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Article ; Online: Engineering nanoparticle therapeutics for food allergy.

Rad, Laila M / Arellano, Gabriel / Podojil, Joseph R / O'Konek, Jessica J / Shea, Lonnie D / Miller, Stephen D

The Journal of allergy and clinical immunology

2023 Volume 153, Issue 3, Page(s) 549–559

Abstract: Food allergy is a growing public health issue among children and adults that can lead to life-threatening anaphylaxis following allergen exposure. The criterion standard for disease management includes food avoidance and emergency epinephrine ... ...

Abstract	Food allergy is a growing public health issue among children and adults that can lead to life-threatening anaphylaxis following allergen exposure. The criterion standard for disease management includes food avoidance and emergency epinephrine administration because current allergen-specific immunotherapy treatments are limited by adverse events and unsustained desensitization. A promising approach to remedy these shortcomings is the use of nanoparticle-based therapies that disrupt disease-driving immune mechanisms and induce more sustained tolerogenic immune pathways. The pathophysiology of food allergy includes multifaceted interactions between effector immune cells, including lymphocytes, antigen-presenting cells, mast cells, and basophils, mainly characterized by a T
MeSH term(s)	Child ; Adult ; Humans ; Food Hypersensitivity ; Desensitization, Immunologic ; Food ; Allergens ; Nanoparticles
Chemical Substances	Allergens
Language	English
Publishing date	2023-11-04
Publishing country	United States
Document type	Journal Article ; Review
ZDB-ID	121011-7
ISSN	1097-6825 ; 1085-8725 ; 0091-6749
ISSN (online)	1097-6825 ; 1085-8725
ISSN	0091-6749
DOI	10.1016/j.jaci.2023.10.013
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Article ; Online: Potential targeting of B7-H4 for the treatment of cancer.

Podojil, Joseph R / Miller, Stephen D

Immunological reviews

2017 Volume 276, Issue 1, Page(s) 40–51

Abstract: Observations noting the presence of white blood cell infiltrates within tumors date back more than a century, however the cellular and molecular mechanisms regulating tumor immunity continue to be elucidated. The recent successful use of monoclonal ... ...

Abstract	Observations noting the presence of white blood cell infiltrates within tumors date back more than a century, however the cellular and molecular mechanisms regulating tumor immunity continue to be elucidated. The recent successful use of monoclonal antibodies to block immune regulatory pathways to enhance tumor-specific immune responses for the treatment of cancer has encouraged the identification of additional immune regulatory receptor/ligand pathways. Over the past several years, a growing body of data has identified B7-H4 (VTCN1/B7x/B7S1) as a potential therapeutic target for the treatment of cancer. The potential clinical significance of B7-H4 is supported by the high levels of B7-H4 expression found in numerous tumor tissues and correlation of the level of expression on tumor cells with adverse clinical and pathologic features, including tumor aggressiveness. The biological activity of B7-H4 has been associated with decreased inflammatory CD4
MeSH term(s)	Animals ; Antibodies, Monoclonal/therapeutic use ; Antigens, Neoplasm/immunology ; Antigens, Neoplasm/metabolism ; Forkhead Transcription Factors/metabolism ; Humans ; Immunotherapy/methods ; Macrophages/immunology ; Neoplasms/immunology ; Neoplasms/therapy ; T-Lymphocytes, Regulatory/immunology ; Tumor Escape ; Tumor Microenvironment ; V-Set Domain-Containing T-Cell Activation Inhibitor 1/immunology ; V-Set Domain-Containing T-Cell Activation Inhibitor 1/metabolism
Chemical Substances	Antibodies, Monoclonal ; Antigens, Neoplasm ; FOXP3 protein, human ; Forkhead Transcription Factors ; V-Set Domain-Containing T-Cell Activation Inhibitor 1 ; VTCN1 protein, human
Language	English
Publishing date	2017-03
Publishing country	England
Document type	Journal Article ; Review
ZDB-ID	391796-4
ISSN	1600-065X ; 0105-2896
ISSN (online)	1600-065X
ISSN	0105-2896
DOI	10.1111/imr.12530
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Article ; Online: Tolerogenic Immune-Modifying Nanoparticles Encapsulating Multiple Recombinant Pancreatic β Cell Proteins Prevent Onset and Progression of Type 1 Diabetes in Nonobese Diabetic Mice.

