Philip Askenase, MD
Research & Publications
Biography
News
Research Summary
Dissection of crucial cellular and molecular interactions guiding the traffic and eventual recruitment of antigen-specific T cells, out of the blood vessels, and into the tissues, at specific sites of immune reactivity, such as allergic responses (asthma) or protective responses, expulsion of helminth worms from the GI tract, or ticks from the skin.
Determination that micro-mediators, such as serotonin and leukotrienes, released by mediator-containing cells, such as mast cells or platelets, are of crucial importance in alteration of the local vasculature to allow penetration into the tissues by antigen-specific T cells, that arrive and interact with local antigen-presenting cells that present relevant peptides of antigens, causing release of cytokines by the T cells, to mediate local inflammation and allergy, or in contrast, immune protection and resistance.
Specialized Terms: Therapeutic B cell and T cell exosomes; therapeutic mesenchymal stem cell-derived exosomes; allergies and neuropsychiatric diseases; poison ivy; multiple sclerosis; autism, spinal cord injury.
Extensive Research Description
T Cell Mediated Suppression via miRNA in Nanovesicle Exosomes Acting Between Cells.
An immensely exciting project in our laboratory stems from our recent discovery that a T cell suppressive factor (TsF) that inhibits effector Th1 and Th2 cells in vivo, contains an a small RNA. We postulated it that it is a regulatory miRNAthat acts by being transported between cells; from the suppressive/regulatory T cells to target effector T cells via carriage in exosomes. These are nanovesicles (50-150 nm) secreted by all cells, present in all fluids and made in some form by all species down to and including fungi and bacteria suppress immune responses. Remarkably, exosomes contain proteins and RNAsthat target other cells to pass signaling and genetic functional information. Subsequent study in our system, employing affinity columns, Solexa sequencing, knock out mice and bioinformatics, ascertained definitively that it is miRNA-150, that is know to participate in other elements of the immune system. The effect produced is systematic and thus endocrine in nature. Thus, suppressive exosomes can be found in the blood serum of mice tolerized to induce the suppressive T cells that release supernatant of miRNA containing exosomes.
Current clinical efforts are to isolate exosomes in the blood of patients, say with cancer to detect markers of particular tumors as part of “liquiddiagnosis” as adjunct or replacement of biopsies. This cell to cell transfer of active genetic information, here for systemic immune regulation in a mammalian system is unprecedented and paradigm breaking. It is likely that interference with this newly recognized mode of antigen-specific T cell suppression can be used therapeutically, or inhibited with antagomirs where indicated. Antagomirs that block the active Exosome-transferred miRNA could oppose oncogenes or reverse immunosuppression in cancer. Exosomes also could create a new pathway in specific immunotherapy that could compliment existing non-specific treatments, resulting in less toxic side effects, greater specificity, and safer use of higher doses of current non-specific drugs (steroids) and biologics (anti-TNF etc). Alternatively, in vitro alteration of syngeneic exosomes for in vivo therapeutic use to alter immune responses, opens an entirely new avenue of possible immunotherapy. In fact, we also are working with healing exosomes of mesenchymal stem cells for treatment of spinal cord injuries. Finally, detection and analysis of exosomes in the blood is a new method of determining the patient’s immune response.
Overall, the goals of these studies are to determine links between these basic findings in mice with diseases in humans, and to dissect out the participation of the recent discoveries that B1 B cells, serotonin, serum complement and iNKT cells, as well as intercellular nanovesicle exosomes passing regulatory miRNAs between cells, participate in critical interactions leading to T cell effector and regulatory functions that may be harnessed for diagnosis and therapy of a variety of diseases, including allergies, autoimmunity and cancer.
Coauthors
Research Interests
Agammaglobulinemia; Allergy and Immunology; Autistic Disorder; DiGeorge Syndrome; Multiple Sclerosis; Toxicodendron; T-Lymphocytes; Common Variable Immunodeficiency; Exosomes; Neuropsychiatry
Selected Publications
- Systems Vaccinology in HIV Vaccine Development.Zhang J, Askenase P, Crumpacker CS. Systems Vaccinology in HIV Vaccine Development. Vaccines 2022, 10 PMID: 36298489, PMCID: PMC9611490, DOI: 10.3390/vaccines10101624.
