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Incorporation of CpG oligodeoxynucle...

Anderson, Ryan Berger.

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Incorporation of CpG oligodeoxynucleotides into alpha2-macroglobulin: Development of a novel vaccine adjuvant delivery mechanism .

Record Type:	Language materials, printed : Monograph/item
Title/Author:	Incorporation of CpG oligodeoxynucleotides into alpha2-macroglobulin: Development of a novel vaccine adjuvant delivery mechanism ./
Author:	Anderson, Ryan Berger.
Description:	146 p.
Notes:	Adviser: Salvatore V. Pizzo.
Contained By:	Dissertation Abstracts International68-02B.
Subject:	Health Sciences, Immunology. -
Online resource:	http://pqdd.sinica.edu.tw/twdaoapp/servlet/advanced?query=3253698

Incorporation of CpG oligodeoxynucleotides into alpha2-macroglobulin: Development of a novel vaccine adjuvant delivery mechanism .
Anderson, Ryan Berger.

Incorporation of CpG oligodeoxynucleotides into alpha2-macroglobulin: Development of a novel vaccine adjuvant delivery mechanism . - 146 p.

Adviser: Salvatore V. Pizzo.

Thesis (Ph.D.)--Duke University, 2007.

Bacterial DNA is immunostimulatory, and the motifs responsible for this activity are unmethylated CpG dinucleotides. Following cellular uptake, CpG-containing oligodeoxynucleotides (CpG ODN) are trafficked to the endosome where they bind Toll-like receptor 9 (TLR9) to initiate a signaling cascade that culminates in the release of numerous pro-inflammatory cytokines. Because of their immunostimulatory properties, CpG ODN are being clinically evaluated as treatments and vaccine adjuvants for infectious diseases, cancer, and allergic disorders.Subjects--Topical Terms:

1017716
Health Sciences, Immunology.

Incorporation of CpG oligodeoxynucleotides into alpha2-macroglobulin: Development of a novel vaccine adjuvant delivery mechanism .
LDR:03626nam 2200301 a 45 001 973219
005 20110928
008 110928s2007 eng d
035 $a (UMI)AAI3253698
035 $a AAI3253698
040 $a UMI $c UMI
100 1 $a Anderson, Ryan Berger. $3 1297175
245 1 0 $a Incorporation of CpG oligodeoxynucleotides into alpha2-macroglobulin: Development of a novel vaccine adjuvant delivery mechanism .
300 $a 146 p.
500 $a Adviser: Salvatore V. Pizzo.
500 $a Source: Dissertation Abstracts International, Volume: 68-02, Section: B, page: 0901.
502 $a Thesis (Ph.D.)--Duke University, 2007.
520 $a Bacterial DNA is immunostimulatory, and the motifs responsible for this activity are unmethylated CpG dinucleotides. Following cellular uptake, CpG-containing oligodeoxynucleotides (CpG ODN) are trafficked to the endosome where they bind Toll-like receptor 9 (TLR9) to initiate a signaling cascade that culminates in the release of numerous pro-inflammatory cytokines. Because of their immunostimulatory properties, CpG ODN are being clinically evaluated as treatments and vaccine adjuvants for infectious diseases, cancer, and allergic disorders.
520 $a alpha2-Macroglobulin (alpha2M) is a human plasma protein that binds and modulates the activity of a variety of cytokines, growth factors, enzymes, and antigens. Upon proteolytic activation, alpha 2M is converted to its receptor recognized form, alpha2M*, and rapidly binds to and is internalized by immune competent cells expressing the alpha2M* endocytic receptor, LRP, and is then trafficked to the endosome. Based on these interactions, alpha2M seems to play an important role at sites of infection and inflammation by controlling the level of proteinase activity, modulating cytokine signals, and enhancing antigen processing for the adaptive immune response.
520 $a Here, we report the first evidence that alpha2M* binds and forms stable complexes with nucleic acids. We have characterized the mechanisms and stoichiometry of this interaction, examined the pH and temperature stability of these complexes, and identified structural variables in the nucleic acids, namely length, base composition, and chemical modifications, that affect the nature of this interaction. We hypothesized that CpG ODN incorporation into alpha 2M* may alter their immunostimulatory properties. Murine macrophages (MOs) treated with alpha2M*-ODN complexes respond more rapidly and produce a greater cytokine response than those treated with free CpG ODN alone. Treating human PBMCs with alpha2M*-ODN complexes likewise demonstrated their enhanced ability to elicit immune responses. This was due to more rapid uptake and CpG ODN protection from degradation by extracellular nucleases. Co-incorporation of both protein ligands and CpG ODN into alpha 2M* yields ternary complexes; these may permit the simultaneous delivery of both protein antigens and adjuvants to immune competent cells, potentially greatly enhancing the adaptive immune response and protective immunity.
520 $a Based on the findings that incorporation into alpha2M* confers enhanced immunostimulatory activity of CpG ODN, this technology may be exploited to improve CpG ODN-based therapeutics by increasing efficacy, minimizing side effects, reducing dosing requirements, and reducing cost.
590 $a School code: 0066.
650 4 $a Health Sciences, Immunology. $3 1017716
650 4 $a Health Sciences, Pathology. $3 1017854
690 $a 0571
690 $a 0982
710 2 0 $a Duke University. $3 569686
773 0 $t Dissertation Abstracts International $g 68-02B.
790 $a 0066
790 1 0 $a Pizzo, Salvatore V., $e advisor
791 $a Ph.D.
792 $a 2007
856 4 0 $u http://pqdd.sinica.edu.tw/twdaoapp/servlet/advanced?query=3253698