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1.
Front Med (Lausanne) ; 9: 1070529, 2022.
Article in English | MEDLINE | ID: mdl-36619639

ABSTRACT

In addition to complications of acute diseases, chronic viral infections are linked to both malignancies and autoimmune disorders. Lack of adequate treatment options for Epstein-Barr virus (EBV), Human T-lymphotropic virus type 1 (HTLV-1), and human papillomavirus (HPV) remains. The NexImmune Artificial Immune Modulation (AIM) nanoparticle platform can be used to direct T cell responses by mimicking the dendritic cell function. In one application, AIM nanoparticles are used ex vivo to enrich and expand (E+E) rare populations of multi-antigen-specific CD8+ T cells for use of these cells as an AIM adoptive cell therapy. This study has demonstrated using E+E CD8+ T cells, the functional relevance of targeting EBV, HTLV-1, and HPV. Expanded T cells consist primarily of effector memory, central memory, and self-renewing stem-like memory T cells directed at selected viral antigen peptides presented by the AIM nanoparticle. T cells expanded against either EBV- or HPV-antigens were highly polyfunctional and displayed substantial in vitro cytotoxic activity against cell lines expressing the respective antigens. Our initial work was in the context of exploring T cells expanded from healthy donors and restricted to human leukocyte antigen (HLA)-A*02:01 serotype. AIM Adoptive Cell Therapies (ACT) are also being developed for other HLA class I serotypes. AIM adoptive cell therapies of autologous or allogeneic T cells specific to antigens associated with acute myeloid leukemia and multiple myeloma are currently in the clinic. The utility and flexibility of the AIM nanoparticle platform will be expanded as we advance the second application, an AIM injectable off-the-shelf nanoparticle, which targets multiple antigen-specific T cell populations to either activate, tolerize, or destroy these targeted CD8+ T cells directly in vivo, leaving non-target cells alone. The AIM injectable platform offers the potential to develop new multi-antigen specific therapies for treating infectious diseases, cancer, and autoimmune diseases.

2.
Int J Mol Sci ; 22(4)2021 Feb 18.
Article in English | MEDLINE | ID: mdl-33670600

ABSTRACT

Rheumatoid arthritis (RA) is an autoimmune disease characterized by chronic inflammation of the synovial joints. Inflammation, new blood vessel formation (angiogenesis) and bone resorption (osteoclastogenesis) are three key processes involved in the joint damage and deformities of arthritis. Various gut microbiota-derived metabolites are implicated in RA pathogenesis. However, there is barely any information about the impact of two such metabolites, indole-3-aldehyde (IAld) and indole-3-acetic acid (I3AA), on arthritis-related processes. We conducted a comparative analysis of IAld and I3AA using established cell-based models to understand how they might influence RA pathogenesis. Although structurally similar, the bioactivities of these two metabolites were profoundly different. IAld but not I3AA, inhibited the expression of pro-inflammatory cytokines (IL-1ß and IL-6) in RAW 264.7 (RAW) cells stimulated with heat-killed M. tuberculosis sonicate (Mtb) and lipopolysaccharide (LPS). IAld also exhibited pro-angiogenic activity and pro-osteoclastogenic activity. In contrast, I3AA exhibited anti-angiogenic activity on endothelial cell tube formation but had no effect on osteoclastogenesis. Both IAld and I3AA have been proposed as aryl hydrocarbon receptor (AhR) agonists. Use of CH-223191, an inhibitor of the AhR, suppressed the anti-angiogenic activity of I3AA but failed to mitigate the effects of IAld. Further investigation of the anti-inflammatory activities of IAld and I3AA in LPS-treated RAW cells indicated that inhibition of MyD88-dependent activation of NF-κB and MAPK pathways was not likely involved. Our results suggest that the relative bioavailability of these indole derivatives may differentially impact RA progression and possibly other diseases that share similar cellular processes.