- Exosome Carrier Effects; Resistance to Digestion in Phagolysosomes May Assist Transfers to Targeted Cells; II Transfers of miRNAs Are Better Analyzed via Systems Approach as They Do Not Fit Conventional Reductionist Stoichiometric ConceptsAskenase PW. Exosome Carrier Effects; Resistance to Digestion in Phagolysosomes May Assist Transfers to Targeted Cells; II Transfers of miRNAs Are Better Analyzed via Systems Approach as They Do Not Fit Conventional Reductionist Stoichiometric Concepts International Journal Of Molecular Sciences 2022, 23: 6192. PMID: 35682875, PMCID: PMC9181154, DOI: 10.3390/ijms23116192.
- Rare Skin Reactions after mRNA Vaccination, Similar to Jones–Mote Basophil ResponsesAskenase PW. Rare Skin Reactions after mRNA Vaccination, Similar to Jones–Mote Basophil Responses New England Journal Of Medicine 2021, 385: 1720-1721. PMID: 34706177, PMCID: PMC8609603, DOI: 10.1056/nejmc2111452.
- Small extracellular vesicles released by infused mesenchymal stromal cells target M2 macrophages and promote TGF‐β upregulation, microvascular stabilization and functional recovery in a rodent model of severe spinal cord injuryNakazaki M, Morita T, Lankford KL, Askenase PW, Kocsis JD. Small extracellular vesicles released by infused mesenchymal stromal cells target M2 macrophages and promote TGF‐β upregulation, microvascular stabilization and functional recovery in a rodent model of severe spinal cord injury Journal Of Extracellular Vesicles 2021, 10: e12137. PMID: 34478241, PMCID: PMC8408371, DOI: 10.1002/jev2.12137.
- Antibodies Enhance the Suppressive Activity of Extracellular Vesicles in Mouse Delayed-Type HypersensitivityNazimek K, Bustos-Morán E, Blas-Rus N, Nowak B, Totoń-Żurańska J, Seweryn MT, Wołkow P, Woźnicka O, Szatanek R, Siedlar M, Askenase PW, Sánchez-Madrid F, Bryniarski K. Antibodies Enhance the Suppressive Activity of Extracellular Vesicles in Mouse Delayed-Type Hypersensitivity Pharmaceuticals 2021, 14: 734. PMID: 34451831, PMCID: PMC8398949, DOI: 10.3390/ph14080734.
- Exosomes provide unappreciated carrier effects that assist transfers of their miRNAs to targeted cells; I. They are ‘The Elephant in the Room’Askenase PW. Exosomes provide unappreciated carrier effects that assist transfers of their miRNAs to targeted cells; I. They are ‘The Elephant in the Room’ RNA Biology 2021, 18: 2038-2053. PMID: 33944671, PMCID: PMC8582996, DOI: 10.1080/15476286.2021.1885189.
- Antigen-specific, antibody-coated, exosome-like nanovesicles deliver suppressor T-cell microRNA-150 to effector T cells to inhibit contact sensitivityBryniarski K, Ptak W, Jayakumar A, Püllmann K, Caplan MJ, Chairoungdua A, Lu J, Adams BD, Sikora E, Nazimek K, Marquez S, Kleinstein SH, Sangwung P, Iwakiri Y, Delgato E, Redegeld F, Blokhuis BR, Wojcikowski J, Daniel AW, Kormelink T, Askenase PW. Antigen-specific, antibody-coated, exosome-like nanovesicles deliver suppressor T-cell microRNA-150 to effector T cells to inhibit contact sensitivity Journal Of Allergy And Clinical Immunology 2013, 132: 170-181.e9. PMID: 23727037, PMCID: PMC4176620, DOI: 10.1016/j.jaci.2013.04.048.
- Stimulatory Lipids Accumulate in the Mouse Liver within 30 min of Contact Sensitization to Facilitate the Activation of Naïve iNKT Cells in a CD1d‐Dependent FashionDey N, Szczepanik M, Lau K, Majewska‐Szczepanik M, Askenase PW. Stimulatory Lipids Accumulate in the Mouse Liver within 30 min of Contact Sensitization to Facilitate the Activation of Naïve iNKT Cells in a CD1d‐Dependent Fashion Scandinavian Journal Of Immunology 2011, 74: 52-61. PMID: 21352253, DOI: 10.1111/j.1365-3083.2011.02540.x.
- Participation of Inkt Cells in the Early and Late Components of Tc1‐Mediated DNFB Contact Sensitivity: Cooperative Role of γδ‐T CellsAskenase PW, Majewska‐Szczepanik M, Kerfoot S, Szczepanik M. Participation of Inkt Cells in the Early and Late Components of Tc1‐Mediated DNFB Contact Sensitivity: Cooperative Role of γδ‐T Cells Scandinavian Journal Of Immunology 2011, 73: 465-477. PMID: 21272050, DOI: 10.1111/j.1365-3083.2011.02522.x.
