Siao MC, Maniatis T, Eggan K. Non-cell autonomous effect of glia on motor neurons in an embryonic stem cell-based ALS model. Nat Neurosci. 2007 May;10(5):608-614. Epub 2007 Apr 15. Abstract

Momeni P, Schymick J, Jain S, Cookson MR, Cairns NJ, Greggio E, Greenway MJ, Berger S, Pickering-Brown S, Chio A, Fung HC, Holtzman DM, Huey ED, Wassermann EM, Adamson J, Hutton ML, Rogaeva E, St George-Hyslop P, Rothstein JD, Hardiman O, Grafman J, Singleton A, Hardy J, Traynor BJ. Analysis of IFT74 as a candidate gene for chromosome 9p-linked ALS-FTD. BMC Neurol. 2006 Dec 13;6:44. Abstract

Nagai M, Re DB, Nagata T, Chalazonitis A, Jessell TM, Wichterle H, Przedborski S. Astrocytes expressing ALS-linked mutated SOD1 release factors selectively toxic to motor neurons. Nat Neurosci. 2007 May;10(5):615-622. Epub 2007 Apr 15. Abstract

Neumann M, Sampathu DM, Kwong LK, Truax AC, Micsenyi MC, Chou TT, Bruce J, Schuck T, Grossman M, Clark CM, McCluskey LF, Miller BL, Masliah E, Mackenzie IR, Feldman H, Feiden W, Kretzschmar HA, Trojanowski JQ, Lee VM. Ubiquitinated TDP-43 in frontotemporal lobar degeneration and amyotrophic lateral sclerosis. Science. 2006 Oct 6;314(5796):130-3. Abstract

Tan CF, Eguchi H, Tagawa A, Onodera O, Iwasaki T, Tsujino A, Nishizawa M, Kakita A, Takahashi H. TDP-43 immunoreactivity in neuronal inclusions in familial amyotrophic lateral sclerosis with or without SOD1 gene mutation. Acta Neuropathol (Berl). 2007 May;113(5):535-42. Epub 2007 Feb 27. Abstract

View all comments by David M.A. Mann

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