Vaccine Rouses Mouse Immune System to Fight Motor Neuron Disease

In amyotrophic lateral sclerosis, motor neurons in the spinal cord need some TLC, but the immune cells that could give it are locked out of the central nervous system. According to a study in the April 22 Journal of Neuroscience by Michal Schwartz of the Weizmann Institute of Science in Rehovot, Israel, the barrier is the choroid plexus. This epithelial structure constitutes the blood-cerebrospinal fluid border and manufactures CSF. The choroid plexus allows certain types of T cell and macrophage through in healthy mice but not in ALS mice, Schwartz and colleagues report.

The researchers vaccinated ALS mice with a fragment of myelin oligodendrocyte glycoprotein (MOG), which is made by brain cells. This gave T cells the key to the plexus, and the mice survived longer. “We are boosting the immune system to help the body cure itself,” said Schwartz. However, that treatment itself raises questions. T cells also attack MOG in people who have multiple sclerosis, and scientists induce a type of MS in mice by injecting them with MOG as well. For Schwartz, MOG was simply a convenient way to activate T cells, and she believes a different antigen might do the same in people without inciting MS. However, Stanley Appel of the Houston Methodist Neurological Institute, who was not involved in the study, thinks that in human studies other antigens would still have potential to trade ALS for MS.

The immune response in ALS comprises both neuroprotective and neurotoxic components (reviewed in Hooten et al., 2015; Zhao et al., 2013). Though the immune-privileged central nervous system is separated from the bloodstream by the blood-brain barrier, several studies have indicated that circulating regulatory T cells and anti-inflammatory macrophages can get in when needed. Once in the brain, they promote protective responses (reviewed in Gendelman and Appel, 2011).

The Schwartz lab has posited that they enter by way of the choroid plexus, a structure composed of the innermost meninges and lining of the brain’s ventricles, which envelops the blood vessels entering the brain (Baruch and Schwartz, 2013). Other scientists have also suggested the choroid plexus or meninges allow immune cell infiltration (Kivisäkk et al., 2003; Kivisäkk et al., 2009). Throughout life, Schwartz claims, immune cells seep through the plexus and populate the CSF. Her group reported that T cells promote their own entry by releasing interferon-γ, which induces the choroid plexus cells to turn up expression of chemokines and adhesion molecules that facilitate passage of the blood cells (Kunis et al., 2013). Schwartz and colleagues have found that the plexus allows additional immune cell traffic after spinal cord injury (Shechter et al., 2013). She has proposed that the choroid plexus gateway might malfunction in people who have neurodegenerative disease, allowing neurotoxic immune responses to dominate (Schwartz and Baruch, 2014). 

To investigate this idea, joint first authors Gilad Kunis and Kuti Baruch examined recruitment of immune cells into the spinal cord of mice expressing the mutant ALS gene SOD1. Blood macrophages and regulatory T cells rarely entered the cord, they observed by microscopy. Moreover, the choroid plexus of mSOD1 mice contained less interferon-γ mRNA than the choroid plexus of wild-type animals. The gate was locked shut in the ALS model, the authors concluded.

Kunis and Baruch reasoned that if they activated T cells to make interferon-γ, the plexus would let the cells through. For this proof-of-principle study, they chose to inject the mice with the MOG fragment, which they had used before to promote recovery from spinal injury in rats (Hauben et al., 2001). Sure enough, regulatory T cells and macrophages began to infiltrate the choroid plexus and spinal cord of the immunized mice (see image below). The treated mice lost as many motor neurons as saline-injected mSOD1 mice. However, the neurons that survived were larger and healthier in the immunized animals. In addition to a two-week life extension, the vaccinated mice maintained grip strength for longer than controls.

Open floodgates.

Immune cells (green) infiltrate the choroid plexus of vaccinated ALS mice. [Image courtesy of Kunis et al., The Journal of Neuroscience, 2015.]

Myelin oligodendroyte protein injections induce experimental autoimmune encephalitis, a mouse model of multiple sclerosis. Indeed, the vaccinated mice exhibited a temporary weakness akin to MS. The authors used a standard EAE scoring scale to assess the mice on symptoms such as a limp tail and weak hind legs. These symptoms peaked about two weeks after immunization, and then began to decline.

