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100 1 a| Blanchfield, Jennifer.?| UNAUTHORIZED;

245 10 a| Antigen-specific tolerogenic vaccines inhibit autoimmune disease in a rodent model of multiple sclerosis /c| by Jennifer Lori Blanchfield.;

260 a| [Greenville, N.C.] :b| East Carolina University,c| 2010.;

300 a| 196 pages :b| illustrations (some color), digital, PDF file.;

336 a| text2| rdacontent;

337 a| computer2| rdamedia;

338 a| online resource2| rdacarrier;

490 1 a| ECU Brody School of Medicine thesis;

500 a| Presented to the faculty of the Department of Microbiology and Immunology.;

500 a| Advisor: Mark D. Mannie.;

500 a| Title from PDF t.p. (viewed December 6, 2010).;

502 b| Ph.D.c| East Carolina Universityd| 2010.;

504 a| Includes bibliographical references.;

520 3 a| Multiple sclerosis (MS) is considered to be a T cell-mediated autoimmune disease directed against myelinated nerves within the central nervous system. Current therapies available to MS patients have low efficacy and are immunosuppressive. Novel therapies that negatively regulate or delete autoreactive T cells, i.e., induce antigen-specific T cell tolerance, are key for the development of more efficacious and perhaps curative therapies. Our laboratory has developed a vaccine platform comprised of cytokine-antigen fusion proteins to promote T cell tolerance. In this study, GM-CSF and M-CSF cytokines were tested as domains in cytokine-neuroantigen (NAg) fusion proteins to assess targeting of NAg to different antigen presenting cell (APC) subsets. Fusion proteins were designed with a cytokine N-terminal domain and the encephalitogenic peptide 69-88 of guinea pig myelin basic protein (GP69-88) as the C-terminal domain. Studies measuring T cell activation in vitro, prevention of experimental autoimmune encephalomyelitis (EAE), and treatment of EAE showed that GMCSF-NAg was the most potent fusion protein, with the following rank order of activity (GMCSF-NAg MCSF-NAg GP69-88). GMCSF-NAg was 1000-fold more potent than GP69-88 in stimulating myelin basic protein (MBP)-specific T cell proliferation. The mechanism by which GMCSF-NAg promoted T cell activation involved cytokine receptor-mediated uptake of NAg by APC, since free GM-CSF inhibited the GMCSF-NAg potentiated response. GMCSF-NAg potently targeted NAg to dendritic cells and macrophages in vitro, but not to B or T cell APC. Covalent linkage between GM-CSF and NAg was required for enhanced potency of GMCSF-NAg in vitro and for the prevention and treatment of EAE in vivo. In conclusion, GMCSF-NAg potently targeted self-antigen to myeloid APC subsets and caused profound antigen-specific tolerance in EAE. In the future, cytokine-NAg fusion proteins may provide a novel tool to develop antigen-specific, tolerogenic vaccines for the treatment of MS.;

538 a| System requirements: Adobe Reader.;

538 a| Mode of access: World Wide Web.;

650 2 a| Multiple Sclerosisx| therapy.=| ^A923936;

650 2 a| Autoimmune Diseasesx| therapy.=| ^A925772;

650 2 a| Cytokins.?| UNAUTHORIZED;

653 a| Health Sciences, Immunology;

700 1 a| Mannie, Mark D.?| UNAUTHORIZED;

710 2 a| East Carolina University.b| Department of Microbiology and Immunology.?| UNAUTHORIZED;

830 0 a| ECU Brody School of Medicine thesis.=| ^A964744;

856 40 z| Access via ScholarShipu| http://hdl.handle.net/10342/2900;

949 a| Click on web addressw| ASISh| JOYNER101;

949 a| Click on web addressw| ASISh| HSL111;

994 a| C0b| NEH;

096 a| WL 360;

596 a| 1 4;

998 a| 2386779;

999 a| CLICK ON WEB ADDRESSw| ASISc| 1i| 2386779-1001l| JNETm| JOYNERr| Ys| Yt| JNE3ETDu| 12/30/2010x| ETDz| JERESOURCE;

999 a| CLICK ON WEB ADDRESSw| ASISc| 1i| 2386779-2001l| HSLELECm| HSLr| Ys| Yt| HEETDu| 12/30/2010x| ETDz| HERESOURCE;

Antigen-specific tolerogenic vaccines inhibit autoimmune disease in a rodent model of multiple sclerosis / by Jennifer Lori Blanchfield.

Author/creator	Blanchfield, Jennifer
Other author	Mannie, Mark D.
Other author	East Carolina University. Department of Microbiology and Immunology.
Format	Theses and dissertations
Publication Info	[Greenville, N.C.] : East Carolina University, 2010.
Description	196 pages : illustrations (some color), digital, PDF file.
Supplemental Content	Access via ScholarShip
Subjects	Multiple Sclerosis--therapy. Autoimmune Diseases--therapy. Cytokins.

Series	ECU Brody School of Medicine thesis ECU Brody School of Medicine thesis. ^A964744
Summary	Multiple sclerosis (MS) is considered to be a T cell-mediated autoimmune disease directed against myelinated nerves within the central nervous system. Current therapies available to MS patients have low efficacy and are immunosuppressive. Novel therapies that negatively regulate or delete autoreactive T cells, i.e., induce antigen-specific T cell tolerance, are key for the development of more efficacious and perhaps curative therapies. Our laboratory has developed a vaccine platform comprised of cytokine-antigen fusion proteins to promote T cell tolerance. In this study, GM-CSF and M-CSF cytokines were tested as domains in cytokine-neuroantigen (NAg) fusion proteins to assess targeting of NAg to different antigen presenting cell (APC) subsets. Fusion proteins were designed with a cytokine N-terminal domain and the encephalitogenic peptide 69-88 of guinea pig myelin basic protein (GP69-88) as the C-terminal domain. Studies measuring T cell activation in vitro, prevention of experimental autoimmune encephalomyelitis (EAE), and treatment of EAE showed that GMCSF-NAg was the most potent fusion protein, with the following rank order of activity (GMCSF-NAg MCSF-NAg GP69-88). GMCSF-NAg was 1000-fold more potent than GP69-88 in stimulating myelin basic protein (MBP)-specific T cell proliferation. The mechanism by which GMCSF-NAg promoted T cell activation involved cytokine receptor-mediated uptake of NAg by APC, since free GM-CSF inhibited the GMCSF-NAg potentiated response. GMCSF-NAg potently targeted NAg to dendritic cells and macrophages in vitro, but not to B or T cell APC. Covalent linkage between GM-CSF and NAg was required for enhanced potency of GMCSF-NAg in vitro and for the prevention and treatment of EAE in vivo. In conclusion, GMCSF-NAg potently targeted self-antigen to myeloid APC subsets and caused profound antigen-specific tolerance in EAE. In the future, cytokine-NAg fusion proteins may provide a novel tool to develop antigen-specific, tolerogenic vaccines for the treatment of MS.
General note	Presented to the faculty of the Department of Microbiology and Immunology.
General note	Advisor: Mark D. Mannie.
General note	Title from PDF t.p. (viewed December 6, 2010).
Dissertation note	Ph.D. East Carolina University 2010.
Bibliography note	Includes bibliographical references.
Technical details	System requirements: Adobe Reader.
Technical details	Mode of access: World Wide Web.

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Antigen-specific tolerogenic vaccines inhibit autoimmune disease in a rodent model of multiple sclerosis / by Jennifer Lori Blanchfield.

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