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KJ Peine Dissertation 0527 .pdf (2.43 MB)

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Formulation of Particulate-based Immunomodulatory Therapeutics for the Treatment of Diseases

Peine, Kevin J
http://rave.ohiolink.edu/etdc/view?acc_num=osu1400852793

Abstract Details

2014, Doctor of Philosophy, Ohio State University, Molecular, Cellular and Developmental Biology.
Immunomodulatory therapies provide a promising route for the treatment of infectious or autoimmune diseases. Generally, treatments for infectious diseases target pathogens directly, which overtime, can lead to antimicrobial resistance. Amplifying the host immune response for clearance of pathogens could likely limit the emergence of resistance. Compounds such as the toll-like receptor (TLR) agonists polyinosinic:polycytidylic acid (poly I:C), cytosine bonded to guanine on a phosphodiester backbone (CpG), and resiquimod, or other products that amplify an immune response could be used for the clearance of infections however, systemic delivery is not ideal due to solubility and toxicity concerns. Conversely, autoimmune disease therapies induce wide-spread immune suppression which can result in opportunistic diseases. Antigen specific immunomodulatory therapies could solve this problem by inhibiting the immune response in an antigen specific manner, therefore inhibiting disease, while the remainder of the immune system is functional. For both the delivery of TLR agonists and antigen specific suppression of the immune system, particulate vehicles can provide significant advantages such as increased solubility, reduced toxicity, decreased clearance from circulation and passive targeting of phagocytic cells, like antigen presenting cells (APCs). Targeting APCs is beneficial for the creation of immunomodulatory therapies because APCs are vital for the initiation of a variety of immune responses. This work shows liposomal encapsulation of resiquimod or a novel immunostimulatory compound, pentalinonsterol, decreases parasite burden in the liver, spleen, and bone marrow of mice infected with Leishmania donovani. Furthermore, both compounds enhance T cell proliferation and increase production of cytokines that indicate a shift towards a TH1 immune response. Another particulate carrier formulated from the acid sensitive polymer acetalated dextran (Ac-DEX) encapsulated CpG and poly I:C and induced a pro-inflammatory cytokine profile when cultured with RAW macrophages, indicating its potential use for therapies or subunit vaccine formulations. Finally, Ac-DEX encapsulating a tolerogenic compound (ex. dexamethasone or rapamycin) and a disease-associated antigen were able to decrease symptoms in a multiple sclerosis animal model and inhibit onset of disease in a type 1 diabetes mouse model, in an antigen specific manner. These symptom decreases coincided with lower inflammatory cytokine production from splenocytes, after being re-stimulated with a disease-associated antigen. Here, particulate-based therapies are used to mediate both inflammatory responses towards and infectious pathogen and to induce antigen specific immune suppression for the treatment of autoimmune disorders.
Kristy Ainslie (Advisor)
Eric Bachelder (Committee Member)
Amy Lovett-Racke (Committee Member)
Carol Whitacre (Committee Member)
155 p.
Chemical Engineering; Immunology; Pharmaceuticals

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Citations

  • Peine, K. J. (2014). Formulation of Particulate-based Immunomodulatory Therapeutics for the Treatment of Diseases [Doctoral dissertation, Ohio State University]. OhioLINK Electronic Theses and Dissertations Center. http://rave.ohiolink.edu/etdc/view?acc_num=osu1400852793

    APA Style (7th edition)

  • Peine, Kevin. Formulation of Particulate-based Immunomodulatory Therapeutics for the Treatment of Diseases. 2014. Ohio State University, Doctoral dissertation. OhioLINK Electronic Theses and Dissertations Center, http://rave.ohiolink.edu/etdc/view?acc_num=osu1400852793.

    MLA Style (8th edition)

  • Peine, Kevin. "Formulation of Particulate-based Immunomodulatory Therapeutics for the Treatment of Diseases." Doctoral dissertation, Ohio State University, 2014. http://rave.ohiolink.edu/etdc/view?acc_num=osu1400852793

    Chicago Manual of Style (17th edition)

osu1400852793
499
© 2014, all rights reserved.
This open access ETD is published by The Ohio State University and OhioLINK.