The role of the immune system in ALS remains very controversial. Recent advances in understanding the role of inflammation in several neurodegenerative conditions have focused many researchers towards inflammation, now dubbed "neuroinflammation." However, the thinking in this field is still narrowly focused on the CNS compartment. It is common knowledge among immunologists that the immune system patrols the whole body, including so-called immunoprivileged sites such as the CNS. The paper by Michal Schwartz and her group proposes for the first time that there is value in modulating the peripheral immune system to obtain neuroprotection. This approach is very interesting and should generate more work in the future.

The role of the adaptive and innate immune systems in the neurodegenerative process remains a mystery. There are still many open questions about cell types, cell-cell interactions, and molecular targets that are involved in regulating immune response in the CNS, and also about how the peripheral immune compartment regulates the CNS response. We need more work on the...  Read more

The role of the immune system in ALS remains very controversial. Recent advances in understanding the role of inflammation in several neurodegenerative conditions have focused many researchers towards inflammation, now dubbed "neuroinflammation." However, the thinking in this field is still narrowly focused on the CNS compartment. It is common knowledge among immunologists that the immune system patrols the whole body, including so-called immunoprivileged sites such as the CNS. The paper by Michal Schwartz and her group proposes for the first time that there is value in modulating the peripheral immune system to obtain neuroprotection. This approach is very interesting and should generate more work in the future.

The role of the adaptive and innate immune systems in the neurodegenerative process remains a mystery. There are still many open questions about cell types, cell-cell interactions, and molecular targets that are involved in regulating immune response in the CNS, and also about how the peripheral immune compartment regulates the CNS response. We need more work on the basic biological process before we can understand the overall role of the immune system in neurodegeneration.

Although this paper reports substantial life extension in the SOD1 mouse by vaccination with Cop-1, some important controls for the study were not performed or identified. Our experience in working with SOD1 G93A mice clearly indicates that drug studies in this model must be controlled for gender and litter, and a sufficient number of animals must be used to obtain confirmatory results. The inherent variability in the model makes these controls essential. Additionally, the authors had indicated that the adjuvant itself showed some protective effect. It would have been nice to have a PBS control in the SOD1 model to allow segregation of adjuvant effect from the Copaxone effect. It is also unclear why the dosing paradigm used in the SOD1 model is different from the protocol used in the EAE model. It will be important to identify differences in immune response with these different dosing paradigms to identify the cell type and changes in the immune system that is protective in the SOD1 model.

Without a clear understanding of the mechanism of action by Copaxone, its clinical application to human ALS patients will be a big challenge. The identification of biomarkers that indicate a successful immune response will enable us to identify the optimal dosing strategy and also monitor ALS patients in clinical studies.

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Reply by Michal Schwartz.
Studies over the last five years have provided evidence that the body’s ability to withstand injurious conditions in the CNS, regardless of their primary cause, is dependent on the peripheral immune system. Our group showed, for example, that CNS insults elicit an adaptive immune response mediated by T cells directed to self-antigens residing in the site of the lesion; in other words, the insult evokes an autoimmune response. These findings, substantiated by numerous others, led our group to formulate the concept of "protective autoimmunity," characterized as the body’s defense mechanism against harmful substances of endogenous origin, in contrast to the well-recognized classical immunity that defends the body against alien chemical or biological agents. According to this concept, autoimmune disease results not from an aberrant propensity of the body to elicit autoimmunity, but from the body’s failure, having elicited autoimmunity, to properly control it.

Since the purpose of the protective autoimmune response is to combat the effects of...  Read more

Reply by Michal Schwartz.
Studies over the last five years have provided evidence that the body’s ability to withstand injurious conditions in the CNS, regardless of their primary cause, is dependent on the peripheral immune system. Our group showed, for example, that CNS insults elicit an adaptive immune response mediated by T cells directed to self-antigens residing in the site of the lesion; in other words, the insult evokes an autoimmune response. These findings, substantiated by numerous others, led our group to formulate the concept of "protective autoimmunity," characterized as the body’s defense mechanism against harmful substances of endogenous origin, in contrast to the well-recognized classical immunity that defends the body against alien chemical or biological agents. According to this concept, autoimmune disease results not from an aberrant propensity of the body to elicit autoimmunity, but from the body’s failure, having elicited autoimmunity, to properly control it.

Since the purpose of the protective autoimmune response is to combat the effects of destructive self-compounds (for example, to help the body withstand a toxic excess of glutamate), the specificity of the response does not depend on the identity of the offending self-compound or the primary cause of any disease, but rather on the site of the lesion. In all cases, antigen-specific T cells home to the lesion site, where they are activated by their specific antigen to secrete cytokines. These and possibly other secreted substances, by appropriately activating and orchestrating the microglial response, are directly responsible for the beneficial effect.

In seeking a way to safely augment the autoimmune response for therapeutic purposes, we conducted experiments with the synthetic copolymer Cop-1, not because of its documented efficacy as a treatment for multiple sclerosis, but because it can cross-react with self-antigens without causing autoimmune disease. Results from other laboratories as well as ours had suggested that the ability of Cop-1 to harness an autoimmune response safely is attributable to the fact that its cross-reaction with self-antigens is weak. In other words, we chose Cop-1 not for its therapeutic efficacy against autoimmune disease, but for its safety. Our studies with Cop-1 showed that its beneficial effect on protective autoimmunity is mediated by activated Th1 cells, through their secretion of IFN-γ. Repeated administration of Cop-1 (the protocol used for multiple sclerosis) wipes out the benefit as it shifts the T cells away from the Th1 phenotype.

In Kipnis J, Schwartz M, 2002, we described the dual action of Cop-1, which allows it to act, depending on the regimen employed, either as a suppressor of autoimmune disease (by repeated injection) or an activator of protective autoimmunity for neurodegenerative diseases (by single injection or occasional repeated injections for chronic maintenance of protection). It is obvious that, since the conditions underlying autoimmune disease and autoimmune neuroprotection are not the same, finding a suitable regimen for neuroprotection that will ensure the chronic presence of Cop-1-reactive Th1 cells is critical. In developing Cop-1 as a therapeutic treatment for ALS, we will need to know, for example, how often the treatment should be administered, whether or not to use an adjuvant and if so, what adjuvant, etc. The protocol established for multiple sclerosis will not work for ALS.

References:
Kipnis J, Schwartz M. Dual action of glatiramer acetate (Cop-1) in the treatment of CNS autoimmune and neurodegenerative disorders. Trends Mol. Med. 2002; 8: 319-323. Abstract

View all comments by Michal Schwartz