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Principal Investigator: Jamil Azzi
Organization: BRIGHAM AND WOMEN'S HOSPITAL
Fiscal Year: 2024
Award: $440,383
Funding agency: National Institute of Allergy and Infectious Diseases
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.
Terms: <Acute><Affect><Allografting><Antigens><Assay><Autocrine Systems><Autoregulation><BALB C Mouse><BALB/c><Basal Transcription Factor><Basal transcription factor genes><Binding><Bioassay><Biological Assay><CD8><CD8 Cell><CD8 T cells><CD8 lymphocyte><CD8+ T cell><CD8+ T-Lymphocyte><CD8-Positive Lymphocytes><CD8-Positive T-Lymphocytes><CD8B><CD8B1><CD8B1 gene><Cardiac Transplantation><Cell Body><Cell Communication and Signaling><Cell Function><Cell Physiology><Cell Process><Cell Signaling><Cells><Cellular Function><Cellular Physiology><Cellular Process><ChIP Sequencing><ChIP-seq><ChIPseq><Chronic><Clinical Treatment Moab><Co-Immunoprecipitations><Complex><Data><Dose><Eragrostis><Exhibits><FDA approved><FOXP3><FOXP3 gene><Flow Cytofluorometries><Flow Cytofluorometry><Flow Cytometry><Flow Microfluorimetry><Flow Microfluorometry><Forkhead Box P3><Gene Expression><Gene Transcription><General Transcription Factor Gene><General Transcription Factors><Generations><Genes><Genetic><Genetic Transcription><Grafting Procedure><Heart Grafting><Heart Transplantation><Homeostasis><Human><IFN><IRF-1><IRF1><IRF1 gene><Immune><Immunes><Immunomodulation><Impairment><In Vitro><Inbred BALB C Mice><Infiltration><Inflammation><Inflammatory><Innate Immunity><Interferon Regulatory Factor 1><Interferons><Intracellular Communication and Signaling><JM2><LYT3><Luciferase Immunologic><Luciferases><Macrophage><Macrophage Migration Inhibition Factors><Macrophage Migration Inhibitory Factor><Mediating><Mice><Mice Mammals><Migration Inhibition Factor><Migration Inhibitory Factor><Modeling><Modern Man><Molecular><Molecular Interaction><Monoclonal Antibodies><Murine><Mus><MyD32 protein><Myeloid Cells><Mφ><Native Immunity><Natural Immunity><Non-Specific Immunity><Nonspecific Immunity><Organ Transplantation><Organ Transplants><Outcome><Pathway interactions><Phenotype><Physiological Homeostasis><Play><Process><Proliferating><RNA Expression><Receptor Protein><Regimen><Regulatory T-Lymphocyte><Role><SCURFIN><Signal Pathway><Signal Transduction><Signal Transduction Systems><Signaling><Solid><Specificity><Subcellular Process><Surface><T cell receptor repertoire sequencing><T cell receptor sequencing><T memory cell><T-Cells><T-Lymphocyte><T8 Cells><T8 Lymphocytes><TCR repertoire sequencing><TCR sequencing><TCR-seq><TCRseq><Tamoxifen><Techniques><Technology><Teff><Teff cell><Testing><Therapeutic><Transcription><Transcription Factor Proto-Oncogene><Transcription factor genes><Transgenic Mice><Transplant Recipients><Transplantation><Transplantation Tolerance><Treatment Efficacy><Treg><Work><adaptive immunity><allograft rejection><alloimmunity><arylpyruvate keto-enol tautomerase><autocrine><biological signal transduction><cardiac allograft><cardiac graft><chromatin immunoprecipitation-sequencing><clinical relevance><clinically relevant><conditional knock-out><conditional knockout><cytokine><cytotoxic><draining lymph node><effector T cell><exhaustion><flow cytophotometry><heart allograft><heart transplant><immune modulation><immune regulation><immunogen><immunologic reactivity control><immunomodulatory><immunoregulation><immunoregulatory><in vivo><insight><interferon-stimulated gene factor 1><intervention efficacy><isoimmunity><mAbs><memory T lymphocyte><monoclonal Abs><new drug treatments><new drugs><new pharmacological therapeutic><new therapeutics><new therapy><next generation therapeutics><novel><novel drug treatments><novel drugs><novel pharmaco-therapeutic><novel pharmacological therapeutic><novel therapeutics><novel therapy><organ allograft><organ graft><organ xenograft><p-hydroxyphenylpyruvate tautomerase><pathway><phenylpyruvate tautomerase><programs><promoter><promotor><receptor><regional lymph node><regulatory T-cells><response><social role><therapeutic efficacy><therapeutic target><therapy efficacy><thymus derived lymphocyte><transcription factor><transcriptomics><translational opportunities><translational potential><transplant><transplant model><transplant patient>