Subject(s)
Arthritis, Rheumatoid/immunology , Autoimmune Diseases/immunology , Cytokines/immunology , Indoleacetic Acids/immunology , Indoles/immunology , Microbiota/immunology , Animals , Arthritis, Rheumatoid/metabolism , Autoimmune Diseases/metabolism , Cell Differentiation/drug effects , Cell Differentiation/immunology , Cells, Cultured , Cytokines/metabolism , Hot Temperature , Human Umbilical Vein Endothelial Cells/drug effects , Human Umbilical Vein Endothelial Cells/immunology , Human Umbilical Vein Endothelial Cells/physiology , Humans , Indoleacetic Acids/metabolism , Indoleacetic Acids/pharmacology , Indoles/metabolism , Indoles/pharmacology , Lipopolysaccharides/immunology , Lipopolysaccharides/pharmacology , Macrophages/drug effects , Macrophages/immunology , Macrophages/metabolism , Mice , Mycobacterium tuberculosis/immunology , Mycobacterium tuberculosis/metabolism , Neovascularization, Physiologic/drug effects , Neovascularization, Physiologic/immunology , Osteoclasts/cytology , Osteoclasts/drug effects , Osteoclasts/immunology , RAW 264.7 Cells
3.
Clin Immunol ; 212: 108361, 2020 03.
Article in English | MEDLINE | ID: mdl-32058071

ABSTRACT

Until recently, autoimmune disease research has primarily been focused on elucidating the role of the adaptive immune system. In the past decade or so, the role of the innate immune system in the pathogenesis of autoimmunity has increasingly been realized. Recent findings have elucidated paradigm-shifting concepts, for example, the implications of "trained immunity" and a dysbiotic microbiome in the susceptibility of predisposed individuals to clinical autoimmunity. In addition, the application of modern technologies such as the quantum dot (Qdot) system and 'Omics' (e.g., genomics, proteomics, and metabolomics) data-processing tools has proven fruitful in revisiting mechanisms underlying autoimmune pathogenesis and in identifying novel therapeutic targets. This review highlights recent findings discussed at the American Autoimmune Related Disease Association (AARDA) 2019 colloquium. The findings covering autoimmune diseases and autoinflammatory diseases illustrate how new developments in common innate immune pathways can contribute to the better understanding and management of these immune-mediated disorders.


Subject(s)
Autoimmune Diseases/immunology , Autoimmunity/immunology , Immunity, Innate/immunology , Immunologic Memory/immunology , Inflammation/immunology , Alarmins/immunology , Animals , Dysbiosis/immunology , Hereditary Autoinflammatory Diseases/immunology , Humans , Microbiota/immunology , Pathogen-Associated Molecular Pattern Molecules/immunology
4.
Cell Immunol ; 339: 59-67, 2019 05.
Article in English | MEDLINE | ID: mdl-30638679

ABSTRACT

Observations in patients with autoimmune diseases and studies in animal models of autoimmunity have revealed that external environmental factors including exposure to microbes and the state of the host gut microbiota can influence susceptibility to autoimmunity and subsequent disease development. Mechanisms underlying these outcomes continue to be elucidated. These include deviation of the cytokine response and imbalance between pathogenic versus regulatory T cell subsets. Furthermore, specific commensal organisms are associated with enhanced severity of arthritis in susceptible individuals, while exposure to certain microbes or helminths can afford protection against this disease. In addition, the role of metabolites (e.g., short-chain fatty acids, tryptophan catabolites), produced either by the microbes themselves or from their action on dietary products, in modulation of arthritis is increasingly being realized. In this context, re-setting of the microbial dysbiosis in RA using prebiotics, probiotics, or fecal microbial transplant is emerging as a promising approach for the prevention and treatment of arthritis. It is hoped that advances in defining the interplay between gut microbiota, dietary products, and bioactive metabolites would help in the development of therapeutic regimen customized for the needs of individual patients in the near future.


