title: Opioid growth factor and low-dose naltrexone impair central nervous system infiltration by CD4 + T lymphocytes in established experimental autoimmune encephalomyelitis, a model of multiple sclerosis.
abstract: Multiple sclerosis (MS) is an autoimmune disease of the central nervous system (CNS), characterized by infiltrating myelin-reactive T lymphocytes and demyelinating lesions. Experimental autoimmune encephalomyelitis (EAE) is the animal model widely utilized to study MS. EAE is mediated by CD4(+) T cells and can be induced in EAE-susceptible mice through immunization with a myelin antigen, such as proteolipid protein 139-151 (PLP139-151) in SJL mice. In this PLP-induced EAE model, autoreactive CD4(+) T cells migrate from peripheral tissues into the CNS where they are reactivated resulting in CNS damage. Th1 and Th17 cells produce the pro-inflammatory cytokines IFNγ and IL-17, respectively, that have been shown to have pathogenic roles in EAE and MS. Anti-inflammatory Th2, IL-4 secreting cells, have been indicated to inhibit EAE exacerbation. However, given the inflammatory environment of EAE, Th2 effector cells are outnumbered by Th1/Th17 cells. Regulatory CD4(+) T cells suppress immune reactions and have been demonstrated to be dysfunctional in MS patients. Opioid growth factor (OGF), chemically termed [Met(5)]-enkephalin, is a negative growth factor that interacts with the OGF receptor. The OGF-OGFr axis can be activated through exogenous administration of OGF or a low dosage of naltrexone (LDN), an opioid antagonist. We have previously demonstrated that modulation of the OGF-OGFr axis results in alleviation from relapse-remitting EAE, and that CNS-infiltrating CD3(+) T cells are diminished with exogenous OGF or intermittent blockade with LDN administration. In this paper, we aimed to determine whether OGF or LDN alter the Th effector responses of CD4(+) T lymphocytes within the CNS in established EAE. We report in these studies that the numbers of CD4(+) T lymphocytes in the CNS of EAE mice are decreased following treatment with OGF for five days but not LDN. However, modulation of the OGF-OGFr axis did not result in changes to CD4(+) Th effector cell responses in the CNS of EAE mice.
authors.affiliation: Department of Neural & Behavioral Science, The Pennsylvania State University College of Medicine, Hershey, Pennsylvania 17033, USA.
authors.forename: Leslie A
authors.initials: LA
authors.lastname: Hammer
authors.affiliation: Department of Microbiology & Immunology, The Pennsylvania State University College of Medicine, Hershey, Pennsylvania 17033, USA.
authors.forename: Hanspeter
authors.initials: H
authors.lastname: Waldner
authors.affiliation: Department of Neural & Behavioral Science, The Pennsylvania State University College of Medicine, Hershey, Pennsylvania 17033, USA.
authors.forename: Ian S
authors.initials: IS
authors.lastname: Zagon
authors.affiliation: Department of Neural & Behavioral Science, The Pennsylvania State University College of Medicine, Hershey, Pennsylvania 17033, USA pxm9@psu.edu.
authors.forename: Patricia J
authors.initials: PJ
authors.lastname: McLaughlin
mesh_terms: D000818:Animals; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology*; D002490:Central Nervous System / Q000473:pathology*; D004195:Disease Models, Animal; D004681:Encephalomyelitis, Autoimmune, Experimental / Q000473:pathology*; D004744:Enkephalin, Methionine / Q000008:administration & dosage*; D005260:Female; D051379:Mice; D009103:Multiple Sclerosis / Q000473:pathology*; D009271:Naltrexone / Q000008:administration & dosage*; D009292:Narcotic Antagonists / Q000008:administration & dosage*
chemical_list: D009292:Narcotic Antagonists; D004744:Enkephalin, Methionine; D009271:Naltrexone
keywords: IL-17; IL-2; IL-4; OGF; cytokines; flow cytometry; low-dose naltrexone; multiple sclerosis; spinal cord