Podojil, Joseph R / Genardi, Samantha / Chiang, Ming-Yi / Kakade, Sandeep / Neef, Tobias / Murthy, Tushar / Boyne, Michael T / Elhofy, Adam / Miller, Stephen D

Journal of immunology (Baltimore, Md. : 1950)

2022 Volume 209, Issue 3, Page(s) 465–475

Abstract: Type 1 diabetes (T1D) is an autoimmune disease characterized by T and B cell responses to proteins expressed by insulin-producing pancreatic β cells, inflammatory lesions within islets (insulitis), and β cell loss. We previously showed that Ag-specific ... ...

Abstract	Type 1 diabetes (T1D) is an autoimmune disease characterized by T and B cell responses to proteins expressed by insulin-producing pancreatic β cells, inflammatory lesions within islets (insulitis), and β cell loss. We previously showed that Ag-specific tolerance targeting single β cell protein epitopes is effective in preventing T1D induced by transfer of monospecific diabetogenic CD4 and CD8 transgenic T cells to NOD.
MeSH term(s)	Animals ; Diabetes Mellitus, Experimental/pathology ; Diabetes Mellitus, Type 1 ; Epitopes ; Insulin ; Insulin-Secreting Cells ; Mice ; Mice, Inbred NOD ; Mice, SCID ; Nanoparticles ; Proteins
Chemical Substances	Epitopes ; Insulin ; Proteins
Language	English
Publishing date	2022-06-20
Publishing country	United States
Document type	Journal Article ; Research Support, Non-U.S. Gov't ; Research Support, N.I.H., Extramural
ZDB-ID	3056-9
ISSN	1550-6606 ; 0022-1767 ; 1048-3233 ; 1047-7381
ISSN (online)	1550-6606
ISSN	0022-1767 ; 1048-3233 ; 1047-7381
DOI	10.4049/jimmunol.2200208
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Article ; Online: Methodology for

Podojil, Joseph R / Ifergan, Igal / Chiang, Ming-Yi / Meeks, Joshua J / Miller, Stephen D

Bio-protocol

2020 Volume 10, Issue 11, Page(s) e3644

Abstract: Methods to test both the functionality and mechanism of action for human recombinant proteins and ... ...

Abstract	Methods to test both the functionality and mechanism of action for human recombinant proteins and antibodies
Language	English
Publishing date	2020-06-05
Publishing country	United States
Document type	Journal Article
ZDB-ID	2833269-6
ISSN	2331-8325 ; 2331-8325
ISSN (online)	2331-8325
ISSN	2331-8325
DOI	10.21769/BioProtoc.3644
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Article ; Online: Interferon-γ controls aquaporin 4-specific Th17 and B cells in neuromyelitis optica spectrum disorder.

Arellano, Gabriel / Loda, Eileah / Chen, Yanan / Neef, Tobias / Cogswell, Andrew C / Primer, Grant / Joy, Godwin / Kaschke, Kevin / Wills, Samantha / Podojil, Joseph R / Popko, Brian / Balabanov, Roumen / Miller, Stephen D

Brain : a journal of neurology

2023 Volume 147, Issue 4, Page(s) 1344–1361

Abstract: Neuromyelitis optica spectrum disorder (NMOSD) is a CNS autoimmune inflammatory disease mediated by T helper 17 (Th17) and antibody responses to the water channel protein, aquaporin 4 (AQP4), and associated with astrocytopathy, demyelination and axonal ... ...

