title: Selective Targeting of a Disease-Related Conformational Isoform of Macrophage Migration Inhibitory Factor Ameliorates Inflammatory Conditions.
abstract: Macrophage migration inhibitory factor (MIF), a proinflammatory cytokine and counterregulator of glucocorticoids, is a potential therapeutic target. MIF is markedly different from other cytokines because it is constitutively expressed, stored in the cytoplasm, and present in the circulation of healthy subjects. Thus, the concept of targeting MIF for therapeutic intervention is challenging because of the need to neutralize a ubiquitous protein. In this article, we report that MIF occurs in two redox-dependent conformational isoforms. We show that one of the two isoforms of MIF, that is, oxidized MIF (oxMIF), is specifically recognized by three mAbs directed against MIF. Surprisingly, oxMIF is selectively expressed in the plasma and on the cell surface of immune cells of patients with different inflammatory diseases. In patients with acute infections or chronic inflammation, oxMIF expression correlated with inflammatory flare-ups. In addition, anti-oxMIF mAbs alleviated disease severity in mouse models of acute and chronic enterocolitis and improved, in synergy with glucocorticoids, renal function in a rat model of crescentic glomerulonephritis. We conclude that oxMIF represents the disease-related isoform of MIF; oxMIF is therefore a new diagnostic marker for inflammation and a relevant target for anti-inflammatory therapy.
authors.affiliation: Baxter Biomedical Research Center, Baxter Innovations GmbH, 2304 Orth/Donau, Austria;
authors.forename: Michael
authors.initials: M
authors.lastname: Thiele
authors.affiliation: Baxter Biomedical Research Center, Baxter Innovations GmbH, 2304 Orth/Donau, Austria; randolf_kerschbaumer@baxter.com.
authors.forename: Randolf J
authors.initials: RJ
authors.lastname: Kerschbaumer
authors.affiliation: Imperial College Renal and Transplant Centre, Hammersmith Hospital, London W12 0NN, United Kingdom;
authors.forename: Frederick W K
authors.initials: FW
authors.lastname: Tam
authors.affiliation: Baxter Biomedical Research Center, Baxter Innovations GmbH, 2304 Orth/Donau, Austria;
authors.forename: Dirk
authors.initials: D
authors.lastname: Völkel
authors.affiliation: Baxter Biomedical Research Center, Baxter Innovations GmbH, 2304 Orth/Donau, Austria;
authors.forename: Patrice
authors.initials: P
authors.lastname: Douillard
authors.affiliation: Baxter Biomedical Research Center, Baxter Innovations GmbH, 2304 Orth/Donau, Austria;
authors.forename: Alexander
authors.initials: A
authors.lastname: Schinagl
authors.affiliation: Baxter Biomedical Research Center, Baxter Innovations GmbH, 2304 Orth/Donau, Austria;
authors.forename: Harald
authors.initials: H
authors.lastname: Kühnel
authors.affiliation: Imperial College Renal and Transplant Centre, Hammersmith Hospital, London W12 0NN, United Kingdom;
authors.forename: Jennifer
authors.initials: J
authors.lastname: Smith
authors.affiliation: Imperial College Renal and Transplant Centre, Hammersmith Hospital, London W12 0NN, United Kingdom;
authors.forename: John P
authors.initials: JP
authors.lastname: McDaid
authors.affiliation: Imperial College Renal and Transplant Centre, Hammersmith Hospital, London W12 0NN, United Kingdom;
authors.forename: Gurjeet
authors.initials: G
authors.lastname: Bhangal
authors.affiliation: Imperial College Renal and Transplant Centre, Hammersmith Hospital, London W12 0NN, United Kingdom;
authors.forename: Mei-Ching
authors.initials: MC
authors.lastname: Yu
