Identification of CD8+ T lymphocytes as a critical step in the recovery from paclitaxel-induced peripheral neuropathy

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 group CIPN can persist into survivorship. Mechanism(s) that regulate recovery from CIPN have not been studied. We investigated whether T lymphocytes play a role in regulating CIPN recovery. In WT and Rag1−/− mice mechanical hyperalgesia developed immediately following paclitaxel treatment but was significantly prolonged in Rag1−/− mice. When Rag1−/− mice were reconstituted with CD3+ T cells recovery was measured at rates comparable to WT mice. Next, we investigated if T lymphocytes are present in lumbar dorsal root ganglia (DRGs) that innervate the hind paws where hyperalgesia is measured. Increased numbers of CD3+ T lymphocytes were detected in lumbar DRGs of paclitaxel-treated mice when compared to vehicle-treated mice on day 7 and the majority were CD8+ T lymphocytes. Reconstitution of Rag1−/− mice with either CD8+ or CD4+ lymphocytes showed that only those mice that received CD8+ lymphocytes recovered from paclitaxel-induced neuropathy. Furthermore, blockade of IL-10 by intrathecal injection of anti-IL-10 antibody delayed recovery. Down-regulation of peripheral monocyte recruitment by anti-CCR2 antibody inhibited CD8+ T lymphocyte-mediated recovery as well suggesting that the interplay between CD8+ lymphocytes and monocytes is crucial for recovery from pac litaxel-induced neuropathy.