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The novel role of MIF-CD74 inflammatory pathway in immune regulation

Award Number: R01AI179986
ORGANIZATION: NATIONAL INSTITUTE OF ALLERGY & INFECTIOUS DISEASES
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 12/01/2023
PERIOD OF PERFORMANCE END DATE: 10/31/2028

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The novel role of MIF-CD74 inflammatory pathway in immune regulation - Inflammation negatively affects Tregs stability and suppressive function, impairs the induction of solid organ transplant tolerance and enhances acute and chronic rejection, leading to worse recipients’ long-term outcomes. Insights into key inflammatory pathways that suppress Tregs during allo-immune activation can revolutionize our therapeutic approach to promoting stable endogenous Tregs. Our work strongly suggests that an inflammatory cytokine, macrophage migration inhibitory factor (MIF), secreted by myeloid cells and alloreactive T cells during rejection and inflammation binds CD74 (MIF receptor) on the surface of activated Tregs to dampen its function and homeostasis with opposite effect on alloreactive T cells. We show that inhibiting this novel pathway either through monoclonal antibodies or genetic deletion promotes immune regulation and induce exhaustion of alloreactive T cells leading to indefinite heart allograft survival in a murine fully mismatched model. MIF is a potent pro-inflammatory cytokine produced and released by immune cells, particularly macrophages, and plays an integral role in innate immunity. However, its role in adaptive immunity is not well known and will be investigated. Our data show that graft infiltrating Tregs and Teff upregulate their expression of MIF receptor CD74. However, graft infiltrating myeloid cells and Teff but not Tregs secrete MIF. MIF then binds to CD74 on Tregs surface to suppress and on Teff to promote their function. Our single cell transcriptomic analysis, TCR sequencing, flow cytometry and functional assays showed that CD74 deficient graft infiltrating Tregs reduced Interferon regulatory factor 1 (IRF1) and shifted toward a more stable Treg phenotype that exhibits superior suppressive ability in vitro and in vivo. IRF1 is a negative regulator of Foxp3 transcriptional activity that contributes significantly to Treg instability in the setting of inflammation. Interestingly, CD74 signaling is exerted through its intracellular-domain (ICD), shown to bind to transcription factors to modulate gene expression. Recent work identified IRF1 as one of the binding TFs for CD74-ICD13. In this application we will test the hypothesis that a novel inflammatory pathway in which MIF produced by myeloid cells and Teff suppresses Treg function through IRF1 mediated CD74 signaling (SA1), while promoting the Teff function (SA2). We will also develop a clinically relevant strategy to dampen the MIF mediated inflammatory process in the allograft using anti-CD74 monoclonal antibody generated in our lab (SA3). This anti-mouse CD74 is equivalent to the FDA approved human anti CD74 (milatuzumab). Hence, this work has high translation potentials.


Issue Date FY	Funding FY	Legal Entity Name	Legal Entity Address	Legal Entity City	Legal Entity State	Legal Entity Zip Code	Legal Entity COUNTY	Legal Entity COUNTRY	Assistance Listing	Award Code	Budget Year	Action Date	Action Type	Action Amount

Issue Date FY: 2026 ( Subtotal = $420,683 )
2026	2026	BRIGHAM & WOMENS HOSPITAL INC	75 FRANCIS ST	BOSTON	MA	02115	SUFFOLK	USA	Allergy and Infectious Diseases Research	000	3	12/5/2025	NON-COMPETING CONTINUATION	$420,683
														Subtotal = $420,683

Issue Date FY: 2025 ( Subtotal = $408,062 )
2025	2025	BRIGHAM & WOMENS HOSPITAL INC	75 FRANCIS ST	BOSTON	MA	02115	SUFFOLK	USA	Allergy and Infectious Diseases Research	000	2	11/7/2024	NON-COMPETING CONTINUATION	$408,062
														Subtotal = $408,062

Issue Date FY: 2024 ( Subtotal = $440,383 )
2024	2024	BRIGHAM & WOMENS HOSPITAL INC	75 FRANCIS ST	BOSTON	MA	02115	SUFFOLK	USA	Allergy and Infectious Diseases Research	001	1	9/3/2024	NEW	$44,039
2024	2024	BRIGHAM & WOMENS HOSPITAL INC	75 FRANCIS ST	BOSTON	MA	02115	SUFFOLK	USA	Allergy and Infectious Diseases Research	000	1	11/28/2023	NEW	$396,344
														Subtotal = $440,383

Grand Total All Awards = $1,269,128

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The novel role of MIF-CD74 inflammatory pathway in immune regulation

Award Number: R01AI179986

ORGANIZATION: NATIONAL INSTITUTE OF ALLERGY & INFECTIOUS DISEASES

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)

PERIOD OF PERFORMANCE START DATE: 12/01/2023

PERIOD OF PERFORMANCE END DATE: 10/31/2028

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