People take aspirin for pain, fever, and even in hopes of warding off a heart attack. Could this old, over-the-counter pill also help control multiple sclerosis? A November 27 report in Science Signaling suggests as much—in mice. Scientists led by Kalipada Pahan, Jesse Brown Veterans Affairs Medical Center in Chicago, claim that a small, daily dose of aspirin suppressed inflammation, demyelination, and autoimmune responses in mice modeling MS. It worked by restoring regulatory T lymphocytes (Tregs), which rein in self-reactive T cells.
Given that Tregs also dwindle in amyotrophic lateral sclerosis, the new data beg the question of whether aspirin could benefit ALS patients. “In both MS and ALS, the number and function of Tregs decrease, resulting in aberrant immune responses and increased inflammation,” Pahan wrote to Alzforum, “It has been already shown that infusion of Tregs slows the progression of ALS, so there is a possibility that low-dose aspirin may delay the progression of ALS via boosting Tregs.”
However, Pahan cautioned that long-term use of even baby aspirin (81 mg/day) may cause stomach upset and heartburn. Bradley Turner, University of Melbourne, Australia, also urged caution, noting there is little evidence of a connection between aspirin and ALS. “It is unclear whether the same mechanisms are operating in ALS and its animal models. However, this would be an interesting future line of inquiry,” Turner wrote to Alzforum.
Experimental autoimmune encephalitis (EAE), a commonly used model for MS in mice, is an inflammatory demyelinating disease of the central nervous system that is clinically and pathologically similar to MS. First author Susanta Mondal and colleagues induced relapsing-remitting or chronic EAE in five-week-old wild-type mice. Eight days later, the scientists started giving the mice 1 to 3 mg/kg aspirin a day by oral gavage for up to 32 days.
Even at the lowest dose, aspirin halved the clinical scores of both models, reducing limb and tail weakness, paralysis, and death compared with untreated EAE mice. In treated mice, fewer peripheral immune cells infiltrated the spinal cord, expression of pro-inflammatory mediators was lower, and axons in the spinal cord had more myelin. Aspirin seemed to work by preventing an EAE-induced loss of regulatory T cells by increasing the expression of interleukin-11, an immunomodulatory cytokine with anti-autoimmune activity. This prevented development of pro-inflammatory T helper 17 cells, Mondal and colleagues reported.
The results suggest that aspirin could potentially slow progression in people with ongoing disease, Pahan wrote. He plans to next conduct clinical trials of aspirin treatment in patients with MS.
Unlike MS, ALS is not considered primarily an autoimmune disorder. Yet its motoneuron degeneration is accompanied by marked neuroinflammation involving both brain-resident glia and invading monocytes and T cells. Tregs have been reported to become both depleted and dysfunctional in ALS, particularly in people with rapidly progressing disease (Beers et al., 2017).
Some evidence suggests that boosting the number of Tregs could slow ALS progression (see June 2018 news). One experimental attempt involves autologous cell treatment. In mice, this delays progression (Sheean et al., 2018; for review, see Thonhoff et al., 2018). In an open-label pilot study of three patients, led by Stanley Appel and Jason Thonhoff of Houston Methodist, ex-vivo expansion and reinjection of a patient’s own Tregs delayed progression of their ALS (Thonhoff et al., 2018).
Could aspirin shore up the supply of neuroprotective Tregs in ALS? It’s unclear, Turner told Alzforum. Prospective cohort studies found no link between aspirin use and risk for ALS (Fondell et al., 2012). One large population-based, case-control study did suggest aspirin reduced risk, but that finding has yet to be replicated (Tsai et al., 2015). Another study suggested aspirin delayed disease onset in SOD1 G93A mice; however, the doses used were 100 times higher than in the current study, so may not hold at low doses (Barnéoud and Curet, 1999).
“The authors have made an interesting observation linking aspirin, IL-11, and Tregs in EAE mice. Whether this mechanism occurs in humans and ALS is unclear from the paper,” Turner wrote. “Therefore, there is no hard evidence to suggest that people with ALS should be taking aspirin.”
“I would hesitate to extrapolate that much from an animal model,” Thonhoff agreed. However, given that aspirin is inexpensive and available, it would be relatively easy to test it in small pilot trials for MS and ALS patients, he said. If a signal emerges, a larger study would be in order. “We think any treatment that can enhance the Treg population, or prevent the loss of the immunosuppressive functions of Tregs, has a chance to slow down the progression of ALS,” Thonhoff added. However, given the potential side effects and lack of evidence for benefit in people, Thonhoff does not recommend the daily use of aspirin in ALS patients at this time.
Mondal S, Jana M, Dasarathi S, Roy A, Pahan K. Aspirin ameliorates experimental autoimmune encephalomyelitis through interleukin-11–mediated protection of regulatory T cells. Sci. Signal. 27 Nov 2018.
Beers DR, Zhao W, Wang J, Zhang X, Wen S, Neal D, Thonhoff JR, Alsuliman AS, Shpall EJ, Rezvani K, Appel SH. ALS patients’ regulatory T lymphocytes are dysfunctional, and correlate with disease progression rate and severity. JCI Insight. 2017 Mar 9;2(5):e89530. PubMed.
Sheean RK, McKay FC, Cretney E, Bye CR, Perera ND, Tomas D, Weston RA, Scheller KJ, Djouma E, Menon P, Schibeci SD, Marmash N, Yerbury JJ, Nutt SL, Booth DR, Stewart GJ, Kiernan MC, Vucic S, Turner BJ. Association of Regulatory T-Cell Expansion With Progression of Amyotrophic Lateral Sclerosis: A Study of Humans and a Transgenic Mouse Model. JAMA Neurol. 2018 Jun 1;75(6):681-689. PubMed.
Thonhoff JR, Simpson EP, Appel SH. Neuroinflammatory mechanisms in amyotrophic lateral sclerosis pathogenesis. Curr Opin Neurol. 2018 Oct;31(5):635-639. PubMed.
Thonhoff JR, Beers DR, Zhao W, Pleitez M, Simpson EP, Berry JD, Cudkowicz ME, Appel SH. Expanded autologous regulatory T-lymphocyte infusions in ALS: A phase I, first-in-human study. Neurol Neuroimmunol Neuroinflamm. 2018 Jul;5(4):e465. Epub 2018 May 18 PubMed.
Fondell E, O’Reilly ÉJ, Fitzgerald KC, Falcone GJ, McCullough ML, Thun MJ, Park Y, Kolonel LN, Ascherio A. Non-steroidal anti-inflammatory drugs and amyotrophic lateral sclerosis: results from five prospective cohort studies. Amyotroph Lateral Scler. 2012 Oct;13(6):573-9. PubMed.
Tsai CP, Lin FC, Lee JK, Lee CT. Aspirin use associated with amyotrophic lateral sclerosis: a total population-based case-control study. J Epidemiol. 2015;25(2):172-7. Epub 2014 Dec 27 PubMed.
Barnéoud P, Curet O. Beneficial effects of lysine acetylsalicylate, a soluble salt of aspirin, on motor performance in a transgenic model of amyotrophic lateral sclerosis. Exp Neurol. 1999 Feb;155(2):243-51. PubMed.
Danikowski KM, Jayaraman S, Prabhakar BS. Regulatory T cells in multiple sclerosis and myasthenia gravis. J Neuroinflammation. 2017 Jun 9;14(1):117. doi: 10.1186/s12974-017-0892-8. PubMed.
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