"Near Cure" treatment of severe acute EAE in MIF-1-deficient female and male mice with a bifunctional MHCII-derived molecular construct.

Autor: Vandenbark AA; Neuroimmunology Research, R&D-31, VA Portland Health Care System, 3710 SW U.S. Veterans Hospital Rd, Portland, OR 97239, USA; Department of Neurology, Oregon Health & Science University, 3181 SW Sam Jackson Park Rd, Portland, OR 97239, USA; Department of Molecular Microbiology & Immunology, Oregon Health & Science University, 3181 SW Sam Jackson Park Rd, Portland, OR 97239, USA. Electronic address: vandenba@ohsu.edu., Meza-Romero R; Neuroimmunology Research, R&D-31, VA Portland Health Care System, 3710 SW U.S. Veterans Hospital Rd, Portland, OR 97239, USA; Department of Neurology, Oregon Health & Science University, 3181 SW Sam Jackson Park Rd, Portland, OR 97239, USA., Wiedrick J; Biostatistics and Design Program, Oregon Health & Science University, 3181 SW Sam Jackson Park Rd, Portland, OR 97239, USA., Gerstner G; College of Osteopathic Medicine of the Pacific-Northwest, Western University of Health Sciences, 200 Mullins Dr., Lebanon, OR, USA., Seifert H; Department of Dermatology, Oregon Health & Science University, 3181 SW Sam Jackson Park Rd, Portland, OR 97239, USA., Kent G; Department of Dermatology, Oregon Health & Science University, 3181 SW Sam Jackson Park Rd, Portland, OR 97239, USA., Piechycna M; Department of Internal Medicine, Section of Rheumatology, Allergy & Immunology, Yale University School of Medicine, New Haven, CT 06520, USA., Benedek G; Tissue Typing and Immunogenetics Unit, Hadassah Medical Organization and Faculty of Medicine, Hebrew University of Jerusalem, Israel., Bucala R; Department of Internal Medicine, Section of Rheumatology, Allergy & Immunology, Yale University School of Medicine, New Haven, CT 06520, USA., Offner H; Neuroimmunology Research, R&D-31, VA Portland Health Care System, 3710 SW U.S. Veterans Hospital Rd, Portland, OR 97239, USA; Department of Neurology, Oregon Health & Science University, 3181 SW Sam Jackson Park Rd, Portland, OR 97239, USA; Department of Anesthesiology and Perioperative Medicine, Oregon Health & Science University, 3181 SW Sam Jackson Park Rd, Portland, OR 97239, USA.
Jazyk: angličtina
Zdroj: Cellular immunology [Cell Immunol] 2022 Aug; Vol. 378, pp. 104561. Date of Electronic Publication: 2022 Jun 11.
DOI: 10.1016/j.cellimm.2022.104561
Abstrakt: Our previous studies demonstrated increased serum levels of macrophage migration inhibitory factor (MIF-1) and its homologue, MIF-2, in males during MS progression; and that genetically high-MIF-expressing male subjects with relapsing multiple sclerosis (MS) had a significantly greater risk of conversion to progressive MS than lower-MIF-expressing males and females. However, female MS subjects with severe disease expressed higher levels of CD74, the common MIF-1/MIF-2 receptor, on blood cells. In the murine model of MS, experimental autoimmune encephalomyelitis (EAE), both male and female mice lacking MIF-1 and/or MIF-2 were clinically improved during development of moderately severe disease, thus implicating both homologs as co-pathogenic contributors. The current study using MIF-deficient mice with severe acute EAE revealed a highly significant reduction of EAE scores in MIF-1-deficient females, in contrast to only minor and delayed reduction of clinical signs in MIF-1-deficient males. However, clinical EAE scores and factor expression were strongly suppressed in males and further reduced in females after treatment of WT and MIF-1-, MIF-2- and MIF-1/2-DUAL-deficient female and male mice with a MHCII DRα1-MOG-35-55 molecular construct that competitively inhibits MIF-1 & MIF-2 signaling through CD74 as well as T cell activation. These results suggest sex-dependent differences in which the absence of the MIF-1 and/or MIF-2 genotypes may permit stronger compensatory CD74-dependent EAE-inducing responses in males than in females. However, EAE severity in both sexes could still be reduced nearly to background (a "near cure") with DRα1-MOG-35-55 blockade of compensatory MIF and CD74-dependent factors known to attract peripheral inflammatory cells into the spinal cord tissue.
(Published by Elsevier Inc.)
Databáze: MEDLINE
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