TY - JOUR
T1 - “Near Cure” treatment of severe acute EAE in MIF-1-deficient female and male mice with a bifunctional MHCII-derived molecular construct
AU - Vandenbark, Arthur A.
AU - Meza-Romero, Roberto
AU - Wiedrick, Jack
AU - Gerstner, Grant
AU - Seifert, Hilary
AU - Kent, Gail
AU - Piechycna, Marta
AU - Benedek, Gil
AU - Bucala, Richard
AU - Offner, Halina
N1 - Funding Information:
This work was funded by the Department of Veterans Affairs, Veterans Health Administration, Office of Research and Development, Biomedical Laboratory Research and Development Merit Review Award 2I01 BX000226 (AV), BLR&D Merit Review for Pre-IND studies of Drugs and Biologics Award 5I01 BX005112 (AV), Senior Research Career Scientist Award 1IK6BX004209 (AV), the National Institute of Allergy and Infectious Diseases awards 2R42AI122574 (AV) and R21 AI148409 (HO), and the National Institute of Arthritis and Musculoskeletal and Skin Diseases award 1R01AR078334 (RB). The contents do not represent the views of the Department of Veterans Affairs or the US Government.
Publisher Copyright:
© 2022
PY - 2022/8
Y1 - 2022/8
N2 - 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.
AB - 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.
KW - Central nervous system (CNS)
KW - Cytokines/chemokines
KW - DRα1-MOG-35-55 construct, CD74
KW - Eperimental autoimmune encephalomyelitis (EAE)
KW - Inflammation
KW - Macrophage migration inhibitory factors (MIF-1 & MIF-2)
KW - Multiple sclerosis (MS)
KW - Sex differences
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U2 - 10.1016/j.cellimm.2022.104561
DO - 10.1016/j.cellimm.2022.104561
M3 - Article
C2 - 35738135
AN - SCOPUS:85132733490
VL - 378
JO - Cellular Immunology
JF - Cellular Immunology
SN - 0008-8749
M1 - 104561
ER -