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Regulatory T Cells Attenuate Th17 Cell-Mediated Nigrostriatal Dopaminergic Neurodegeneration in a Model of Parkinson's Disease
Nitrated alpha-synuclein (N-alpha-syn) immunization elicits adaptive immune responses to novel antigenic epitopes that exacerbate neuroinflammation and nigrostriatal degeneration in the 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) model of Parkinson's disease. We show that such neuroimmu...
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| Published in: | The Journal of immunology (1950) 2010-03, Vol.184 (5), p.2261-2271 |
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| Main Authors: | , , , , , |
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| cites | cdi_FETCH-LOGICAL-c427t-e41fe3137acc78d3d68399633d5842a2b2483c288b936ba73f2042712fab58663 |
| container_end_page | 2271 |
| container_issue | 5 |
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| container_title | The Journal of immunology (1950) |
| container_volume | 184 |
| creator | Reynolds, Ashley D Stone, David K Hutter, Jessica A. L Benner, Eric J Mosley, R. Lee Gendelman, Howard E |
| description | Nitrated alpha-synuclein (N-alpha-syn) immunization elicits adaptive immune responses to novel antigenic epitopes that exacerbate neuroinflammation and nigrostriatal degeneration in the 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) model of Parkinson's disease. We show that such neuroimmune degenerative activities, in significant measure, are Th17 cell-mediated, with CD4(+)CD25(+) regulatory T cell (Treg) dysfunction seen among populations of N-alpha-syn-induced T cells. In contrast, purified vasoactive intestinal peptide induced and natural Tregs reversed N-alpha-syn T cell nigrostriatal degeneration. Combinations of adoptively transferred N-alpha-syn and vasoactive intestinal peptide immunocytes or natural Tregs administered to MPTP mice attenuated microglial inflammatory responses and led to robust nigrostriatal protection. Taken together, these results demonstrate Treg control of N-alpha-syn-induced neurodestructive immunity and, as such, provide a sound rationale for future Parkinson's disease immunization strategies. |
| doi_str_mv | 10.4049/jimmunol.0901852 |
| format | article |
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L ; Benner, Eric J ; Mosley, R. Lee ; Gendelman, Howard E</creator><creatorcontrib>Reynolds, Ashley D ; Stone, David K ; Hutter, Jessica A. L ; Benner, Eric J ; Mosley, R. Lee ; Gendelman, Howard E</creatorcontrib><description>Nitrated alpha-synuclein (N-alpha-syn) immunization elicits adaptive immune responses to novel antigenic epitopes that exacerbate neuroinflammation and nigrostriatal degeneration in the 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) model of Parkinson's disease. We show that such neuroimmune degenerative activities, in significant measure, are Th17 cell-mediated, with CD4(+)CD25(+) regulatory T cell (Treg) dysfunction seen among populations of N-alpha-syn-induced T cells. In contrast, purified vasoactive intestinal peptide induced and natural Tregs reversed N-alpha-syn T cell nigrostriatal degeneration. Combinations of adoptively transferred N-alpha-syn and vasoactive intestinal peptide immunocytes or natural Tregs administered to MPTP mice attenuated microglial inflammatory responses and led to robust nigrostriatal protection. Taken together, these results demonstrate Treg control of N-alpha-syn-induced neurodestructive immunity and, as such, provide a sound rationale for future Parkinson's disease immunization strategies.