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Treatment with CD20-specific antibody prevents and reverses autoimmune diabetes in mice.

ABSTRACT: The precise roles of B cells in promoting the pathogenesis of type 1 diabetes remain undefined. Here, we demonstrate that B cell depletion in mice can prevent or delay diabetes, reverse diabetes after frank hyperglycemia, and lead to the development of cells that suppress disease. To determine the efficacy and potential mechanism of therapeutic B cell depletion, we generated a transgenic NOD mouse expressing human CD20 (hCD20) on B cells. A single cycle of treatment with an antibody specific for hCD20 temporarily depleted B cells and significantly delayed and/or reduced the onset of diabetes. Furthermore, disease established to the point of clinical hyperglycemia could be reversed in over one-third of diabetic mice. Why B cell depletion is therapeutic for a variety of autoimmune diseases is unclear, although effects on antibodies, cytokines, and antigen presentation to T cells are thought to be important. In B cell-depleted NOD mice, we identified what we believe is a novel mechanism by which B cell depletion may lead to long-term remission through expansion of Tregs and regulatory B cells. Our results demonstrate clinical efficacy even in established disease and identify mechanisms for therapeutic action that will guide design and evaluation of parallel studies in patients.

SUBMITTER: Hu CY

PROVIDER: S-EPMC2096456 | biostudies-literature | 2007 Dec

REPOSITORIES: biostudies-literature

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Treatment with CD20-specific antibody prevents and reverses autoimmune diabetes in mice.

Hu Chang-yun CY Rodriguez-Pinto Daniel D Du Wei W Ahuja Anupama A Henegariu Octavian O Wong F Susan FS Shlomchik Mark J MJ Wen Li L

The Journal of clinical investigation 20071201 12

The precise roles of B cells in promoting the pathogenesis of type 1 diabetes remain undefined. Here, we demonstrate that B cell depletion in mice can prevent or delay diabetes, reverse diabetes after frank hyperglycemia, and lead to the development of cells that suppress disease. To determine the efficacy and potential mechanism of therapeutic B cell depletion, we generated a transgenic NOD mouse expressing human CD20 (hCD20) on B cells. A single cycle of treatment with an antibody specific for ...[more]

PMID: 18060033

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Project description:Chemotherapy-induced peripheral neuropathy (CIPN) is a disabling condition accompanying several cancer drugs, including the front-line chemotherapeutic agent paclitaxel. Although CIPN can force dose reduction or even discontinuation of chemotherapy, affecting survival in cancer patients, there is no US Food and Drug Administration-approved treatment for CIPN. CIPN in mice is characterized by neuropathic pain (eg, mechanical allodynia) in association with oxidative stress and neuroinflammation in dorsal root ganglia (DRGs), as well as retraction of intraepidermal nerve fibers. Here, we report that paclitaxel-induced mechanical allodynia is associated with transcriptional increase in matrix metalloproteinase (MMP) 2 and 9 and decrease in metallopeptidase inhibitor 1 (TIMP1), a strong endogenous MMP9 inhibitor. Consistently, MMP9 protein levels are increased in DRG neurons in vivo and in vitro after paclitaxel treatment, and it is demonstrated, for the first time, that intrathecal injections of exogenous TIMP1 or a monoclonal antibody targeting MMP9 (MMP9 mAb) significantly prevented and reversed paclitaxel-induced mechanical allodynia in male and female mice. Analyses of DRG tissues showed that MMP9 mAb significantly decreased oxidative stress and neuroinflammatory mediators interleukin-6 and tumor necrosis factor α, as well as prevented paclitaxel-induced loss of intraepidermal nerve fibers. These findings suggest that MMP signaling plays a key role in paclitaxel-induced peripheral neuropathy, and MMP9 mAb may offer new therapeutic approaches for the treatment of CIPN. PERSPECTIVE: Chemotherapy-induced peripheral neuropathy (CIPN) remains ineffectively managed in cancer patients, potentially leading to the discontinuation of an otherwise life-saving treatment. Here, we demonstrate that a monoclonal antibody targeting MMP9 alleviates neuropathic pain and several mechanisms linked to CIPN. This study is particularly relevant, because a humanized MMP9 antibody is already in advanced clinical trials for the treatment of colitis and cancer, and it may be straightforwardly repurposed for the relief of CIPN.

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Treatment with CD20-specific antibody prevents and reverses autoimmune diabetes in mice.

Publications

Treatment with CD20-specific antibody prevents and reverses autoimmune diabetes in mice.

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