title: CD8+ T Cells and Endogenous IL-10 Are Required for Resolution of Chemotherapy-Induced Neuropathic Pain.
abstract: Chemotherapy-induced peripheral neuropathy (CIPN), characterized by pain and numbness in hands and feet, is a common side effect of cancer treatment. In most patients, symptoms of CIPN subside after treatment completion. However, in a substantial subgroup, CIPN persists long into survivorship. Impairment in pain resolution pathways may explain persistent CIPN. We investigated the contribution of T cells and endogenous interleukin (IL)-10 to resolution of CIPN. Paclitaxel-induced mechanical allodynia was prolonged in T-cell-deficient (Rag1-/-) mice compared with wild-type (WT) mice. There were no differences between WT and Rag1-/-mice in severity of paclitaxel-induced mechanical allodynia. Adoptive transfer of either CD3+or CD8+, but not CD4+, T cells to Rag1-/-mice normalized resolution of CIPN. Paclitaxel treatment increased the number of T cells in lumbar dorsal root ganglia (DRG), where CD8+T cells were the major subset. Inhibition of endogenous IL-10 signaling by intrathecal injection of anti-IL-10 to WT mice or Rag1-/-mice reconstituted with CD8+T cells delayed recovery from paclitaxel-induced mechanical allodynia. Recovery was also delayed in IL-10 knock-out mice. Conversely, administration of exogenous IL-10 attenuated paclitaxel-induced allodynia. In vitro, IL-10 suppressed abnormal paclitaxel-induced spontaneous discharges in DRG neurons. Paclitaxel increased DRG IL-10 receptor expression and this effect requires CD8+T cells. In conclusion, we identified a novel mechanism for resolution of CIPN that requires CD8+T cells and endogenous IL-10. We propose that CD8+T cells increase DRG IL-10 receptor expression and that IL-10 suppresses the abnormal paclitaxel-induced spontaneous discharges by DRG neurons to promote recovery from CIPN.
  
  
  
  Chemotherapy-induced peripheral neuropathy persists after completion of cancer treatment in a significant subset of patients, whereas others recover. Persistent neuropathy after completion of cancer treatment severely affects quality of life. We propose that understanding how neuropathy resolves will identify novel avenues for treatment. We identified a novel and critical role for CD8+T cells and for endogenous IL-10 in recovery from paclitaxel-induced neuropathy in mice. Enhancing the capacity of CD8+T cells to promote resolution or increasing IL-10 signaling are promising targets for novel interventions. Clinically, peripheral blood CD8+T-cell function and/or the capacity of individuals to produce IL-10 may represent biomarkers of risk for developing persistent peripheral neuropathy after completion of cancer treatment.
authors: Laboratory of Neuroimmunology, Division of Internal Medicine, and.
authors: Karen
authors: K
authors: Krukowski
authors: Laboratory of Translational Immunology, and.|Laboratory of Neuroimmunology and Developmental Origins of Disease, University Medical Center Utrecht, 3584EA Utrecht, The Netherlands.
authors: Niels
authors: 0000-0003-0039-7063
authors: N
authors: Eijkelkamp
authors: Laboratory of Neuroimmunology, Division of Internal Medicine, and.
authors: Geoffroy
authors: 0000-0001-6752-3592
authors: G
authors: Laumet
authors: Laboratory of Translational Immunology, and.
authors: C Erik
authors: CE
authors: Hack
authors: Department of Anesthesiology and Pain Medicine Research, The University of Texas MD Anderson Cancer Center, Houston, Texas 77030, and.
authors: Yan
authors: Y
authors: Li
authors: Department of Anesthesiology and Pain Medicine Research, The University of Texas MD Anderson Cancer Center, Houston, Texas 77030, and.
authors: Patrick M
authors: PM
authors: Dougherty
authors: Laboratory of Neuroimmunology, Division of Internal Medicine, and.
authors: Cobi J
authors: 0000-0002-1928-3050
authors: CJ
authors: Heijnen
authors: Laboratory of Neuroimmunology, Division of Internal Medicine, and AKavelaars@mdanderson.org.
authors: Annemieke
authors: 0000-0001-5162-0419
authors: A
authors: Kavelaars
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents; D018414:CD8-Positive T-Lymphocytes / Q000187:drug effects* / Q000473:pathology; D016753:Interleukin-10 / Q000378:metabolism*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009437:Neuralgia / Q000139:chemically induced* / Q000378:metabolism* / Q000473:pathology; D017239:Paclitaxel / Q000009:adverse effects*; D010147:Pain Measurement / Q000187:drug effects*; D058748:Pain Perception / Q000187:drug effects
chemical_list: D000970:Antineoplastic Agents; C556062:IL10 protein, mouse; D016753:Interleukin-10; D017239:Paclitaxel
keywords: CD8+ T cells; IL-10; chemotherapy-induced peripheral neuropathy