</description><identifier>ISSN: 0022-1767</identifier><identifier>EISSN: 1550-6606</identifier><identifier>DOI: 10.4049/jimmunol.0901852</identifier><identifier>PMID: 20118279</identifier><language>eng</language><publisher>United States: Am Assoc Immnol</publisher><subject>Adoptive Transfer ; alpha-Synuclein - pharmacology ; Animals ; CD4-Positive T-Lymphocytes - drug effects ; CD4-Positive T-Lymphocytes - immunology ; CD4-Positive T-Lymphocytes - metabolism ; Corpus Striatum - drug effects ; Corpus Striatum - metabolism ; Corpus Striatum - pathology ; Dopamine - metabolism ; Flow Cytometry ; Humans ; Immunohistochemistry ; Interferon-gamma - metabolism ; Interleukin-17 - metabolism ; Interleukin-2 Receptor alpha Subunit - metabolism ; Male ; Mice ; Mice, Inbred C57BL ; MPTP Poisoning - immunology ; MPTP Poisoning - metabolism ; MPTP Poisoning - therapy ; Neurons - drug effects ; Neurons - immunology ; Neurons - metabolism ; Substantia Nigra - drug effects ; Substantia Nigra - metabolism ; Substantia Nigra - pathology ; T-Lymphocytes, Helper-Inducer - immunology ; T-Lymphocytes, Helper-Inducer - metabolism ; T-Lymphocytes, Regulatory - immunology ; T-Lymphocytes, Regulatory - metabolism ; T-Lymphocytes, Regulatory - transplantation ; Tumor Necrosis Factor-alpha - metabolism</subject><ispartof>The Journal of immunology (1950), 2010-03, Vol.184 (5), p.2261-2271</ispartof><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c427t-e41fe3137acc78d3d68399633d5842a2b2483c288b936ba73f2042712fab58663</citedby><cites>FETCH-LOGICAL-c427t-e41fe3137acc78d3d68399633d5842a2b2483c288b936ba73f2042712fab58663</cites></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><link.rule.ids>230,315,786,790,891,27957,27958</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/20118279$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Reynolds, Ashley D</creatorcontrib><creatorcontrib>Stone, David K</creatorcontrib><creatorcontrib>Hutter, Jessica A. L</creatorcontrib><creatorcontrib>Benner, Eric J</creatorcontrib><creatorcontrib>Mosley, R. Lee</creatorcontrib><creatorcontrib>Gendelman, Howard E</creatorcontrib><title>Regulatory T Cells Attenuate Th17 Cell-Mediated Nigrostriatal Dopaminergic Neurodegeneration in a Model of Parkinson's Disease</title><title>The Journal of immunology (1950)</title><addtitle>J Immunol</addtitle><description>Nitrated alpha-synuclein (N-alpha-syn) immunization elicits adaptive immune responses to novel antigenic epitopes that exacerbate neuroinflammation and nigrostriatal degeneration in the 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) model of Parkinson's disease. We show that such neuroimmune degenerative activities, in significant measure, are Th17 cell-mediated, with CD4(+)CD25(+) regulatory T cell (Treg) dysfunction seen among populations of N-alpha-syn-induced T cells. In contrast, purified vasoactive intestinal peptide induced and natural Tregs reversed N-alpha-syn T cell nigrostriatal degeneration. Combinations of adoptively transferred N-alpha-syn and vasoactive intestinal peptide immunocytes or natural Tregs administered to MPTP mice attenuated microglial inflammatory responses and led to robust nigrostriatal protection. Taken together, these results demonstrate Treg control of N-alpha-syn-induced neurodestructive immunity and, as such, provide a sound rationale for future Parkinson's disease immunization strategies.</description><subject>Adoptive Transfer</subject><subject>alpha-Synuclein - pharmacology</subject><subject>Animals</subject><subject>CD4-Positive T-Lymphocytes - drug effects</subject><subject>CD4-Positive T-Lymphocytes - immunology</subject><subject>CD4-Positive T-Lymphocytes - metabolism</subject><subject>Corpus Striatum - drug effects</subject><subject>Corpus Striatum - metabolism</subject><subject>Corpus Striatum - pathology</subject><subject>Dopamine - metabolism</subject><subject>Flow Cytometry</subject><subject>Humans</subject><subject>Immunohistochemistry</subject><subject>Interferon-gamma - metabolism</subject><subject>Interleukin-17 - metabolism</subject><subject>Interleukin-2 Receptor alpha Subunit - metabolism</subject><subject>Male</subject><subject>Mice</subject><subject>Mice, Inbred C57BL</subject><subject>MPTP Poisoning - immunology</subject><subject>MPTP Poisoning - metabolism</subject><subject>MPTP Poisoning - therapy</subject><subject>Neurons - drug effects</subject><subject>Neurons - immunology</subject><subject>Neurons - metabolism</subject><subject>Substantia Nigra - drug effects</subject><subject>Substantia Nigra - metabolism</subject><subject>Substantia Nigra - pathology</subject><subject>T-Lymphocytes, Helper-Inducer - immunology</subject><subject>T-Lymphocytes, Helper-Inducer - metabolism</subject><subject>T-Lymphocytes, Regulatory - immunology</subject><subject>T-Lymphocytes, Regulatory - metabolism</subject><subject>T-Lymphocytes, Regulatory - transplantation</subject><subject>Tumor Necrosis Factor-alpha - metabolism</subject><issn>0022-1767</issn><issn>1550-6606</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2010</creationdate><recordtype>article</recordtype><recordid>eNpVUU1v1DAQtRCILoU7J-RbTyn-iu1ckKotBaR-ILScLSeZZF0ce2UnrHrpb8d02wpOo3nz3hvNPITeU3IqiGg-3rppWkL0p6QhVNfsBVrRuiaVlES-RCtCGKuokuoIvcn5lhAiCROv0REjlGqmmhW6_wHj4u0c0x3e4DV4n_HZPENY7Ax4s6XqAayuoHcF6fG1G1PMcyqd9fg87uzkAqTRdfgalhR7GKH0dnYxYBewxVcF8zgO-LtNv1zIMZxkfO4y2Axv0avB-gzvHusx-nnxebP-Wl3efPm2PrusOsHUXIGgA3DKle06pXveS82bRnLe11owy1omNO-Y1m3DZWsVHxgpQsoG29ZaSn6MPh18d0s7Qd9BmJP1ZpfcZNOdidaZ_yfBbc0YfxummVANKQbkYNCV63OC4VlLifmbhXnKwjxmUSQf_t35LHh6fiGcHAhbN273LoHJk_W-0KnZ7_dUC1MbxiTlfwDRO5bw</recordid><startdate>20100301</startdate><enddate>20100301</enddate><creator>Reynolds, Ashley D</creator><creator>Stone, David K</creator><creator>Hutter, Jessica A. L</creator><creator>Benner, Eric J</creator><creator>Mosley, R. Lee</creator><creator>Gendelman, Howard E</creator><general>Am Assoc Immnol</general><scope>CGR</scope><scope>CUY</scope><scope>CVF</scope><scope>ECM</scope><scope>EIF</scope><scope>NPM</scope><scope>AAYXX</scope><scope>CITATION</scope><scope>5PM</scope></search><sort><creationdate>20100301</creationdate><title>Regulatory T Cells Attenuate Th17 Cell-Mediated Nigrostriatal Dopaminergic Neurodegeneration in a Model of Parkinson's Disease</title><author>Reynolds, Ashley D ; Stone, David K ; Hutter, Jessica A. L ; Benner, Eric J ; Mosley, R. Lee ; Gendelman, Howard E</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c427t-e41fe3137acc78d3d68399633d5842a2b2483c288b936ba73f2042712fab58663</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2010</creationdate><topic>Adoptive Transfer</topic><topic>alpha-Synuclein - pharmacology</topic><topic>Animals</topic><topic>CD4-Positive T-Lymphocytes - drug effects</topic><topic>CD4-Positive T-Lymphocytes - immunology</topic><topic>CD4-Positive T-Lymphocytes - metabolism</topic><topic>Corpus Striatum - drug effects</topic><topic>Corpus Striatum - metabolism</topic><topic>Corpus Striatum - pathology</topic><topic>Dopamine - metabolism</topic><topic>Flow Cytometry</topic><topic>Humans</topic><topic>Immunohistochemistry</topic><topic>Interferon-gamma - metabolism</topic><topic>Interleukin-17 - metabolism</topic><topic>Interleukin-2 Receptor alpha Subunit - metabolism</topic><topic>Male</topic><topic>Mice</topic><topic>Mice, Inbred C57BL</topic><topic>MPTP Poisoning - immunology</topic><topic>MPTP Poisoning - metabolism</topic><topic>MPTP Poisoning - therapy</topic><topic>Neurons - drug effects</topic><topic>Neurons - immunology</topic><topic>Neurons - metabolism</topic><topic>Substantia Nigra - drug effects</topic><topic>Substantia Nigra - metabolism</topic><topic>Substantia Nigra - pathology</topic><topic>T-Lymphocytes, Helper-Inducer - immunology</topic><topic>T-Lymphocytes, Helper-Inducer - metabolism</topic><topic>T-Lymphocytes, Regulatory - immunology</topic><topic>T-Lymphocytes, Regulatory - metabolism</topic><topic>T-Lymphocytes, Regulatory - transplantation</topic><topic>Tumor Necrosis Factor-alpha - metabolism</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Reynolds, Ashley D</creatorcontrib><creatorcontrib>Stone, David