Promises and limitations of immune cell-based therapies in neurological disorders

Hu, Xiaoming; Leak, Rehana K.; Thomson, Angus W.; Yu, Fang; Xia, Yuguo; Wechsler, Lawrence R.

doi:10.1038/s41582-018-0028-5

Cited by 40 publications

(38 citation statements)

References 136 publications

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“…We also demonstrate that cisplatin educates CD8 + T cells which can be used to prevent CIPN induced either by cisplatin or paclitaxel. Our work strengthen the prospect for immune cell-based therapies in neurological disorders [25], such as ex vivo education of autologous peripheral CD8 + T cells, to relieve the burden of CIPN and restore quality of life of cancer survivors. Female and male Rag2 −/− mice were treated with cisplatin or PBS on days 0, 1, and 2.…”

Section: Resultssupporting

confidence: 58%

Cisplatin educates CD8+ T cells to prevent and resolve chemotherapy-induced peripheral neuropathy in mice

Laumet

Edralin

Dantzer³

et al. 2019

Pain

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The mechanisms responsible for the persistence of chemotherapy-induced peripheral neuropathy (CIPN) in a significant proportion of cancer survivors are still unknown. Our previous findings show that CD8 + T cells are necessary for the resolution of paclitaxel-induced mechanical allodynia in male mice. In the present study, we demonstrate that CD8 + T cells are not only essential for resolving cisplatin-induced mechanical allodynia, but also to normalize spontaneous pain, numbness, and the reduction in intra-epidermal nerve fiber density in male and female mice. Resolution of CIPN was not observed in Rag2 −/− mice that lack T and B cells. Reconstitution of Rag2 −/− mice with CD8 + T cells prior to cisplatin treatment normalized the resolution of CIPN. In vivo education of CD8 + T cells by cisplatin was necessary to induce resolution of CIPN in Rag2 −/− mice because adoptive transfer of CD8 + T cells from naïve WT mice to Rag2 −/− mice after completion of chemotherapy did not promote resolution of established CIPN. The CD8 + T cell-dependent resolution of CIPN does not require epitope recognition by the T cell receptor (TCR). Moreover, adoptive transfer of cisplatin-educated CD8 + T cells to Rag2 −/− mice prevented CIPN development induced by either cisplatin or paclitaxel, indicating that the activity of the educated CD8 + T is not cisplatin-specific. In conclusion, resolution of CIPN requires in vivo education of CD8 + T cells by exposure to cisplatin. Future studies should examine whether ex vivo CD8 + T cell education could be applied as a therapeutic strategy for treating or preventing CIPN in patients.

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Section: Resultssupporting

confidence: 58%

Cisplatin educates CD8+ T cells to prevent and resolve chemotherapy-induced peripheral neuropathy in mice

Laumet

Edralin

Dantzer³

et al. 2019

Pain

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“…Interestingly, demyelinating disorders actually appeared to be negatively correlated with ICI use (0.08% of ICI reports vs. 0.47% for the full database; IC 025 : − 3.07), although this study was not designed to conclusively exclude drug-AE associations. The lack of associations with other neurologic disorders was also an important finding, given evidence that suggests inflammation may play a critical role in diverse neurologic conditions such as dementia, cerebrovascular disease, amytrophic lateral sclerosis, and others [24][25][26]. However, long-term data will be needed to definitively rule out such associations.…”

Section: Discussionmentioning

confidence: 99%

Neurologic toxicity associated with immune checkpoint inhibitors: a pharmacovigilance study

Johnson¹,

Manouchehri²,

Haugh³

et al. 2019

j. immunotherapy cancer

280

257

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Background: Immune checkpoint inhibitors (ICI) produce durable antitumor responses but provoke autoimmune toxicities, including uncommon but potentially devastating neurologic toxicities. The clinical features, including the spectrum, timing, and outcomes, of ICI-induced neurologic toxicities are not well characterized. Methods: We performed disproportionality analysis using Vigibase, the World Health Organization pharmacovigilance database, comparing neurologic adverse event (AE) reporting in patients receiving ICIs vs. the full database. Neurologic AEs were classified by group queries using Medical Dictionary for Regulatory Activities, between database inception to September 28, 2018. Associations between ICIs and neurologic AEs were assessed using reporting odds ratios (ROR) and information component (IC). IC compares observed and expected values to find associations between drugs and AEs using disproportionate Bayesian reporting; IC 025 (lower end of the IC 95% credibility interval) > 0 is considered statistically significant. Results: Among the full database, 18,518,994 AEs were reported, including 48,653 with ICIs. ICIs were associated with higher incidence of myasthenia gravis (0.47% of ICI reports vs. 0.04% of the full database, ROR 16.5 [95% CI 14. 5-18.9]; IC 025 3.31), encephalitis (0.51% vs. 0.05%, ROR 10.4 [95% CI 9.2-11.8]; IC 025 3.15), peripheral neuropathy (1. 16% vs. 0.67%, IC 025 0.68), and meningitis (0.15% vs. 0.06%, ROR 3.1 [95% CI 2.5-3.9]; IC 025 1.01). Myasthenia gravis and encephalitis were associated with anti-PD-1 whereas other neurologic AEs were associated with anti-CTLA-4. Myasthenia gravis was characterized by high fatality rates (~20%), early onset (median 29 days), and frequent concurrent myocarditis and myositis; whereas other neurologic AEs had lower fatality rates (6-12%), later onset (median 61-80 days), and were non-overlapping. Conclusions: ICIs produce a spectrum of distinct classes of neurologic AEs that can cause significant morbidity and mortality and tend to occur early and with class-specific associations.

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“…Fifth, we focused on macrophages. But of course, lymph nodes also contain T and B cells that are known to play key roles in stroke pathophysiology 53 . Further studies are warranted to investigate the entire spectrum of immune cells that are regulated by cervical lymphatics after stroke.…”

Section: Discussionmentioning

confidence: 99%

Brain-to-cervical lymph node signaling after stroke

et al. 2019

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After stroke, peripheral immune cells are activated and these systemic responses may amplify brain damage, but how the injured brain sends out signals to trigger systemic inflammation remains unclear. Here we show that a brain-to-cervical lymph node (CLN) pathway is involved. In rats subjected to focal cerebral ischemia, lymphatic endothelial cells proliferate and macrophages are rapidly activated in CLNs within 24 h, in part via VEGF-C/VEGFR3 signalling. Microarray analyses of isolated lymphatic endothelium from CLNs of ischemic mice confirm the activation of transmembrane tyrosine kinase pathways. Blockade of VEGFR3 reduces lymphatic endothelial activation, decreases pro-inflammatory macrophages, and reduces brain infarction. In vitro, VEGF-C/VEGFR3 signalling in lymphatic endothelial cells enhances inflammatory responses in co-cultured macrophages. Lastly, surgical removal of CLNs in mice significantly reduces infarction after focal cerebral ischemia. These findings suggest that modulating the brain-to-CLN pathway may offer therapeutic opportunities to ameliorate systemic inflammation and brain injury after stroke.

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Promises and limitations of immune cell-based therapies in neurological disorders

Cited by 40 publications

References 136 publications

Cisplatin educates CD8+ T cells to prevent and resolve chemotherapy-induced peripheral neuropathy in mice

Cisplatin educates CD8+ T cells to prevent and resolve chemotherapy-induced peripheral neuropathy in mice

Neurologic toxicity associated with immune checkpoint inhibitors: a pharmacovigilance study

Brain-to-cervical lymph node signaling after stroke

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