Subject(s)
Arthritis, Rheumatoid/immunology , Autoimmune Diseases/immunology , Autoimmunity/immunology , Gastrointestinal Microbiome/immunology , Animals , Dysbiosis/immunology , Humans , T-Lymphocyte Subsets/immunology
5.
Int J Mol Sci ; 19(9)2018 Aug 24.
Article in English | MEDLINE | ID: mdl-30149545

ABSTRACT

Rheumatoid arthritis (RA) is a chronic, debilitating illness characterized by painful swelling of the joints, inflammation of the synovial lining of the joints, and damage to cartilage and bone. Several anti-inflammatory and disease-modifying drugs are available for RA therapy. However, the prolonged use of these drugs is associated with severe side effects. Furthermore, these drugs are effective only in a proportion of RA patients. Hence, there is a need to search for new therapeutic agents that are effective yet safe. Interestingly, a variety of herbs and other natural products offer a vast resource for such anti-arthritic agents. We discuss here the basic features of RA pathogenesis; the commonly used animal models of RA; the mainstream drugs used for RA; the use of well-characterized natural products possessing anti-arthritic activity; the application of nanoparticles for efficient delivery of such products; and the interplay between dietary products and the host microbiome for maintenance of health and disease induction. We believe that with several advances in the past decade in the characterization and functional studies of natural products, the stage is set for widespread clinical testing and/or use of these products for the treatment of RA and other diseases.


Subject(s)
Anti-Inflammatory Agents/therapeutic use , Arthritis/drug therapy , Arthritis/immunology , Autoimmune Diseases/drug therapy , Biological Products/therapeutic use , Animals , Anti-Inflammatory Agents/pharmacology , Arthritis/etiology , Arthritis, Rheumatoid/drug therapy , Arthritis, Rheumatoid/etiology , Arthritis, Rheumatoid/pathology , Autoimmune Diseases/etiology , Biological Products/pharmacology , Biomarkers , Disease Models, Animal , Drug Carriers , Drug Delivery Systems , Drug Evaluation, Preclinical , Humans , Inflammation Mediators/metabolism , Microbiota , Molecular Targeted Therapy , Nanoparticles/chemistry , Plant Preparations/pharmacology , Plant Preparations/therapeutic use
6.
Emerg Microbes Infect ; 6(6): e46, 2017 Jun 07.
Article in English | MEDLINE | ID: mdl-28588288

ABSTRACT

Humoral responses are essential for the protective efficacy of most Ebola virus (EBOV) candidate vaccines; however, the in vivo development of protective anti-EBOV B-cell responses is poorly defined. Here, by using the virus-like particle (VLP) as a model antigen, we demonstrate that humoral responses are generated through follicular B-cell and T-cell-dependent mechanisms in a mouse model of EBOV infection. In addition, we show that the inclusion of the clinical-grade dsRNA adjuvant known as poly-ICLC in VLP vaccinations both augments and sustains germinal center B-cell reactions, antigen-specific B-cell frequencies and anti-EBOV serum titers. Finally, we used mice that were deficient in either B-cells or T-cell-dependent antibody production to distinguish the contributing roles of EBOV humoral responses. We demonstrate that while anti-EBOV antibody responses promote protection, VLP-vaccinated mice can survive EBOV infection in the absence of detectable anti-EBOV antibodies. Moreover, we found that adjuvant signaling could circumvent the complete requirement for B-cell immunity in protection against EBOV. Collectively, these studies may prove valuable for the characterization and future development of additional EBOV vaccine candidates.


Subject(s)
Antibodies, Viral/blood , Ebola Vaccines/immunology , Ebolavirus/immunology , Hemorrhagic Fever, Ebola/prevention & control , T-Lymphocytes/immunology , Vaccines, Virus-Like Particle/immunology , Adjuvants, Immunologic/administration & dosage , Animals , Antibodies, Viral/immunology , B-Lymphocytes/immunology , Disease Models, Animal , Ebola Vaccines/administration & dosage , Germinal Center/immunology , Hemorrhagic Fever, Ebola/immunology , Mice , RNA, Double-Stranded/immunology
7.
Phys Med Biol ; 61(20): 7300-7333, 2016 10 21.
Article in English | MEDLINE | ID: mdl-27694700

