# Defining the Pathogenic Contribution of High Genotypic MIF Expression

> **NIH NIH R01** · YALE UNIVERSITY · 2022 · $364,815

## Abstract

PROJECT SUMMARY
 Rheumatoid arthritis (RA) remains incurable despite biologic therapies. We previously identified a
functional promoter polymorphism in the gene for macrophage migration inhibitory factor (MIF) - a cytokine
our group first cloned, that is associated with erosive joint destruction in RA. MIF is known to regulate the
innate response by inhibiting glucocorticoid action, suppressing activation-induced apoptosis, and
promoting macrophage retention in tissues. The role of MIF and high expression MIF alleles is not fully
understood however, especially with respect to alterations in the adaptive response that perpetuate
inflammation, pathologic progression, and disease persistence. We have discovered a novel T cell
subpopulation that expresses the MIF receptor (CD74), expands during arthritis, and recapitulates disease
when transferred into naïve hosts. A similar population exists in human rheumatoid synovium. We
hypothesize that CD4+CD74+ T cells play a key role in rheumatoid inflammation, disease progression, and
relapse. We will pursue three Specific Aims in this proposal: 1. Define the pathogenic role of a novel,
MIF receptor expressing T cell sub-population (CD4+CD74+ T cells) in inflammatory arthritis. We
hypothesize that CD4+CD74+ T cells express inflammatory cytokines and chemotactic receptors that
contribute to synovial joint destruction. We will characterize the MIF signaling and effector responses of
mouse and human CD4+CD74+ T cells, identify trafficking factors/receptors, and establish their pathogenic
potential. 2. Define the impact of high-genotypic MIF expression on joint immunopathology in a
novel humanized MIF mouse model. We hypothesize that MIF expression drives pathologic CD4+CD74+
T cell trafficking and effector responses, and unremitting arthritis. We will test this hypothesis using novel
humanized MIF mice that express low-expression and high-expression human MIF alleles. 3. Evaluate the
impact of ICBP90 inhibition on MIF expression in humanized MIF mice and in high genotypic MIF
expressing human cells. We identified both the transcription factor (ICBP90) that upregulates MIF
transcription at its variant promoter microsatellite (-794 CATT5-8), and a drug-like molecule (CMFT) that
blocks ICBP90 binding to this promoter site. We hypothesize that ICBP90 inhibition will ameliorate the MIF-
dependent expansion and effector response of CD4+CD74+ T cells. We will test this possibility in
experimental arthritis and examine ICBP90 inhibition in high-genotypic MIF expressing human cells
obtained from peripheral blood and from rheumatoid synovial tissue. The completion of these Aims will
provide insight into the pathologic role of a novel, MIF receptor expressing T cell population and the
contribution of MIF risk alleles to rheumatoid inflammation. These studies also will accelerate consideration
of a precision-based approach for treating RA joint destruction.

## Key facts

- **NIH application ID:** 10402761
- **Project number:** 5R01AR078334-02
- **Recipient organization:** YALE UNIVERSITY
- **Principal Investigator:** RICHARD J BUCALA
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $364,815
- **Award type:** 5
- **Project period:** 2021-06-01 → 2026-05-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10402761

## Citation

> US National Institutes of Health, RePORTER application 10402761, Defining the Pathogenic Contribution of High Genotypic MIF Expression (5R01AR078334-02). Retrieved via AI Analytics 2026-05-26 from https://api.ai-analytics.org/grant/nih/10402761. Licensed CC0.

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