K</creatorcontrib><creatorcontrib>Hutter, Jessica A. L</creatorcontrib><creatorcontrib>Benner, Eric J</creatorcontrib><creatorcontrib>Mosley, R. Lee</creatorcontrib><creatorcontrib>Gendelman, Howard E</creatorcontrib><collection>Medline</collection><collection>MEDLINE</collection><collection>MEDLINE (Ovid)</collection><collection>MEDLINE</collection><collection>MEDLINE</collection><collection>PubMed</collection><collection>CrossRef</collection><collection>PubMed Central (Full Participant titles)</collection><jtitle>The Journal of immunology (1950)</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Reynolds, Ashley D</au><au>Stone, David K</au><au>Hutter, Jessica A. L</au><au>Benner, Eric J</au><au>Mosley, R. Lee</au><au>Gendelman, Howard E</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Regulatory T Cells Attenuate Th17 Cell-Mediated Nigrostriatal Dopaminergic Neurodegeneration in a Model of Parkinson's Disease</atitle><jtitle>The Journal of immunology (1950)</jtitle><addtitle>J Immunol</addtitle><date>2010-03-01</date><risdate>2010</risdate><volume>184</volume><issue>5</issue><spage>2261</spage><epage>2271</epage><pages>2261-2271</pages><issn>0022-1767</issn><eissn>1550-6606</eissn><notes>Contributed equally</notes><abstract>Nitrated alpha-synuclein (N-alpha-syn) immunization elicits adaptive immune responses to novel antigenic epitopes that exacerbate neuroinflammation and nigrostriatal degeneration in the 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) model of Parkinson's disease. We show that such neuroimmune degenerative activities, in significant measure, are Th17 cell-mediated, with CD4(+)CD25(+) regulatory T cell (Treg) dysfunction seen among populations of N-alpha-syn-induced T cells. In contrast, purified vasoactive intestinal peptide induced and natural Tregs reversed N-alpha-syn T cell nigrostriatal degeneration. Combinations of adoptively transferred N-alpha-syn and vasoactive intestinal peptide immunocytes or natural Tregs administered to MPTP mice attenuated microglial inflammatory responses and led to robust nigrostriatal protection. Taken together, these results demonstrate Treg control of N-alpha-syn-induced neurodestructive immunity and, as such, provide a sound rationale for future Parkinson's disease immunization strategies.</abstract><cop>United States</cop><pub>Am Assoc Immnol</pub><pmid>20118279</pmid><doi>10.4049/jimmunol.0901852</doi><tpages>11</tpages><oa>free_for_read</oa></addata></record> |
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| identifier | ISSN: 0022-1767 |
| ispartof | The Journal of immunology (1950), 2010-03, Vol.184 (5), p.2261-2271 |
| issn | 0022-1767 1550-6606 |
| language | eng |
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| source | EZB Electronic Journals Library |
| subjects | Adoptive Transfer alpha-Synuclein - pharmacology Animals CD4-Positive T-Lymphocytes - drug effects CD4-Positive T-Lymphocytes - immunology CD4-Positive T-Lymphocytes - metabolism Corpus Striatum - drug effects Corpus Striatum - metabolism Corpus Striatum - pathology Dopamine - metabolism Flow Cytometry Humans Immunohistochemistry Interferon-gamma - metabolism Interleukin-17 - metabolism Interleukin-2 Receptor alpha Subunit - metabolism Male Mice Mice, Inbred C57BL MPTP Poisoning - immunology MPTP Poisoning - metabolism MPTP Poisoning - therapy Neurons - drug effects Neurons - immunology Neurons - metabolism Substantia Nigra - drug effects Substantia Nigra - metabolism Substantia Nigra - pathology T-Lymphocytes, Helper-Inducer - immunology T-Lymphocytes, Helper-Inducer - metabolism T-Lymphocytes, Regulatory - immunology T-Lymphocytes, Regulatory - metabolism T-Lymphocytes, Regulatory - transplantation Tumor Necrosis Factor-alpha - metabolism |
| title | Regulatory T Cells Attenuate Th17 Cell-Mediated Nigrostriatal Dopaminergic Neurodegeneration in a Model of Parkinson's Disease |
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