Abstract	Neuromyelitis optica spectrum disorder (NMOSD) is a CNS autoimmune inflammatory disease mediated by T helper 17 (Th17) and antibody responses to the water channel protein, aquaporin 4 (AQP4), and associated with astrocytopathy, demyelination and axonal loss. Knowledge about disease pathogenesis is limited and the search for new therapies impeded by the absence of a reliable animal model. In our work, we determined that NMOSD is characterized by decreased IFN-γ receptor signalling and that IFN-γ depletion in AQP4201-220-immunized C57BL/6 mice results in severe clinical disease resembling human NMOSD. Pathologically, the disease causes autoimmune astrocytic and CNS injury secondary to cellular and humoral inflammation. Immunologically, the absence of IFN-γ allows for increased expression of IL-6 in B cells and activation of Th17 cells, and generation of a robust autoimmune inflammatory response. Consistent with NMOSD, the experimental disease is exacerbated by administration of IFN-β, whereas repletion of IFN-γ, as well as therapeutic targeting of IL-17A, IL-6R and B cells, ameliorates it. We also demonstrate that immune tolerization with AQP4201-220-coupled poly(lactic-co-glycolic acid) nanoparticles could both prevent and effectively treat the disease. Our findings enhance the understanding of NMOSD pathogenesis and provide a platform for the development of immune tolerance-based therapies, avoiding the limitations of the current immunosuppressive therapies.
MeSH term(s)	Humans ; Animals ; Mice ; Neuromyelitis Optica/pathology ; Aquaporin 4 ; Interferon-gamma/metabolism ; Mice, Inbred C57BL ; B-Lymphocytes ; Autoantibodies/metabolism
Chemical Substances	Aquaporin 4 ; Interferon-gamma (82115-62-6) ; Autoantibodies
Language	English
Publishing date	2023-11-06
Publishing country	England
Document type	Journal Article
ZDB-ID	80072-7
ISSN	1460-2156 ; 0006-8950
ISSN (online)	1460-2156
ISSN	0006-8950
DOI	10.1093/brain/awad373
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Article ; Online: Nanoparticle dose and antigen loading attenuate antigen-specific T-cell responses.

Casey, Liam M / Decker, Joseph T / Podojil, Joseph R / Rad, Laila / Hughes, Kevin R / Rose, Justin A / Pearson, Ryan M / Miller, Stephen D / Shea, Lonnie D

Biotechnology and bioengineering

2022 Volume 120, Issue 1, Page(s) 284–296

Abstract: Immune-mediated hypersensitivities such as autoimmunity, allergy, and allogeneic graft rejection are treated with therapeutics that suppress the immune system, and the lack of specificity is associated with significant side effects. The delivery of ... ...

Abstract	Immune-mediated hypersensitivities such as autoimmunity, allergy, and allogeneic graft rejection are treated with therapeutics that suppress the immune system, and the lack of specificity is associated with significant side effects. The delivery of disease-relevant antigens (Ags) by carrier systems such as poly(lactide-co-glycolide) nanoparticles (PLG-Ag) and carbodiimide (ECDI)-fixed splenocytes (SP-Ag) has demonstrated Ag-specific tolerance induction in model systems of these diseases. Despite therapeutic outcomes by both platforms, tolerance is conferred with different efficacy. This investigation evaluated Ag loading and total particle dose of PLG-Ag on Ag presentation in a coculture system of dendritic cells (DCs) and Ag-restricted T cells, with SP-Ag employed as a control. CD25 expression was observed in nearly all T cells even at low concentrations of PLG-Ag, indicating efficient presentation of Ag by dendritic cells. However, the secretion of IL-2, Th1, and Th2 cytokines (IFNγ and IL-4, respectively) varied depending on PLG-Ag concentration and Ag loading. Concentration escalation of soluble Ag resulted in an increase in IL-2 and IFNγ and a decrease in IL-4. Treatment with PLG-Ag followed a similar trend but with lower levels of IL-2 and IFNγ secreted. Transcriptional Activity CEll ARrays (TRACER) were employed to measure the real-time transcription factor (TF) activity in Ag-presenting DCs. The kinetics and magnitude of TF activity was dependent on the Ag delivery method, concentration, and Ag loading. Ag positively regulated IRF1 activity and, as carriers, NPs and ECDI-treated SP negatively regulated this signaling. The effect of Ag loading and dose on tolerance induction were corroborated in vivo using the delayed-type hypersensitivity (DTH) and experimental autoimmune encephalomyelitis (EAE) mouse models where a threshold of 8 μg/mg Ag loading and 0.5 mg PLG-Ag dose were required for tolerance. Together, the effect of Ag loading and dosing on in vitro and in vivo immune regulation provide useful insights for translating Ag-carrier systems for the clinical treatment of immune disorders.
MeSH term(s)	Animals ; Mice ; T-Lymphocytes ; Interleukin-2 ; Interleukin-4/therapeutic use ; Antigens ; Nanoparticles ; Encephalomyelitis, Autoimmune, Experimental/drug therapy
Chemical Substances	Interleukin-2 ; Interleukin-4 (207137-56-2) ; Antigens
Language	English
Publishing date	2022-10-21
Publishing country	United States
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't
ZDB-ID	280318-5
ISSN	1097-0290 ; 0006-3592
ISSN (online)	1097-0290
ISSN	0006-3592
DOI	10.1002/bit.28252
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Article ; Online: Tolerance Induced by Antigen-Loaded PLG Nanoparticles Affects the Phenotype and Trafficking of Transgenic CD4

