Current pharmaceutical agents that are used for the treatment of immune-mediated inflammatory conditions including autoimmune diseases generally do not lead to remission and frequently carry toxic side effects. Here we propose a strategy that can harness the capacity of the immune system to induce immuno regulatory response that can suppress immune hyperactivity and chronic inflammation in vivo. The product that we propose consists of nanoparticles (NPs) targeted to immune regulatory cells for their expansion and functional activity in vitro and in vivo. Our approach to generate and expand functional immune regulatory cells that become impaired in autoimmune diseases should contribute to restoring immune homeostasis and improve disease outcomes. This approach is especially designed to treat systemic lupus erythematosus. The proof-of-concept for this Phase 1 studies will be to show that our cell-targeted NPs can markedly expand ex vivo both CD4+ and CD8+ Tregs, and TGF-Ã producing NK regulatory cells that we recently described. Complementary experiments in humanizedmice will address the in vivo functional efficacy of those NP-induced immunoregulatory cells insuppressing effector immune responses in vivo, including in an animal model of human lupus. By demonstrating that NP-expanded human immune regulatory cells are functional in vivo in humanized mice, we propose a new nanoimmuno therapeutic approach to restore immune regulation and inducer emission in autoimmune disease. Importantly, this in vivo cell-targeted strategy has the potential to overcome the undesired side effects of the broadly non-specific, anti-inflammatory and immune suppressive drugs presently used to treat autoimmune diseases.
Public Health Relevance Statement: PROJECT NARRATIVE (Relevance to Public Health) According to the National Institutes of Health, up to 23.5 million Americans (more than 7% of the population) suffer from an autoimmune disease - and the prevalence is rising. Autoimmune diseases can cause severe disability due to the lack of a cure, and the drugs used to suppress inflammation focus on delaying disease progression to reduce mortality but often have serious adverse side effects. This proposal describes a new strategy that uses nanoparticles to deliver therapeutic agents in minute amounts (thus minimizing toxicity) for the expansion of immune cells that effectively suppress inflammation and rebalance the autoimmune abnormalities in vivo.
Project Terms: Anti-Inflammatory Agents, Anti-Inflammatories, Anti-inflammatory, Antiinflammatories, Antiinflammatory Agents, antiinflammatory, Antibodies, Antigen-Presenting Cells, accessory cell, Antigens, immunogen, Attention, Autoantibodies, autoimmune antibody, autoreactive antibody, self reactive antibody, Autoantigens, Autologous Antigens, Self-Antigens, Autoimmune Diseases, autoimmune condition, autoimmune disorder, Autoimmunity, Autoimmune Status, B-Lymphocytes, B blood cells, B cell, B cells, B-Cells, B-cell, Biological Assay, Assay, Bioassay, Biologic Assays, Cells, Cell Body, Clinical Trials, Insulin-Dependent Diabetes Mellitus, Brittle Diabetes Mellitus, IDDM, Juvenile-Onset Diabetes Mellitus, Ketosis-Prone Diabetes Mellitus, Sudden-Onset Diabetes Mellitus, T1 DM, T1 diabetes, T1D, T1DM, Type 1 Diabetes Mellitus, Type 1 diabetes, Type I Diabetes Mellitus, insulin dependent diabetes, juvenile diabetes, juvenile diabetes mellitus, ketosis prone diabetes, type I diabetes, type one diabetes, Disease, Disorder, Experimental Autoimmune Encephalomyelitis, EAE, Experimental Allergic Encephalitis, Experimental Allergic Encephalomyelitis, Experimental Autoimmune Encephalitis, autoimmune encephalomyelitis, Engineering, Environment, Flow Cytometry, Flow Cytofluorometries, Flow Cytofluorometry, Flow Microfluorimetry, Flow Microfluorometry, flow cytophotometry, Goals, graft vs host disease, GvHD, Homologous Wasting Disease, Runt Disease, graft versus host disease, graft