Dendritic cells (DCs) are pivotal for the development of experimental autoimmune encephalomyelitis (EAE). However, the mechanisms by which they control disease remain to be determined. This study demonstrates that expression of CC chemokine receptor 4 (CCR4) by DCs is required for EAE induction. CCR4 −/− mice presented enhanced resistance to EAE associated with a reduction in IL-23 and GM-CSF expression in the CNS. Restoring CCR4 on myeloid cells in bone marrow chimeras or intracerebral microinjection of CCR4-competent DCs, but not macrophages, restored EAE in CCR4 −/− mice, indicating that CCR4 + DCs are cellular mediators of EAE development. Mechanistically, CCR4 −/− DCs were less efficient in GM-CSF and IL-23 production and also T H -17 maintenance. Intraspinal IL-23 reconstitution restored EAE in CCR4 −/− mice, whereas intracerebral inoculation using IL-23 −/− DCs or GM-CSF −/− DCs failed to induce disease. Thus, CCR4-dependent GM-CSF production in DCs required for IL-23 release in these cells is a major component in the development of EAE. Our study identified a unique role for CCR4 in regulating DC function in EAE, harboring therapeutic potential for the treatment of CNS autoimmunity by targeting CCR4 on this specific cell type.chemokines | neuroinflammation M ultiple sclerosis (MS) is a chronic demyelinating disease of the human CNS (1). Experimental autoimmune encephalomyelitis (EAE), the animal model of MS, is mediated by myelin-specific CD4 + T cells activated by professional antigenpresenting cells (APCs) in peripheral lymphoid tissues (2, 3). In recent studies, both peripherally derived macrophages and DCs have been shown to present myelin antigens to invading autoreactive T cells in the CNS. This presentation initiates the recruitment of a second wave of leukocytes that damage the target organ via demyelination and axonal degeneration (4-8). Understanding the mechanisms responsible for the recruitment of APCs to the CNS and their local function is essential for the development of therapeutic strategies targeting the effector phase and thereby controlling disease progression.Chemokines and their G protein-coupled receptors are key regulators of leukocyte trafficking (9, 10). The CC chemokine receptor 4 (CCR4) is the cognate receptor for the CC chemokines CCL17 and CCL22, and is expressed on functionally distinct subsets of T cells, including activated T cells, T H 2 cells, and Treg cells. CCR4 has also been found on platelets, NK cells, macrophages, and DCs (11-15). DCs are important cellular sources for CCL17 and, in concert with macrophages, produce CCL22 during both homeostasis and inflammation (16,17). Different studies have suggested a critical role for CCR4 in the pathogenesis of EAE and MS. For example, elevated levels of the CCR4 ligands CCL17 or CCL22 have been found in the cerebrospinal fluid of MS patients (18-20). CCL22 protein has been identified in CNS-infiltrating leukocytes and microglia of EAE-induced mice, and CCR4 is expressed by invading leukocyte subsets (21,22). However, it rema...
Back pain is the second leading cause of disability among American adults and is currently treated either with conservative therapy or interventional pain procedures. However, the question that remains is whether we, as physicians, have adequate therapeutic options to offer to the patients who suffer from chronic low back pain but fail both conservative therapy and interventional pain procedures before they consider surgical options such as discectomy, disc arthroplasty, or spinal fusion. The purpose of this article is to review the potential novel therapies that are on the horizon for the treatment of chronic low back pain. We discuss medications that are currently in use through different phases of clinical trials (I–III) for the treatment of low back pain. In this review, we discuss revisiting the concept of chemonucleolysis using chymopapain, as the first drug in an intradiscal injection to reduce herniated disc size, and newer intradiscal therapies, including collagenase, chondroitinase, matrix metalloproteinases, and ethanol gel. We also review an intravenous glial cell-derived neurotrophic growth factor called artemin, which may repair sensory nerves compressed by herniated discs. Another new drug in development for low back pain without radiculopathy is a subcutaneous monoclonal antibody acting as nerve growth factor called tanezumab. Finally, we discuss how platelet-rich plasma and stem cells are being studied for the treatment of low back pain. We believe that with these new therapeutic options, we can bridge the current gap between conservative/interventional procedures and surgeries in patients with chronic back pain.
Historically, educational accessibility in higher education appeared to be a dynamic and fluid scale with individual rights and accessibility on one side while institutional policies and procedures balanced the other side. Additional weights were applied to both sides of the scale. United States (U.S.) federal laws applied weight to the individual rights and accessibility side. Meanwhile, financial considerations applied weight to the institutional policies side. U.S. universities may have found this balancing act difficult through ongoing legal cases and law revisions. Critical Disability Theory (CDT) provides an alternative viewpoint to review education accessibility. CDT also encourages participation by more campus stakeholders to resolve accessibility issues and promote full accessibility on university campuses. This chapter will explore and explain the complex interconnections of laws, finances and policies in supporting accessibility on campuses and discuss potential guidelines for future institutional policies and procedures related to students with disabilities.
Historically, educational accessibility in higher education appeared to be a dynamic and fluid scale with individual rights and accessibility on one side while institutional policies and procedures balanced the other side. Additional weights were applied to both sides of the scale. United States (U.S.) federal laws applied weight to the individual rights and accessibility side. Meanwhile, financial considerations applied weight to the institutional policies side. U.S. universities may have found this balancing act difficult through ongoing legal cases and law revisions. Critical Disability Theory (CDT) provides an alternative viewpoint to review education accessibility. CDT also encourages participation by more campus stakeholders to resolve accessibility issues and promote full accessibility on university campuses. This chapter will explore and explain the complex interconnections of laws, finances and policies in supporting accessibility on campuses and discuss potential guidelines for future institutional policies and procedures related to students with disabilities.
scite is a Brooklyn-based organization that helps researchers better discover and understand research articles through Smart Citations–citations that display the context of the citation and describe whether the article provides supporting or contrasting evidence. scite is used by students and researchers from around the world and is funded in part by the National Science Foundation and the National Institute on Drug Abuse of the National Institutes of Health.
hi@scite.ai
10624 S. Eastern Ave., Ste. A-614
Henderson, NV 89052, USA
Copyright © 2024 scite LLC. All rights reserved.
Made with 💙 for researchers
Part of the Research Solutions Family.