authors.affiliation: Imperial College Renal and Transplant Centre, Hammersmith Hospital, London W12 0NN, United Kingdom;
authors.forename: Charles D
authors.initials: CD
authors.lastname: Pusey
authors.affiliation: Imperial College Renal and Transplant Centre, Hammersmith Hospital, London W12 0NN, United Kingdom;
authors.forename: H Terence
authors.initials: HT
authors.lastname: Cook
authors.affiliation: Department of Nephrology, Wilhelminenspital, 1160 Vienna, Austria;
authors.forename: Josef
authors.initials: J
authors.lastname: Kovarik
authors.affiliation: Department of Immunology, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA 02215;
authors.forename: Erica
authors.initials: E
authors.lastname: Magelky
authors.affiliation: Department of Pathology, Massachusetts General Hospital, Harvard Medical School, Boston, MA 02214;
authors.forename: Atul
authors.initials: A
authors.lastname: Bhan
authors.affiliation: Baxter Biomedical Research Center, Baxter Innovations GmbH, 2304 Orth/Donau, Austria;
authors.forename: Manfred
authors.initials: M
authors.lastname: Rieger
authors.affiliation: Baxter Biomedical Research Center, Baxter Innovations GmbH, 2304 Orth/Donau, Austria;
authors.forename: Geert C
authors.initials: GC
authors.lastname: Mudde
authors.affiliation: Baxter Biomedical Research Center, Baxter Innovations GmbH, 2304 Orth/Donau, Austria;
authors.forename: Hartmut
authors.initials: H
authors.lastname: Ehrlich
authors.affiliation: Department of Clinical Pharmacology, Medical University Vienna, 1090 Vienna, Austria; and.
authors.forename: Bernd
authors.initials: B
authors.lastname: Jilma
authors.affiliation: Department of Internal Medicine I, Endocrinology, Gastroenterology & Metabolism, Medical University Innsbruck, 6020 Innsbruck, Austria.
authors.forename: Herbert
authors.initials: H
authors.lastname: Tilg
authors.affiliation: Department of Internal Medicine I, Endocrinology, Gastroenterology & Metabolism, Medical University Innsbruck, 6020 Innsbruck, Austria.
authors.forename: Alexander
authors.initials: A
authors.lastname: Moschen
authors.affiliation: Department of Immunology, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA 02215;
authors.forename: Cox
authors.initials: C
authors.lastname: Terhorst
authors.affiliation: Baxter Biomedical Research Center, Baxter Innovations GmbH, 2304 Orth/Donau, Austria;
authors.forename: Friedrich
authors.initials: F
authors.lastname: Scheiflinger
mesh_terms: D000818:Animals; D000911:Antibodies, Monoclonal / Q000276:immunology / Q000627:therapeutic use; D015153:Blotting, Western; D003907:Dexamethasone / Q000276:immunology / Q000627:therapeutic use; D004195:Disease Models, Animal; D004760:Enterocolitis / Q000276:immunology / Q000378:metabolism / Q000517:prevention & control; D005434:Flow Cytometry; D005921:Glomerulonephritis / Q000276:immunology / Q000378:metabolism / Q000517:prevention & control; D005938:Glucocorticoids / Q000276:immunology / Q000627:therapeutic use; D006801:Humans; D007249:Inflammation / Q000276:immunology* / Q000378:metabolism / Q000517:prevention & control*; D008263:Macrophage Migration-Inhibitory Factors / Q000737:chemistry / Q000276:immunology* / Q000378:metabolism; D008297:Male; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D058990:Molecular Targeted Therapy / Q000379:methods*; D010084:Oxidation-Reduction; D011487:Protein Conformation; D020033:Protein Isoforms / Q000737:chemistry / Q000276:immunology / Q000378:metabolism; D011817:Rabbits; D011921:Rats, Inbred WKY
chemical_list: D000911:Antibodies, Monoclonal; D005938:Glucocorticoids; D008263:Macrophage Migration-Inhibitory Factors; D020033:Protein Isoforms; D003907:Dexamethasone