Chitosan IFNgamma-pDNA Nanosphere Therapy and Immunopathology of Allergic Asthma
Principal Investigator: Shyam Mohapatra
Affiliation: University of South Florida
Abstract: With an intent to develop effective prophylaxis or treatment of allergic diseases including allergic asthma, our goal is to examine the safety and efficacy of chitosan IFN-gamma-pDNA nanosphere (CIN) Therapy and the cellular and molecular mechanisms underlying its effectiveness in a mouse model of asthma. Deviation of immune response to allergens from a pathogenic T helper-2 type response to T helper-1 type may provide a practical approach to modifying the course of disease. Administration of IFN-gamma, and IL-12 DNA plasmids significantly decreased airway inflammation and airway hyperresponsiveness in a mouse model of grass allergic asthma. In addition, Adenoviral-mediated IFN-gamma, gene transfer effectively reversed established asthma in BALB/c mouse model. While these studies aid in the mechanistic understanding of IFN-gamma, action in the lung, acute inflammation and immunogenicity to virus remains the major obstacle for the application of viral-mediated gene transfer for treating human asthma. We therefore developed a non-viral strategy that involves the development of chitosan nanospheres containing IFN-gamma, pDNA (CIN), intranasally (i.n.) delivered to the lung, as a strategy for asthma treatment. Our working hypothesis is that i.n. CIN therapy provides for effective prophylaxis or treatment of asthma by inducing changes in expression of cytokine and chemokine genes which result in altered antigen presentation, decreased migration of effector cells into the lung, and apoptosis of inflammatory cells, leading to a global decrease in inflammation and airway remodeling. The specific aims of this research program are as follows: Aim #1. Evaluate chitosan-IFN-gamma-pDNA nanospheres (CIN) as a prophylactic or a therapeutic modality for allergic disease in BALB/c mice. We plan to evaluate the role of CIN in prophylaxis/therapy of allergic asthma in BALB/c mice with respect to magnitude of acute inflammation, duration of protection from asthma and its potential in a chronic asthma model. We will analyze different asthma phenotypes, such as immune deviation of allergic response revealed by a change in T-cell cytokine secretion and antibody response profiles, the airway hyperreactivity and eosinophils in broncho-alveolar lavage, and lung pathology. Aim #2. Elucidate the cellular/molecular mechanism of CIN-induced immunomodulation. We plan to examine the role of T cells, CIN modulation of specific T cell response in the lung including apoptosis of Th2 cells and modulation of the number and activity of dendritic cells in the lung. Aim #3. Elucidate the anti-inflammatory mechanism of CIN-induced protection. We plan to examine the genes, which mediate the effects of CIN, whether CIN affects airway inflammation and airway remodeling in lungs of mice, and whether CIN induces apoptosis of mucus producing goblet cells. It is anticipated that the results of these studies will contribute significantly to our knowledge of asthma and CIN therapy may provide a major breakthrough in management of asthma.
Funding Period: 2003-09-25 - 2009-08-31
more information: NIH RePORT
- Inhibition of respiratory syncytial virus infection with intranasal siRNA nanoparticles targeting the viral NS1 geneWeidong Zhang
Division of Allergy and Immunology-Joy McCann Culverhouse Airway Disease Research Center, Department of Internal Medicine, University of South Florida, MDC-19-Rm 2536, 12901 Bruce B. Downs Boulevard, Tampa, Florida 33612, USA
Nat Med 11:56-62. 2005..Thus, siNS1 nanoparticles may provide an effective inhibition of RSV infection in humans...
- Multifunctional magnetic nanoparticles for targeted deliveryArun Kumar
Division of Allergy and Immunology, Department of Internal Medicine, University of South Florida, Tampa, Florida, USA
Nanomedicine 6:64-9. 2010..The authors demonstrate that a simple external magnetic field is sufficient to target a drug to specific sites in the body without the need for functionalized nanoparticles, at least in selected organs and diseases...
