Multiple sclerosis (MS) and its murine model, experimental autoimmune encephalomyelitis (EAE), are chronic, debilitating autoimmune diseases of the central nervous system (CNS) characterized by extensive demyelination and axonal damage. One of the key cytokines thought to drive the early inflammatory stage of MS to a chonic progressive phase is Macrophage Migration Inhibitory Factor (MIF-1), the first described cytokine/chemokine. MIF-1 levels are increased in MS and this key factor has been implicated as a marker of clinical worsening in MS and as a requirement for disease progression in EAE. Our laboratory designed a potent biological construct called RTL1000 and a second generation derivative, DR?1-MOG-35-55, that bind tightly to the MIF-1 receptor, CD74, and competitively inhibit MIF-1 binding and downstream signaling. Recently, a second ligand for CD74 that is an ancestral functional homolog of MIF-1, called D-dopachrome tautamerase (DDT or MIF-2) was reported. The MIF-2 protein has only 35% homology with MIF-1 and is expressed at equivalent levels in most tissues. MIF-2 biological activities still require binding to CD74 and strongly overlap with those of MIF-1, requiring assessment of both MIF-1 and MIF-2 when evaluating MIF pathogenic activity. We have demonstrated previously that partial MHC class II constructs, including RTL1000 and DR?1-MOG-35-55 have potent therapeutic activity in EAE both are predicted to bind selectively to the same CD74 trimerization domain residues as MIF-1. However, it remains unstudied whether MIF-2 binds to these same regions of CD74 or if MIF-2 can be competitively inhibited by RTL1000 and DR?1-MOG-35-55. Based on our modeling data, we hypothesize that a common region of CD74 binds to distinct regions of the MIF-1 vs. MIF-2 homotrimers and that RTL1000 and DR?1-MOG-35-55 will competitively block binding and downstream signaling of both MIF-1 and MIF-2. This proposal will thus address the following Aims:
Aim 1 : Determine the effects on MIF-1 and MIF-2 binding and signaling using mutated CD74 constructs and interfering peptides based on predicted binding interactions.
Aim 2 : Compare the contributions of MIF-1 vs. MIF-2 on the onset, severity and progression of EAE in WT, MIF-1K, MIF-2KO and MIF double KO C57BL/6 mice.
Aim 3 : Test the ability of RTL1000 and DR?1-MOG-35-55 constructs to inhibit MIF-1 vs. MIF-2 binding and downstream signaling and to treat acute and chronic EAE in MIF-1KO, MIF-2KO and MIF double KO mice vs. WT mice. These studies will establish if RTL1000 and DR?1-MOG-35-55 can also competitively inhibit MIF-2 as well as MIF-1 disease-promoting effects in EAE through blockade of CD74-mediated signaling. Development of these novel therapeutic agents for MS could have a significant impact on the treatment of MS, which remains an important clinical problem for the VA. Version: 2-14-16
The pathogenic contribution of macrophage migration inhibitory factor (MIF)-1 in multiple sclerosis (MS) is well established, but no studies have evaluated the potentially pathogenic role of MIF-2, its recently described functional homolog, in MS. Our studies will determine for the first time the respective roles of MIF-1 vs. MIF-2 in experimental autoimmune encephalomyelitis (EAE), an animal model of MS, as well as the ability of our novel therapies to inhibit clinical and neurodegenerative effects of MIF-2 as well as MIF-1 known to be mediated through the MIF receptor, CD74. Knowledge obtained from these studies will ascertain whether a single therapeutic will be sufficient to successfully treat all MIF-induced, CD74 mediated effects or if additional pathogenic mechanisms exist that will require development of new therapeutics specific for MIF-2. These finding will contribute key new insights into MS pathogenesis that potentially can be reversed through the use of our novel therapeutic agents.
|Meza-Romero, Roberto; Benedek, Gil; Gerstner, Grant et al. (2018) Increased CD74 binding and EAE treatment efficacy of a modified DR?1 molecular construct. Metab Brain Dis :|
|Wang, Jianyi; Ye, Qing; Xu, Jing et al. (2017) DR?1-MOG-35-55 Reduces Permanent Ischemic Brain Injury. Transl Stroke Res 8:284-293|
|Benedek, Gil; Vandenbark, Arthur A; Alkayed, Nabil J et al. (2017) Partial MHC class II constructs as novel immunomodulatory therapy for stroke. Neurochem Int 107:138-147|
|Benedek, Gil; Chaudhary, Priya; Meza-Romero, Roberto et al. (2017) Sex-dependent treatment of chronic EAE with partial MHC class II constructs. J Neuroinflammation 14:100|
|Yang, Liu; Liu, Zhijia; Ren, Honglei et al. (2017) DR?1-MOG-35-55 treatment reduces lesion volumes and improves neurological deficits after traumatic brain injury. Metab Brain Dis 32:1395-1402|
|Yang, Liu; Kong, Ying; Ren, Honglei et al. (2017) Upregulation of CD74 and its potential association with disease severity in subjects with ischemic stroke. Neurochem Int 107:148-155|
|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|
|Meza-Romero, Roberto; Benedek, Gil; Jordan, Kelley et al. (2016) Modeling of both shared and distinct interactions between MIF and its homologue D-DT with their common receptor CD74. Cytokine 88:62-70|
|Meza-Romero, Roberto; Benedek, Gil; Leng, Lin et al. (2016) Predicted structure of MIF/CD74 and RTL1000/CD74 complexes. Metab Brain Dis 31:249-55|
|Benedek, Gil; Meza-Romero, Roberto; Jordan, Kelley et al. (2015) HLA-DR?1-mMOG-35-55 treatment of experimental autoimmune encephalomyelitis reduces CNS inflammation, enhances M2 macrophage frequency, and promotes neuroprotection. J Neuroinflammation 12:123|
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