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

ABSTRACT: 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 this 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 intraepidermal 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 before 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 naive wild-type 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. 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.

SUBMITTER: Laumet G

PROVIDER: S-EPMC6527475 | biostudies-literature | 2019 Jun

REPOSITORIES: biostudies-literature

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

Laumet Geoffroy G Edralin Jules D JD Dantzer Robert R Heijnen Cobi J CJ Kavelaars Annemieke A

Pain 20190601 6

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 this 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 intr ...[more]

PMID: 30720585

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Project description:BackgroundChemotherapy induced peripheral neuropathy (CIPN) has been attributed to chemotherapeutic agents such as cisplatin which adversely affect disease outcome leading to increased cancer related morbidity. The clinical efficacy of systemic gabapentin in neuropathic pain management is limited by central side-effects in addition to a scarceness of conclusive evidence of its efficacy in CIPN management. The topical route therefore may provide a relatively safe alternative for neuropathic pain treatment in general and CIPN in particular.MethodsCisplatin induced neuropathic nociception was established in rats after a single weekly cisplatin injection (3.0 mg/kg, intraperitoneally) for 4 weeks. The evoked neuropathic sensation of allodynia was assessed by plantar application of von Frey monofilaments as the paw withdrawal threshold (PWT), whereas the expression of heat-hypoalgesia was determined on a hot-plate as paw withdrawal latency (PWL). Gabapentin gel (10% w/w) was applied three-times daily on the hind paws while in a concurrent systemic study, gabapentin was administered daily (75 mg/kg, intraperitoneally) for 4 weeks. To assess any evidence of neurological adverse symptoms of cisplatin and the central side-effect propensity of systemic or topical gabapentin, evaluation of motor coordination (rotarod test) and gait (footprint analysis) were performed.ResultsCisplatin invoked a progressive development of neuropathic hind paw allodynia (decreased PWT, days 7-28) and heat hypoalgesia (increased PWL, days 21-28). Topical gabapentin significantly delayed the expression of both allodynia on protocol days 21 and 28 and heat-hypoalgesia (day 28). Systemic gabapentin displayed a comparative anti-neuropathic predisposition through a sustained suppression of tactile allodynia on days 14 and 21-28 as well as thermal hypoalgesia (days 21 and 28). Systemic gabapentin also impaired motor coordination and gait thus affirming its clinically documented central side effects, but these outcomes were not evident after topical treatment.ConclusionsBoth topical and systemic gabapentin exhibit a propensity to attenuate CIPN in a cisplatin paradigm. Gabapentin applied topically may therefore provide an adjunctive or alternative route for CIPN management upon cessation of systemic medications due to intolerable side-effects.

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

Publications

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

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