vs. host disease, Grant, Homeostasis, Autoregulation, Physiological Homeostasis, Human, Modern Man, Immune system, allergic/immunologic body system, allergic/immunologic organ system, Immune Tolerance, Immunologic Tolerance, immune system tolerance, immune unresponsiveness, immunological paralysis, Immunosuppressive Agents, Immunosuppressants, Immunosuppressive drug, Immunosuppressive treatment, immune suppressive agent, immune suppressor, immunosuppressive substance, immunosuppressor, In Vitro, Inflammation, Interleukin-2, Co-Stimulator, Costimulator, Epidermal Thymocyte Activating Factor, IL-2, IL2 Protein, Interleukin 2, Interleukin 2 Precursor, Interleukin II, Interleukine 2, Interleukine 2 Precursor, Interleukine II, Lymphocyte Mitogenic Factor, Mitogenic Factor, T cell growth factor, T-Cell Growth Factor, T-Cell Stimulating Factor, Thymocyte Stimulating Factor, Natural Killer Cells, Cytotoxic cell, K lymphocyte, NK Cells, Learning, Systemic Lupus Erythematosus, Lupus Erythematosus Disseminatus, SLE, Systemic Lupus Erythematous, Systemic Lupus Erythmatosus, disseminated lupus erythematosus, systemic lupus erythematosis, Lymphocyte, Lymphatic cell, Lymphocytic, lymph cell, Methodology, mortality, Multiple Sclerosis, Disseminated Sclerosis, insular sclerosis, Mus, Mice, Mice Mammals, Murine, NIH, National Institutes of Health, United States National Institutes of Health, Peptides, Phenotype, Play, Production, Public Health, Publishing, social role, Role, Safety, Suppressor Cells, Suppressor-Effector T-Cells, T Suppressor Cell, suppressor T lymphocyte, Suppressor-Effector T-Lymphocytes, T-Cells, thymus derived lymphocyte, T-Lymphocyte, Treg, regulatory T-cells, Regulatory T-Lymphocyte, Time, Tissues, Body Tissues, Transforming Growth Factor beta, Bone-Derived Transforming Growth Factor, Milk Growth Factor, Platelet Transforming Growth Factor, TGF B, TGF-beta, TGF-β, TGFbeta, TGFβ, Transforming Growth Factor-Beta Family Gene, Work, cytokine, Generations, Mediating, CD3 Antigens, CD3, CD3 Complex, CD3 molecule, OKT3 antigen, T3 Antigens, T3 Complex, T3 molecule, Chimeric Proteins, Chimera Protein, Fusion Protein, improved, Chronic, Clinical, Encapsulated, Phase, disability, Individual, drug use, Drug usage, Disease Progression, Immunological response, host response, immune system response, immunoresponse, Immune response, Therapeutic, Therapeutic Agents, Inflammatory, Immunes, Immune, Host Defense, Remission, Disease remission, American, Animal Models and Related Studies, model of animal, model organism, Animal Model, PBMC, Peripheral Blood Mononuclear Cell, Toxicities, Toxic effect, Immunomodulation, immune modulation, immune regulation, immunologic reactivity control, immunomodulatory, immunoregulatory, immunoregulation, Disease Outcome, novel, Property, response, Alpha Interleukin 2 Receptor, IL-2Ralpha, IL-2Rα, Low Affinity Interleukin 2 Receptor, alpha-subunit, receptor, interleukin-2, interleukin-2Ralpha, Pathogenicity, Pharmaceutical Agent, Pharmaceuticals, Pharmacological Substance, Pharmacologic Substance, preventing, prevent, CD8, CD8B, CD8B1, LYT3, CD8B1 gene, Address, Artificial nano particles, engineered nano particle, engineered nanoparticle, Artificial nanoparticles, Recombinants, in vivo, Lymphocyte Function, Process, autoreactive T cell, self-reactive T cell, cost, virtual, design, designing, Lupus, novel strategies, new approaches, novel approaches, novel strategy, nanoparticle, nano particle, nano-sized particle, nanosized particle, scale up, cost effective, Population, Prevalence, Impairment, lupus-like, in vitro activity, comparative efficacy, compare efficacy, phase 1 study, Phase I Study, FOXP3 gene, FOXP3, Forkhead Box P3, JM2, SCURFIN, Formulation, humanized mouse, humanized mice, experimental study, experiment, experimental research, human model, model of human, Nanoimmunotherapy, Nano immunotherapy, side effect, effector T cell, Teff cell, Hyperactivity, Autoimmune