Schwartz said her group is now trying out different antigens that would awaken the immune system without this side effect. Though the vaccination does not directly target the cause of ALS, she predicts it could slow or arrest progression in people. Schwartz is also investigating ways to activate the immune response in Alzheimer’s models.

“The study seems logical,” Appel said. “She has well documented that the choroid plexus may play a role in mediating the transfer of cells from the periphery into the CNS.” However, he was not certain it is the only entreé into the nervous system for beneficial immune cells. He noted the new work confirms previous findings that regulatory T cells are protective (see Sep 2008 news on Beers et al., 2008; Chiu et al., 2008; Henkel et al., 2013).

Even so, he questioned this vaccination approach for human ALS, even with a different antigen. “Anything that would give rise to γ-interferon is likely to be associated with experimental autoimmune encephalitis, and to trigger multiple sclerosis,” Appel cautioned. He and collaborators in the group ALS Finding a Cure are trying a different way to promote a neuroprotective immune response. They plan to take a patient’s own regulatory T cells, expand them in the laboratory, and then transfuse the amplified supply back into the person.—Amber Dance

Comments

  1. We agree with Appel's work that recruitment of Tregs to the spinal cord parenchyma is beneficial in ALS. Yet it is important to note that the optimal way to bring more Tregs to the CNS may not be by increasing their levels in the circulation; on the contrary, increasing their levels in the circulation may be counterproductive (Schwartz and Baruch, 2014).

    References:

    Schwartz M, Baruch K. The resolution of neuroinflammation in neurodegeneration: leukocyte recruitment via the choroid plexus. EMBO J. 2014 Jan 7;33(1):7-22. Epub 2013 Dec 19 PubMed.

    View all comments by Michal Schwartz

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References

News Citations

  1. Survivor ALS Models—Immunity Protects Against Mutant SOD

Paper Citations

  1. Hooten KG, Beers DR, Zhao W, Appel SH. Protective and Toxic Neuroinflammation in Amyotrophic Lateral Sclerosis. Neurotherapeutics. 2015 Apr;12(2):364-75. PubMed.
  2. Zhao W, Beers DR, Appel SH. Immune-mediated mechanisms in the pathoprogression of amyotrophic lateral sclerosis. J Neuroimmune Pharmacol. 2013 Sep;8(4):888-99. Epub 2013 Jul 25 PubMed.
  3. Gendelman HE, Appel SH. Neuroprotective activities of regulatory T cells. Trends Mol Med. 2011 Dec;17(12):687-8. Epub 2011 Oct 11 PubMed.
  4. Baruch K, Schwartz M. CNS-specific T cells shape brain function via the choroid plexus. Brain Behav Immun. 2013 Nov;34:11-6. Epub 2013 Apr 15 PubMed.
  5. Kivisäkk P, Mahad DJ, Callahan MK, Trebst C, Tucky B, Wei T, Wu L, Baekkevold ES, Lassmann H, Staugaitis SM, Campbell JJ, Ransohoff RM. Human cerebrospinal fluid central memory CD4+ T cells: evidence for trafficking through choroid plexus and meninges via P-selectin. Proc Natl Acad Sci U S A. 2003 Jul 8;100(14):8389-94. Epub 2003 Jun 26 PubMed.
  6. Kivisäkk P, Imitola J, Rasmussen S, Elyaman W, Zhu B, Ransohoff RM, Khoury SJ. Localizing central nervous system immune surveillance: meningeal antigen-presenting cells activate T cells during experimental autoimmune encephalomyelitis. Ann Neurol. 2009 Apr;65(4):457-69. PubMed.
  7. Kunis G, Baruch K, Rosenzweig N, Kertser A, Miller O, Berkutzki T, Schwartz M. IFN-γ-dependent activation of the brain's choroid plexus for CNS immune surveillance and repair. Brain. 2013 Nov;136(Pt 11):3427-40. Epub 2013 Oct 1 PubMed.
  8. Shechter R, Miller O, Yovel G, Rosenzweig N, London A, Ruckh J, Kim KW, Klein E, Kalchenko V, Bendel P, Lira SA, Jung S, Schwartz M. Recruitment of beneficial M2 macrophages to injured spinal cord is orchestrated by remote brain choroid plexus. Immunity. 2013 Mar 21;38(3):555-69. Epub 2013 Mar 7 PubMed.
  9. Schwartz M, Baruch K. The resolution of neuroinflammation in neurodegeneration: leukocyte recruitment via the choroid plexus. EMBO J. 2014 Jan 7;33(1):7-22. Epub 2013 Dec 19 PubMed.
  10. Hauben E, Agranov E, Gothilf A, Nevo U, Cohen A, Smirnov I, Steinman L, Schwartz M. Posttraumatic therapeutic vaccination with modified myelin self-antigen prevents complete paralysis while avoiding autoimmune disease. J Clin Invest. 2001 Aug;108(4):591-9. PubMed.
  11. Beers DR, Henkel JS, Zhao W, Wang J, Appel SH. CD4+ T cells support glial neuroprotection, slow disease progression, and modify glial morphology in an animal model of inherited ALS. Proc Natl Acad Sci U S A. 2008 Oct 7;105(40):15558-63. Epub 2008 Sep 22 PubMed.
  12. Chiu IM, Chen A, Zheng Y, Kosaras B, Tsiftsoglou SA, Vartanian TK, Brown RH Jr, Carroll MC. T lymphocytes potentiate endogenous neuroprotective inflammation in a mouse model of ALS. Proc Natl Acad Sci U S A. 2008 Nov 18;105(46):17913-8. Epub 2008 Nov 7 PubMed.
  13. Henkel JS, Beers DR, Wen S, Rivera AL, Toennis KM, Appel JE, Zhao W, Moore DH, Powell SZ, Appel SH. Regulatory T-lymphocytes mediate amyotrophic lateral sclerosis progression and survival. EMBO Mol Med. 2013 Jan;5(1):64-79. PubMed.