- Epidemiologic, experimental, and clinical links between respiratory syncytial virus infection and asthmaShyam S Mohapatra
Department of Internal Medicine, Division of Allergy and Immunology, University of South Florida College of Medicine, James A Haley Veterans Hospital, 12901 Bruce B Downs Blvd, Tampa, Florida 33612, USA
Clin Microbiol Rev 21:495-504. 2008..Studies to date demonstrate that there is a significant association between RSV infection and childhood asthma and that preventing severe primary RSV infections can decrease the risk of childhood asthma...
- Natriuretic peptide receptor a as a novel anticancer targetXiaoyuan Kong
Joy McCann Culverhouse Airway Disease and Nanomedicine Research Center, Allergy and Immunology Division, Department of Internal Medicine, University of South Florida College of Medicine, Tampa, FL 33612, USA
Cancer Res 68:249-56. 2008..These results suggest that NPRA is involved in tumor angiogenesis and represents a new target for cancer therapy...
- Role of natriuretic peptide signaling in modulating asthma and inflammationShyam S Mohapatra
Division of Allergy and Immunology JMC Airway Disease Research Center, Department of Internal Medicine, University of South Florida and VA Hospital, Tampa, FL 33612, USA
Can J Physiol Pharmacol 85:754-9. 2007..This report will review and critically evaluate the role of the ANP pathway in asthma and inflammation...
- Development of hyaluronic acid-Fe2O3 hybrid magnetic nanoparticles for targeted delivery of peptidesArun Kumar
Division of Allergy and Immunology, Department of Internal Medicine, College of Medicine, University of South Florida, Tampa, Florida 33612, USA
Nanomedicine 3:132-7. 2007..Results show that these particles delivered peptides at about 100% level. These HA-iron oxide nanoparticles are expected to be useful in developing effective tissue and cell targeting systems...
- Thiolated chitosan/DNA nanocomplexes exhibit enhanced and sustained gene deliveryDongwon Lee
Department of Internal Medicine, University of South Florida College of Medicine and James A Haley Veteran s Hospital, 12901 Bruce B Downs Blvd, Tampa, Florida 33612, USA
Pharm Res 24:157-67. 2007..Herein, we report on a highly effective gene delivery system utilizing a 33-kDa thiol-modified chitosan derivative...
- Folate receptor-mediated cancer cell specific gene delivery using folic acid-conjugated oligochitosansDongwon Lee
Department of Internal Medicine, Division of Allergy and Immunology, Joy McCann Culverhouse Airway Disease Center, University of South Florida, College of Medicine, James A. Haley Veteran's Hospital, Tampa, FI 33612, USA
J Nanosci Nanotechnol 6:2860-6. 2006..Taken together, these results demonstrate that FACN provides a promising carrier for cancer gene therapy...
- Thiolated chitosan nanoparticles enhance anti-inflammatory effects of intranasally delivered theophyllineDong Won Lee
Division of Allergy and Immunology and Joy McCann Culverhouse Airway Disease Center, Department of Internal Medicine, University of South Florida College of Medicine and James A, Haley Veteran s Hospital, Tampa, FL 33612, USA
Respir Res 7:112. 2006..It was hypothesized that adsorption of theophylline to chitosan nanoparticles modified by the addition of thiol groups would improve theophylline absorption by the bronchial epithelium and enhance its anti-inflammatory effects...
- Immunobiology of grass pollen allergensShyam S Mohapatra
Department of Internal Medicine, Division of Allergy and Immunology and the James A Haley Veterans Hospital, University of South Florida, College of Medicine, 12901 Bruce B Downs Boulevard, Tampa, FL 33612, USA
Curr Allergy Asthma Rep 5:381-7. 2005..This review is focused on the structure and immunobiology of the grass allergens and highlights how recent advances in the field have contributed to superior diagnosis and immunotherapy for allergy to grass pollens...
- Modulation of lung inflammation by vessel dilator in a mouse model of allergic asthmaXiaoqin Wang
Division of Allergy and Immunology, University of South Florida, Tampa, FL 33612, USA
Respir Res 10:66. 2009..In this report, we evaluated the effects of vessel dilator (VD), another N-terminal natriuretic peptide covering amino acids 31-67 of proANF, on acute lung inflammation in a mouse model of allergic asthma...