Could an FDA-approved drug that trains the immune system on tumors benefit the brain? According to a report in the January 18 Nature Medicine, an antibody that boosts the cancer-fighting ability of T cells also prods them to issue a rallying cry that calls peripheral macrophages to the central nervous system. Scientists led by Michal Schwartz, Weizmann Institute of Science, Rehovot, Israel, report that these immune cells then clear Aβ plaques and improve memory in mouse models of Alzheimer’s disease.
“These data add to the growing body of evidence suggesting that peripheral adaptive immunity plays a role in the pathophysiology of Alzheimer’s disease,” said Guillaume Dorothee, INSERM, Paris, who was not involved in the work. “In line with other recent studies, this suggests that immunomodulatory strategies in the periphery may have therapeutic potential in AD.” The ideal immune target and strategy still remain to be determined, he said.
Previously, Schwartz and colleagues reported essentially the same outcomes in mouse models when they used genetic methods to temporarily deplete regulatory T cells in the periphery—effectively easing the brakes on the immune system (Sep 2015 news). This response depended on a burst of interferon-γ (IFN-γ) from circulating effector T cells. The cytokine stimulated the choroid plexus to recruit monocyte-derived macrophages from the periphery to the brain. There, the myeloid cells surrounded and cleared Aβ plaques. In the current study, the group wanted to test a more clinically relevant strategy for eliciting an IFN-γ response from effector T cells.
The FDA-approved melanoma drug pembrolizumab from Merck elicits a similar IFN-γ response. Known as KEYTRUDA, this antibody neutralizes the programmed T cell death 1 (PD-1) receptor on effector T cells. PD-1 normally keeps T cell activity in check and suppresses tumor-fighting activity. It is known as an immune checkpoint. Without PD-1, these cells release IFN-γ and can once again kill tumors (Mamalis et al., 2014). In this paper, the research group tested a similar anti-PD-1 antibody, specifically for use in animals.
To investigate, first author Kuti Baruch from Schwartz's group, collaborating with Ido Amit's immunogenomics group, tested the effects of the anti-PD-1 antibody in 10-month-old 5XFAD mice, which had accumulated significant cerebral Aβ plaques. The researchers injected the mice intraperitoneally twice, three days apart, with either the PD-1 antibody or an IgG control. Some animals got a second round of treatment a month later.
The anti-PD-1 antibody appeared to elicit a robust IFN-γ response. A week after the first injection, more CD4+ T cells from the treated mice were producing IFN-γ and RNA sequencing revealed an IFN-γ-associated expression profile at the choroid plexus. The researchers isolated the choroid plexus from mouse brain and analyzed it, but did not compare it to other tissues. More myeloid cells infiltrated the brains of treated mice, while astrogliosis and Aβ plaque load in the hippocampi and cerebral cortices fell by half. Mice that got a second round of injections wound up with even less Aβ.
These pathology benefits seemed to translate to behavior, the scientists reported. A month after the first round of injections, treated mice remembered the location of a hidden platform in a radial arm water maze better than untreated controls. Mice given a second round of treatment performed almost as well as wild types. Cognitive deficits returned in mice that got only one set of injections, suggesting that repeat dosing is needed to maintain benefits.
The results appeared to extend to other mouse models of Alzheimer’s. In eight- or 11-month-old APP/PS1 mice, the anti-PD-1 antibody reduced Aβ plaque area and number by at least half. No behavioral assays were reported for these mice.
“This is the first time immunotherapy based on immune checkpoint blockade is suggested in the context of a neurodegenerative disease,” Schwartz told Alzforum, adding, “Since it is based on an existing FDA-approved therapy for cancer, it can potentially be immediately tested in patients suffering from Alzheimer’s disease.” She pointed out that the therapy is not directed against any specific disease pathology, but rather helps the immune system “cleanse” the brain of toxic materials, including Aβ. She plans to explore whether blocking other immune checkpoints treats AD mouse models. A Merck representative said the company has no current plans to test pembrolizumab in AD.
Though Schwartz’ data imply that boosting systemic immunity could help clear Aβ when a full load of amyloid pathology is present in the brain, Dorothee found a different result at an earlier stage of pathogenesis in mice, when plaques first appeared (Apr 2015 conference news). In that soon-to-be-published study, microgliosis rose and performance on behavioral outcomes improved when regulatory T cells were stimulated, not inhibited. Disease worsened in their absence. “To me this suggests a complex and dynamic process that involves multiple immune effectors, with changes depending on the state of neuroinflammation and the stage of disease progression,” Dorothee said.
Gabriela Constantin, University of Verona, Italy, agreed that PD-1 inhibition should be studied at earlier stages of AD in models (see full comment below). Constantin and Dorothee noted that removal of β-amyloid by any means has yet to show a clinical benefit in human trials. They proposed testing PD-1 therapy in tau models, which Schwartz is currently doing. In addition, Constantin said that PD-1 blockade exaggerates inflammatory disease in animal models (Salama et al., 2003). Researchers should investigate how such outcomes will affect AD, she cautioned. Side effects of pembrolizumab include inflammatory reactions in the lung, liver, and other organs.—Gwyneth Dickey Zakaib
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Research Models Citations
- Mamalis A, Garcha M, Jagdeo J. Targeting the PD-1 pathway: a promising future for the treatment of melanoma. Arch Dermatol Res. 2014 Aug;306(6):511-9. Epub 2014 Mar 11 PubMed.
- Salama AD, Chitnis T, Imitola J, Ansari MJ, Akiba H, Tushima F, Azuma M, Yagita H, Sayegh MH, Khoury SJ. Critical role of the programmed death-1 (PD-1) pathway in regulation of experimental autoimmune encephalomyelitis. J Exp Med. 2003 Jul 7;198(1):71-8. PubMed.
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- Browne TC, McQuillan K, McManus RM, O'Reilly JA, Mills KH, Lynch MA. IFN-γ Production by amyloid β-specific Th1 cells promotes microglial activation and increases plaque burden in a mouse model of Alzheimer's disease. J Immunol. 2013 Mar 1;190(5):2241-51. PubMed.
- McManus RM, Higgins SC, Mills KH, Lynch MA. Respiratory infection promotes T cell infiltration and amyloid-β deposition in APP/PS1 mice. Neurobiol Aging. 2014 Jan;35(1):109-21. PubMed.
- Saresella M, Calabrese E, Marventano I, Piancone F, Gatti A, Calvo MG, Nemni R, Clerici M. PD1 negative and PD1 positive CD4+ T regulatory cells in mild cognitive impairment and Alzheimer's disease. J Alzheimers Dis. 2010;21(3):927-38. PubMed.
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- Baruch K, Deczkowska A, Rosenzweig N, Tsitsou-Kampeli A, Sharif AM, Matcovitch-Natan O, Kertser A, David E, Amit I, Schwartz M. PD-1 immune checkpoint blockade reduces pathology and improves memory in mouse models of Alzheimer's disease. Nat Med. 2016 Feb;22(2):135-7. Epub 2016 Jan 18 PubMed.