External Citations

  1. SOD1
  2. ALS Finding a Cure

Further Reading

Papers

  1. Zhao W, Beers DR, Liao B, Henkel JS, Appel SH. Regulatory T lymphocytes from ALS mice suppress microglia and effector T lymphocytes through different cytokine-mediated mechanisms. Neurobiol Dis. 2012 Dec;48(3):418-28. PubMed.
  2. Appel SH, Beers DR, Henkel JS. T cell-microglial dialogue in Parkinson's disease and amyotrophic lateral sclerosis: are we listening?. Trends Immunol. 2010 Jan;31(1):7-17. PubMed.
  3. Reynolds AD, Stone DK, Hutter JA, Benner EJ, Mosley RL, Gendelman HE. Regulatory T cells attenuate Th17 cell-mediated nigrostriatal dopaminergic neurodegeneration in a model of Parkinson's disease. J Immunol. 2010 Mar 1;184(5):2261-71. PubMed.
  4. Reynolds AD, Banerjee R, Liu J, Gendelman HE, Mosley RL. Neuroprotective activities of CD4+CD25+ regulatory T cells in an animal model of Parkinson's disease. J Leukoc Biol. 2007 Nov;82(5):1083-94. PubMed.
  5. Banerjee R, Mosley RL, Reynolds AD, Dhar A, Jackson-Lewis V, Gordon PH, Przedborski S, Gendelman HE. Adaptive immune neuroprotection in G93A-SOD1 amyotrophic lateral sclerosis mice. PLoS One. 2008 Jul 23;3(7):e2740. PubMed.
  6. Hauben E, Agranov E, Gothilf A, Nevo U, Cohen A, Smirnov I, Steinman L, Schwartz M. Posttraumatic therapeutic vaccination with modified myelin self-antigen prevents complete paralysis while avoiding autoimmune disease. J Clin Invest. 2001 Aug;108(4):591-9. PubMed.

Primary Papers

  1. Kunis G, Baruch K, Miller O, Schwartz M. Immunization with a Myelin-Derived Antigen Activates the Brain's Choroid Plexus for Recruitment of Immunoregulatory Cells to the CNS and Attenuates Disease Progression in a Mouse Model of ALS. J Neurosci. 2015 Apr 22;35(16):6381-93. PubMed.

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