The autoimmune inflammation of rheumatoid arthritis (RA) induces profound invasive and proliferative changes in the joint synovium. Our research has focused on the role of the cytokine MIF, which we initially cloned together with its two-component receptor and found to sustain inflammatory responses by counter-regulating glucocorticoid action and inhibiting activation-induced apoptosis. We identified functional polymorphisms in the MIF promoter that are associated with disease severity and we developed an anti-MIF monoclonal antibody that has entered phase I clinical testing. While investigating the mechanistic basis for phenotypic differences between MIF and MIF receptor deficient mice, we discovered a new MIF-like cytokine encoded by the Ddt locus. Our data indicate that DDT is expressed in RA and exerts immunoregulatory functions by interacting with the CD74, ligand- binding component of the MIF receptor. DDT shares structural features with MIF but there are differences that are important in considering the therapeutic inhibition of these cytokines or thei signaling pathways. In this renewal application, we will determine the distinct immunologic actions of the novel cytokine DDT by pursuing three Specific Aims: 1. Define the Mechanism of DDT Signal Transduction. We hypothesize that DDT initiates signal transduction via the canonical MIF ligand-binding receptor CD74, and that it recruits additional co-receptors (CD44, CXCR2/4) to mediate shared or unique effector responses. We will ask if DDT, which lacks the pseudo-(E)LR motif by which MIF interacts with CXCR2/4, activates these or related co-receptors. We also will examine if DDT shares MIF's role in suppressing insulin signaling, as metabolic dysfunction and atherogenesis are important sequela of long-standing rheumatoid inflammation. 2. Define the Functional Importance of DDT in Inflammatory Arthritis. We hypothesize that DDT exerts a non-redundant role in the immunopathogenesis of inflammatory arthritis. We will define the phenotype of DDT-KO and MIF-DDT double-knockout (DKO) mice in experimental arthritis and compare them to MIF-KO and MIF receptor-KO (CD74-KO) mice. We will examine cross-regulation of MIF and DDT signaling in monocytes and fibroblasts from corresponding genetically-defined mouse strains. 3. Evaluate the Therapeutic Potential of Pharmacologic DDT Inhibition. We hypothesize that DDT neutralization ameliorates arthritis by innate and/or adaptive immune mechanisms. We will test a novel anti-DDT mAb and a soluble CD74-Fc fusion protein, which binds both MIF and DDT. We also will test the therapeutic activity of a small molecule, selective DDT inhibitor identified by computational screening. The discovery of DDT as a novel cytokine interacting with the MIF receptor CD74 was unforeseen but requires close examination for a better understanding of these cytokines in synovial inflammation and for the effective application of pharmacologic inhibitors.

Public Health Relevance

Our knowledge of rheumatoid arthritis is incomplete and long-lasting remissions remain difficult to achieve. A genetic association between the immune cytokine MIF (macrophage migration inhibitory factor) and rheumatoid arthritis has been described, and a MIF-directed therapy has advanced into clinical testing. Investigation of the mechanism of action of DDT, a newly discovered MIF family cytokine, will accelerate the development of new and effective therapies for autoimmune arthritis.

Agency
National Institute of Health (NIH)
Institute
National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS)
Type
Research Project (R01)
Project #
5R01AR049610-15
Application #
9228236
Study Section
Arthritis, Connective Tissue and Skin Study Section (ACTS)
Program Officer
Mao, Su-Yau
Project Start
2002-08-21
Project End
2019-02-28
Budget Start
2017-03-01
Budget End
2018-02-28
Support Year
15
Fiscal Year
2017
Total Cost
$318,431
Indirect Cost
$127,181
Name
Yale University
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
043207562
City
New Haven
State
CT
Country
United States
Zip Code
06520
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Ochi, Akinobu; Chen, Dong; Schulte, Wibke et al. (2017) MIF-2/D-DT enhances proximal tubular cell regeneration through SLPI- and ATF4-dependent mechanisms. Am J Physiol Renal Physiol 313:F767-F780
Radomir, Lihi; Cohen, Sivan; Kramer, Matthias P et al. (2017) T Cells Regulate Peripheral Naive Mature B Cell Survival by Cell-Cell Contact Mediated through SLAMF6 and SAP. J Immunol 199:2745-2757
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Benedek, Gil; Meza-Romero, Roberto; Jordan, Kelley et al. (2017) MIF and D-DT are potential disease severity modifiers in male MS subjects. Proc Natl Acad Sci U S A 114:E8421-E8429
You, Sungyong; Koh, Jung Hee; Leng, Lin et al. (2017) The Tumor-like Phenotype of Rheumatoid Synovium: Molecular Profiling and Prospects for Precision Medicine. Arthritis Rheumatol :
Yoo, Seung-Ah; Leng, Lin; Kim, Bum-Joon et al. (2016) MIF allele-dependent regulation of the MIF coreceptor CD44 and role in rheumatoid arthritis. Proc Natl Acad Sci U S A 113:E7917-E7926
Djudjaj, Sonja; Lue, Hongqi; Rong, Song et al. (2016) Macrophage Migration Inhibitory Factor Mediates Proliferative GN via CD74. J Am Soc Nephrol 27:1650-64

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