Document text
Principal Investigator: Hao Cheng
Organization: DREXEL UNIVERSITY
Fiscal Year: 2023
Award: $350,000
Funding agency: National Institute of Allergy and Infectious Diseases
Project Summary
The immune system protects people from pathogens. However, it sometimes generates abnormal immune
reactions against harmless environmental antigens or patient’s own antigens, leading to allergy or autoimmune
diseases, respectively. These hypersensitivity disorders affect millions of Americans and are life-threatening in
severe conditions. Current therapeutic strategies often require lifelong treatment and/or broad
immunosuppression, causing adverse effects. The induction of antigen-specific immune tolerance is a promising
strategy to treat hypersensitivity without compromising immune protection because this strategy either
specifically eliminate the disease-related immune cells or restrains their hypersensitive response, leaving the
immune system intact. The tolerance may last lifelong once established. Although progress has been made in
this area, technologies that induce efficient antigen-specific immune tolerance remain to be developed. The key
to success in tolerance induction is the precise modulation of targeted immune cells. Compared to small drug
molecules, a set of proteins translated from delivered messenger RNAs (mRNAs) in immune cells can work
coordinately to transform the cells in a more precise manner. The success of COVID-19 mRNA vaccines has
validated mRNA delivery as a platform for antigen-specific immune stimulation. However, mRNA delivery for
inducing immune tolerance, an opposite effect as immune stimulation, has not been established. This is because
most reported mRNA delivery nanocarriers cause inflammatory response and/or cannot target the right antigen-
presenting cells (APCs) to initiate the process of tolerance induction. We have recently shown that our polymeric
nanoparticle could efficiently target liver sinusoidal endothelial cells (LSECs), which are a type of APCs naturally
helping the immune system maintain tolerance. We hypothesize that nanocarriers derived from this polymeric
nanoparticle can co-deliver antigens and mRNAs encoding tolerogenic proteins to LSECs to induce antigen-
specific immune tolerance. In our preliminary study, we demonstrated that such a nanocarrier can deliver mRNA
to LSECs in mice for protein translation after systemic administration. We also demonstrated that the nanocarrier
loaded with an antigen can inhibit the antigen-specific T cells from being restimulated after in vivo treatment of
mice. We will test our hypothesis by 1) evaluating diverse nanocarrier formulations encapsulating antigen and
mRNA in vitro; 2) investigating the biodistribution of selected nanocarriers and their tolerogenic potential in vivo;
3) demonstrating nanocarrier efficacy in animal disease models and elucidating the mechanism. Our proposed
study is expected to have a broad scientific and societal impact by achieving antigen-specific tolerance via mRNA
delivery.
Terms: <1,2-Ethanediol><2-Hydroxyethanol><Adoptive Transfer><Adverse effects><Affect><Allergens><Allergy><American><Animal Disease Models><Animal Model><Animal Models and Related Studies><Antigen Presentation><Antigen Targeting><Antigen-Presenting Cells><Antigenic Determinants><Antigens><Area><Asthma><Autoimmune Diseases><Autoimmune Status><Autoimmunity><Binding Determinants><Biocompatible Materials><Biodistribution><Biomaterials><Bone Marrow><Bone Marrow Reticuloendothelial System><Bone-Derived Transforming Growth Factor><Bronchial Asthma><CD4 Cells><CD4 Positive T Lymphocytes><CD4 T cells><CD4 helper T cell><CD4 lymphocyte><CD4+ T-Lymphocyte><CD4-Positive Lymphocytes><CD86><CD86 gene><COVID-19><COVID19><CSIF><CSIF-10><CV-19><CV19><Cell Body><Cells><Cellular