ABSTRACT

We investigate an optimization-based reconstruction, with an emphasis on image-artifact reduction, from data collected in C-arm cone-beam computed tomography (CBCT) employed in image-guided interventional procedures. In the study, an image to be reconstructed is formulated as a solution to a convex optimization program in which a weighted data divergence is minimized subject to a constraint on the image total variation (TV); a data-derivative fidelity is introduced in the program specifically for effectively suppressing dominant, low-frequency data artifact caused by, e.g. data truncation; and the Chambolle-Pock (CP) algorithm is tailored to reconstruct an image through solving the program. Like any other reconstructions, the optimization-based reconstruction considered depends upon numerous parameters. We elucidate the parameters, illustrate their determination, and demonstrate their impact on the reconstruction. The optimization-based reconstruction, when applied to data collected from swine and patient subjects, yields images with visibly reduced artifacts in contrast to the reference reconstruction, and it also appears to exhibit a high degree of robustness against distinctively different anatomies of imaged subjects and scanning conditions of clinical significance. Knowledge and insights gained in the study may be exploited for aiding in the design of practical reconstructions of truly clinical-application utility.


Subject(s)
Artifacts , Cone-Beam Computed Tomography/instrumentation , Image Processing, Computer-Assisted/methods , Algorithms , Animals , Humans , Liver Diseases/diagnostic imaging , Liver Diseases/pathology , Phantoms, Imaging , Swine
8.
PLoS Pathog ; 12(3): e1005466, 2016 Mar.
Article in English | MEDLINE | ID: mdl-27031835

ABSTRACT

Little is known about the repertoire of cellular factors involved in the replication of pathogenic alphaviruses. To uncover molecular regulators of alphavirus infection, and to identify candidate drug targets, we performed a high-content imaging-based siRNA screen. We revealed an actin-remodeling pathway involving Rac1, PIP5K1- α, and Arp3, as essential for infection by pathogenic alphaviruses. Infection causes cellular actin rearrangements into large bundles of actin filaments termed actin foci. Actin foci are generated late in infection concomitantly with alphavirus envelope (E2) expression and are dependent on the activities of Rac1 and Arp3. E2 associates with actin in alphavirus-infected cells and co-localizes with Rac1-PIP5K1-α along actin filaments in the context of actin foci. Finally, Rac1, Arp3, and actin polymerization inhibitors interfere with E2 trafficking from the trans-Golgi network to the cell surface, suggesting a plausible model in which transport of E2 to the cell surface is mediated via Rac1- and Arp3-dependent actin remodeling.


Subject(s)
Alphavirus Infections/genetics , Alphavirus/genetics , Cell Movement/genetics , RNA, Small Interfering/genetics , Actins/metabolism , Alphavirus/metabolism , Alphavirus Infections/metabolism , Cell Movement/physiology , DNA Replication/genetics , Humans , Protein Transport/genetics , trans-Golgi Network/genetics , trans-Golgi Network/metabolism
9.
Article in English | MEDLINE | ID: mdl-16685926

ABSTRACT

We investigated a method, motion compensated integration (MCI), for enhancing stent Contrast-to-Noise Ratio (CNR) such that stent deployment may be more easily assessed. MCI registers fluoroscopic frames on the basis of stent motion and performs pixel-wise integration to reduce noise. Registration is based on marker balls, high contrast interventional devices which guide the clinician in stent placement. It is assumed that stent motion is identical to that of the marker balls. Detecting marker balls and identifying their centroids with a high degree of accuracy is a non-trivial task. To address the required registration accuracy, in this work we examine MCI's visualization benefit as a function of registration error. We employ adaptive forced choice experiments to quantify human discrimination fidelity. Perception results are contrasted with CNR measurements. For each level of registration inaccuracy investigated, MCI conferred a benefit (p < 0.05) on stent deployment assessment suggesting the technique is tolerant of modest registration error. We also consider the blurring effect of cardiac motion during the x-ray pulse and select frames for integration as a function of cardiac phase imaged.


Subject(s)
Artifacts , Blood Vessel Prosthesis , Coronary Artery Disease/surgery , Fluoroscopy/methods , Prosthesis Implantation/methods , Radiographic Image Enhancement/methods , Stents , Coronary Artery Disease/diagnostic imaging , Fluoroscopy/instrumentation , Humans , Imaging, Three-Dimensional/methods , Models, Biological , Models, Statistical , Motion , Radiographic Image Interpretation, Computer-Assisted/methods , Reproducibility of Results , Sensitivity and Specificity , Subtraction Technique , Surgery, Computer-Assisted/methods , Systems Integration
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