Neef, Tobias / Ifergan, Igal / Beddow, Sara / Penaloza-MacMaster, Pablo / Haskins, Kathryn / Shea, Lonnie D / Podojil, Joseph R / Miller, Stephen D

Cells

2021 Volume 10, Issue 12

Abstract: We have shown that PLG nanoparticles loaded with peptide antigen can reduce disease in animal models of autoimmunity and in a phase 1/2a clinical trial in celiac patients. Clarifying the mechanisms by which antigen-loaded nanoparticles establish ... ...

Abstract	We have shown that PLG nanoparticles loaded with peptide antigen can reduce disease in animal models of autoimmunity and in a phase 1/2a clinical trial in celiac patients. Clarifying the mechanisms by which antigen-loaded nanoparticles establish tolerance is key to further adapting them to clinical use. The mechanisms underlying tolerance induction include the expansion of antigen-specific CD4
MeSH term(s)	Animals ; Antigens/immunology ; Antigens/pharmacology ; Antigens, Viral/immunology ; Antigens, Viral/pharmacology ; CD4-Positive T-Lymphocytes/drug effects ; CD4-Positive T-Lymphocytes/immunology ; CD8-Positive T-Lymphocytes/drug effects ; CD8-Positive T-Lymphocytes/immunology ; Celiac Disease/genetics ; Celiac Disease/immunology ; Celiac Disease/therapy ; Cell Lineage/drug effects ; Cell Lineage/immunology ; Epitopes, T-Lymphocyte/immunology ; Epitopes, T-Lymphocyte/pharmacology ; Glycoproteins/immunology ; Glycoproteins/pharmacology ; Humans ; Immune Tolerance/drug effects ; Immune Tolerance/immunology ; Mice ; Mice, Transgenic ; Nanoparticles/chemistry ; Ovalbumin/immunology ; Ovalbumin/pharmacology ; Peptide Fragments/immunology ; Peptide Fragments/pharmacology ; Peptides/immunology ; Peptides/pharmacology ; Polylactic Acid-Polyglycolic Acid Copolymer/chemistry ; Polylactic Acid-Polyglycolic Acid Copolymer/pharmacology ; T-Lymphocytes, Regulatory/drug effects ; T-Lymphocytes, Regulatory/immunology ; Viral Proteins/immunology ; Viral Proteins/pharmacology
Chemical Substances	Antigens ; Antigens, Viral ; Epitopes, T-Lymphocyte ; Glycoproteins ; OVA 323-339 ; Peptide Fragments ; Peptides ; Viral Proteins ; glycoprotein peptide 33-41, Lymphocytic choriomeningitis virus ; Polylactic Acid-Polyglycolic Acid Copolymer (1SIA8062RS) ; Ovalbumin (9006-59-1)
Language	English
Publishing date	2021-12-07
Publishing country	Switzerland
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't
ZDB-ID	2661518-6
ISSN	2073-4409 ; 2073-4409
ISSN (online)	2073-4409
ISSN	2073-4409
DOI	10.3390/cells10123445
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Article ; Online: Targeting the B7 family of co-stimulatory molecules: successes and challenges.