- Epicutaneous Immunization with Protein Antigen in the Presence of TLR4 Ligand Induces TCRαβ+CD4+ T Contrasuppressor Cells That Reverse Skin-Induced Suppression of Th1-Mediated Contact SensitivityPtak W, Majewska M, Bryniarski K, Ptak M, Lobo FM, Zając K, Askenase PW, Szczepanik M. Epicutaneous Immunization with Protein Antigen in the Presence of TLR4 Ligand Induces TCRαβ+CD4+ T Contrasuppressor Cells That Reverse Skin-Induced Suppression of Th1-Mediated Contact Sensitivity The Journal Of Immunology 2009, 182: 837-850. PMID: 19124727, DOI: 10.4049/jimmunol.182.2.837.
- NK cell mediated contact sensitivity is elicitable 1 hour after immunization and depends on IFN-? and IL-12 productionAskenase PW, Majewska M, and Szczepanik M. NK cell mediated contact sensitivity is elicitable 1 hour after immunization and depends on IFN-? and IL-12 production. Submitted 2009.
- Role of B-1 cells in early acquired protection from pneumococcal pneumonia: Immune B-1 cells reconstitute defective protection on AID-/- miceYamamoto N, Kerfoot S, and Askenase PW. Role of B-1 cells in early acquired protection from pneumococcal pneumonia: Immune B-1 cells reconstitute defective protection on AID-/- mice. Submitted 2009
- Identification of Initiator B Cells, a Novel Subset of Activation-Induced Deaminase-Dependent B-1-Like Cells That Mediate Initiation of Contact SensitivityKerfoot SM, Szczepanik M, Tung JW, Askenase PW. Identification of Initiator B Cells, a Novel Subset of Activation-Induced Deaminase-Dependent B-1-Like Cells That Mediate Initiation of Contact Sensitivity The Journal Of Immunology 2008, 181: 1717-1727. PMID: 18641308, DOI: 10.4049/jimmunol.181.3.1717.
- c-Jun NH2-Terminal Kinase 2 Inhibits Gamma Interferon Production during Anaplasma phagocytophilum Infection▿Pedra JH, Mattner J, Tao J, Kerfoot SM, Davis RJ, Flavell RA, Askenase PW, Yin Z, Fikrig E. c-Jun NH2-Terminal Kinase 2 Inhibits Gamma Interferon Production during Anaplasma phagocytophilum Infection▿ Infection And Immunity 2007, 76: 308-316. PMID: 17998313, PMCID: PMC2223674, DOI: 10.1128/iai.00599-07.
- Interleukin 5 Plays an Essential Role in Elicitation of Contact Sensitivity through Dual Effects on Eosinophils and B-1 CellsItakura A, Kikuchi Y, Kouro T, Ikutani M, Takaki S, Askenase PW, Takatsu K. Interleukin 5 Plays an Essential Role in Elicitation of Contact Sensitivity through Dual Effects on Eosinophils and B-1 Cells International Archives Of Allergy And Immunology 2006, 140: 8-16. PMID: 16772721, DOI: 10.1159/000092705.
- Delayed-type hypersensitivity in mast cell-deficient mice: dependence on platelets for expression of contact sensitivity.Geba GP, Ptak W, Anderson GM, Paliwal V, Ratzlaff RE, Levin J, Askenase PW. Delayed-type hypersensitivity in mast cell-deficient mice: dependence on platelets for expression of contact sensitivity. The Journal Of Immunology 1996, 157: 557-65. PMID: 8752902, DOI: 10.4049/jimmunol.157.2.557.
- Molecular regulation of tumor necrosis factor-alpha and lymphotoxin production in T cells. Inhibition by prostaglandin E2.Ferreri NR, Sarr T, Askenase PW, Ruddle NH. Molecular regulation of tumor necrosis factor-alpha and lymphotoxin production in T cells. Inhibition by prostaglandin E2. Journal Of Biological Chemistry 1992, 267: 9443-9449. PMID: 1533632, DOI: 10.1016/s0021-9258(19)50443-4.
- Role of Gamma/Delta T Cells as Positive Regulators of Alpha/Beta TCR+ Effector T Cells in Allergic Contact SensitivityAskenase PW, Ptak W. Role of Gamma/Delta T Cells as Positive Regulators of Alpha/Beta TCR+ Effector T Cells in Allergic Contact Sensitivity International Archives Of Allergy And Immunology 1992, 99: 246-251. PMID: 34167199, DOI: 10.1159/000236258.