Immune Function><Chemicals><Cytokine Synthesis Inhibitory Factor><Dendritic Cells><Dihydroxyethanes><Dioxanedione Polymer with Dimethyldioxanedione Polymer><Disease><Disease Outcome><Disorder><Disseminated Sclerosis><Drugs><EAE><Encapsulated><Endothelial Cells><Epitopes><Esters><Ethanediols><Ethylene Glycols><Experimental Allergic Encephalitis><Experimental Allergic Encephalomyelitis><Experimental Autoimmune Encephalitis><Experimental Autoimmune Encephalomyelitis><Fluorescence><Formulation><Glycolic-Lactic Acid Polyester><HLA-DR Associated Protein II><Hepatic Cells><Hepatic Parenchymal Cell><Hepatocyte><Hybrids><Hypersensitivity><IGAAD><IL-10><IL10><IL10A><Immune><Immune Targeting><Immune Tolerance><Immune reaction><Immune response><Immune system><Immunes><Immunologic Stimulation><Immunologic Tolerance><Immunological Stimulation><Immunological response><Immunomodulation><Immunostimulation><Immunosuppression><Immunosuppression Effect><Immunosuppressive Effect><In Vitro><Infection><Inflammatory><Inflammatory Response><Inhibitor of GZMA-Activated DNase><Injections><Interleukin 10 Precursor><Interleukin-10><Life><Ligand Binding><Lipids><Liver><Liver Cells><Medical><Medication><Messenger RNA><Methods><Mice><Mice Mammals><Milk Growth Factor><Modeling><Monoethylene Glycol><Mouse Protein><Multiple Sclerosis><Murine><Mus><Organ><Ovalbumin><Patients><Peptides><Persons><Pharmaceutic Preparations><Pharmaceutical Preparations><Phenotype><Phosphatase 2A Inhibitor I2PP2A><Platelet Transforming Growth Factor><Play><Poly(Lactide-Co-Glycolide)><Polyglactin><Polymers><Polynucleotides><Population><Predisposition><Process><Production><Proliferating><Proteins><RNA delivery><RNA vaccine><RNA-based vaccine><Regulatory T-Lymphocyte><Reporting><Research><Role><SET Translocation Inhibitor-2 of Protein Phosphatase-2A><Set protein><Susceptibility><T-Cells><T-Lymphocyte><T4 Cells><T4 Lymphocytes><TGF B><TGF-beta><TGF-β><TGFbeta><TGFβ><Tail><Technology><Template Activating Factor I Beta><Testing><Therapeutic><Transforming Growth Factor beta><Transforming Growth Factor-Beta Family Gene><Transgenic Organisms><Translating><Translations><Treg><Up-Regulation><Upregulation><Veiled Cells><Veins><Viral Diseases><Virus Diseases><Work><accessory cell><allergic airway epithelium inflammation><allergic airway inflammation><anergy><antigen-specific T cells><autoimmune condition><autoimmune disorder><autoimmune encephalomyelitis><autoimmunity disease><biological material><cell transformation><class material><corona virus disease 2019><coronavirus disease 2019><coronavirus disease-19><coronavirus infectious disease-19><course material><curricular material><cytokine><design><designing><drug/agent><ethylene glycol><exhaustion><extracellular><hepatic body system><hepatic organ system><host response><immune function><immune modulation><immune regulation><immune suppression><immune suppressive activity><immune suppressive function><immune system response><immune system tolerance><immune unresponsiveness><immunogen><immunologic reactivity control><immunological paralysis><immunomodulatory><immunoreaction><immunoregulation><immunoregulatory><immunoresponse><immunosuppressive activity><immunosuppressive function><immunosuppressive response><in vivo><insight><instructional materials><insular sclerosis><learning materials><mRNA><mRNA vaccine><mRNA-based vaccine><model of animal><mouse model><murine model><nano materials><nano particle><nano polymer><nano-sized particle><nanocarrier><nanomaterials><nanoparticle><nanopolymer><nanosized particle><nanovessel><novel><pathogen><polymer><polymeric><programs><regulatory T-cells><response><restraint><small molecule><social role><success><thymus derived lymphocyte><transformed cells><transgenic><translation><viral infection><virus infection><virus-induced disease>