Podojil, Joseph R / Miller, Stephen D

BioDrugs : clinical immunotherapeutics, biopharmaceuticals and gene therapy

2013 Volume 27, Issue 1, Page(s) 1–13

Abstract: As more patient data is cross-referenced with animal models of disease, the primary focus on T(h)1 autoreactive effector cell function in autoimmune diseases, such as rheumatoid arthritis and multiple sclerosis, has shifted towards the role of T(h)17 ... ...

Abstract	As more patient data is cross-referenced with animal models of disease, the primary focus on T(h)1 autoreactive effector cell function in autoimmune diseases, such as rheumatoid arthritis and multiple sclerosis, has shifted towards the role of T(h)17 autoreactive effector cells and the ability of regulatory T cells (T(reg)) to modulate the pro-inflammatory autoimmune response. Therefore, the currently favored hypothesis is that a delicate balance between T(h)1/17 effector cells and T(reg) cell function is critical in the regulation of inflammatory autoimmune disease. An intensive area of research with regard to the T(h)1/17:T(reg) cell balance is the utilization of blockade and/or ligation of various co-stimulatory or co-inhibitory molecules, respectively, during ongoing disease to skew the immune response toward a more tolerogenic/regulatory state. Currently, FDA-approved therapies for multiple sclerosis patients are all aimed at the suppression of immune cell function. The other favored method of treatment is a modulation or deletion of autoreactive immune cells via short-term blockade of activating co-stimulatory receptors via treatment with fusion proteins such as CTLA4-Ig and CTLA4-FasL. Based on the initial success of CTLA4-Ig, there are additional fusion proteins that are currently under development. Examples of the more recently identified B7/CD28 family members are PD-L1, PD-L2, inducible co-stimulatory molecule-ligand (ICOS-L), B7-H3, and B7-H4, all of which may emerge as potential fusion protein therapeutics, each with unique, yet often overlapping functions. The expression of both stimulatory and inhibitory B7 molecules seems to play an essential role in modulating immune cell function through a variety of mechanisms, which is supported by findings that suggest each B7 molecule has developed its own indispensable niche in the immune system. As more data are generated, the diagnostic and therapeutic potential of the above B7 family-member-derived fusion proteins becomes ever more apparent. Besides defining the biology of these B7/CD28 family members in vivo, additional difficulty in the development of these therapies lies in maintaining the normal immune functions of recognition and reaction to non-self-antigens following viral or bacterial infection in the patient. Further complicating the clinical translation of these therapies, the mechanism of action identified for a particular reagent may depend upon the method of immune-cell activation and the subset of immune cells targeted in the study.
MeSH term(s)	Abatacept ; Animals ; B7 Antigens/immunology ; CD28 Antigens/immunology ; Humans ; Immune Tolerance ; Immunoconjugates/immunology ; Immunoconjugates/therapeutic use ; Immunosuppressive Agents/immunology ; Immunosuppressive Agents/therapeutic use ; Inducible T-Cell Co-Stimulator Protein/immunology ; Multiple Sclerosis/drug therapy ; Multiple Sclerosis/immunology ; Th1 Cells/drug effects ; Th1 Cells/immunology
Chemical Substances	B7 Antigens ; CD28 Antigens ; Immunoconjugates ; Immunosuppressive Agents ; Inducible T-Cell Co-Stimulator Protein ; Abatacept (7D0YB67S97)
Language	English
Publishing date	2013-01-18
Publishing country	New Zealand
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't ; Review
ZDB-ID	1364202-9
ISSN	1179-190X ; 1173-8804
ISSN (online)	1179-190X
ISSN	1173-8804
DOI	10.1007/s40259-012-0001-6
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Article ; Online: Masked Delivery of Allergen in Nanoparticles Safely Attenuates Anaphylactic Response in Murine Models of Peanut Allergy.

Hughes, Kevin R / Saunders, Michael N / Landers, Jeffrey J / Janczak, Katarzyna W / Turkistani, Hamza / Rad, Laila M / Miller, Stephen D / Podojil, Joseph R / Shea, Lonnie D / O'Konek, Jessica J

Frontiers in allergy

2022 Volume 3, Page(s) 829605

Abstract: Food allergy is a growing health concern worldwide. Current allergen-specific immunotherapy (AIT) approaches require frequent dosing over extended periods of time and may induce anaphylaxis due to allergen-effector cell interactions. A critical need ... ...

Abstract	Food allergy is a growing health concern worldwide. Current allergen-specific immunotherapy (AIT) approaches require frequent dosing over extended periods of time and may induce anaphylaxis due to allergen-effector cell interactions. A critical need remains to develop novel approaches that refine AIT for the treatment of food allergies. Previous studies show that poly(lactide-co-glycolide) (PLG) nanoscale particles (NP) effectively suppress Th1- and Th17-driven immune pathologies. However, their ability to suppress the distinct Th2-polarized immune responses driving food allergy are unknown. Herein, we describe the safety and efficacy of NPs containing encapsulated peanut allergen in desensitizing murine models of peanut allergy. Peanut extract encapsulation allowed for the safe intravenous delivery of allergen relative to non-encapsulated approaches. Application of 2-3 doses, without the need for dose escalation, was sufficient to achieve prophylactic and therapeutic efficacy, which correlated with suppression of Th2-mediated disease and reduced mast cell degranulation. Efficacy was associated with strong reductions in a broad panel of Th1, Th2, and Th17 cytokines. These results demonstrate the ability of PLG NPs to suppress allergen-specific immune responses to induce a more tolerogenic phenotype, conferring protection from intragastric allergen challenge. These promising studies represent a step forward in the development of improved immunotherapies for food allergy.
Language	English
Publishing date	2022-02-07
Publishing country	Switzerland
Document type	Journal Article
ISSN	2673-6101
ISSN (online)	2673-6101
DOI	10.3389/falgy.2022.829605
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Article ; Online: Nanoparticles reduce monocytes within the lungs to improve outcomes after influenza virus infection in aged mice.

Kelley, William J / Wragg, Kathleen M / Chen, Judy / Murthy, Tushar / Xu, Qichen / Boyne, Michael T / Podojil, Joseph R / Elhofy, Adam / Goldstein, Daniel R

JCI insight

2022 Volume 7, Issue 15

Abstract: Older people exhibit dysregulated innate immunity to respiratory viral infections, including influenza and SARS-CoV-2, and show an increase in morbidity and mortality. Nanoparticles are a potential practical therapeutic that could reduce exaggerated ... ...

Abstract	Older people exhibit dysregulated innate immunity to respiratory viral infections, including influenza and SARS-CoV-2, and show an increase in morbidity and mortality. Nanoparticles are a potential practical therapeutic that could reduce exaggerated innate immune responses within the lungs during viral infection. However, such therapeutics have not been examined for effectiveness during respiratory viral infection, particular in aged hosts. Here, we employed a lethal model of influenza viral infection in vulnerable aged mice to examine the ability of biodegradable, cargo-free nanoparticles, designated ONP-302, to resolve innate immune dysfunction and improve outcomes during infection. We administered ONP-302 via i.v. injection to aged mice at day 3 after infection, when the hyperinflammatory innate immune response was already established. During infection, we found that ONP-302 treatment reduced the numbers of inflammatory monocytes within the lungs and increased their number in both the liver and spleen, without impacting viral clearance. Importantly, cargo-free nanoparticles reduced lung damage, reduced histological lung inflammation, and improved gas exchange and, ultimately, the clinical outcomes in influenza-infected aged mice. In conclusion, ONP-302 improves outcomes in influenza-infected aged mice. Thus, our study provides information concerning a practical therapeutic, which, if translated clinically, could improve disease outcomes for vulnerable older patients suffering from respiratory viral infections.
MeSH term(s)	Animals ; COVID-19 ; Communicable Diseases ; Humans ; Influenza, Human ; Lung/pathology ; Mice ; Monocytes ; Nanoparticles ; Orthomyxoviridae Infections ; SARS-CoV-2
Language	English
Publishing date	2022-08-08
Publishing country	United States
Document type	Journal Article ; Research Support, N.I.H., Extramural
ISSN	2379-3708
ISSN (online)	2379-3708
DOI	10.1172/jci.insight.156320
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