Mesenchymal stem cells do not prevent antibody responses against human α-L-iduronidase when used to treat mucopolysaccharidosis type I
Mucopolysaccharidosis type I (MPSI) is an autosomal recessive disease that leads to systemic lysosomal storage, which is caused by the absence of α-L-iduronidase (IDUA). Enzyme replacement therapy is recognized as the best therapeutic option for MPSI; however, high titers of anti-IDUA antibody have...
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| Veröffentlicht in: | PloS one 2014-03, Vol.9 (3), p.e92420 |
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| creator | Martin, Priscila Keiko Matsumoto Stilhano, Roberta Sessa Samoto, Vivian Yochiko Takiya, Christina Maeda Peres, Giovani Bravin da Silva Michelacci, Yara Maria Correa da Silva, Flavia Helena Pereira, Vanessa Gonçalves D'Almeida, Vânia Marques, Fabio Luiz Navarro Otake, Andreia Hanada Chammas, Roger Han, Sang Won |
| description | Mucopolysaccharidosis type I (MPSI) is an autosomal recessive disease that leads to systemic lysosomal storage, which is caused by the absence of α-L-iduronidase (IDUA). Enzyme replacement therapy is recognized as the best therapeutic option for MPSI; however, high titers of anti-IDUA antibody have frequently been observed. Due to the immunosuppressant properties of MSC, we hypothesized that MSC modified with the IDUA gene would be able to produce IDUA for a long period of time. Sleeping Beauty transposon vectors were used to modify MSC because these are basically less-immunogenic plasmids. For cell transplantation, 4×10(6) MSC-KO-IDUA cells (MSC from KO mice modified with IDUA) were injected into the peritoneum of KO-mice three times over intervals of more than one month. The total IDUA activities from MSC-KO-IDUA before cell transplantation were 9.6, 120 and 179 U for the first, second and third injections, respectively. Only after the second cell transplantation, more than one unit of IDUA activity was detected in the blood of 3 mice for 2 days. After the third cell transplantation, a high titer of anti-IDUA antibody was detected in all of the treated mice. Anti-IDUA antibody response was also detected in C57Bl/6 mice treated with MSC-WT-IDUA. The antibody titers were high and comparable to mice that were immunized by electroporation. MSC-transplanted mice had high levels of TNF-alpha and infiltrates in the renal glomeruli. The spreading of the transplanted MSC into the peritoneum of other organs was confirmed after injection of 111In-labeled MSC. In conclusion, the antibody response against IDUA could not be avoided by MSC. On the contrary, these cells worked as an adjuvant that favored IDUA immunization. Therefore, the humoral immunosuppressant property of MSC is questionable and indicates the danger of using MSC as a source for the production of exogenous proteins to treat monogenic diseases. |
| doi_str_mv | 10.1371/journal.pone.0092420 |
| format | Article |
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Enzyme replacement therapy is recognized as the best therapeutic option for MPSI; however, high titers of anti-IDUA antibody have frequently been observed. Due to the immunosuppressant properties of MSC, we hypothesized that MSC modified with the IDUA gene would be able to produce IDUA for a long period of time. Sleeping Beauty transposon vectors were used to modify MSC because these are basically less-immunogenic plasmids. For cell transplantation, 4×10(6) MSC-KO-IDUA cells (MSC from KO mice modified with IDUA) were injected into the peritoneum of KO-mice three times over intervals of more than one month. The total IDUA activities from MSC-KO-IDUA before cell transplantation were 9.6, 120 and 179 U for the first, second and third injections, respectively. Only after the second cell transplantation, more than one unit of IDUA activity was detected in the blood of 3 mice for 2 days. After the third cell transplantation, a high titer of anti-IDUA antibody was detected in all of the treated mice. Anti-IDUA antibody response was also detected in C57Bl/6 mice treated with MSC-WT-IDUA. The antibody titers were high and comparable to mice that were immunized by electroporation. MSC-transplanted mice had high levels of TNF-alpha and infiltrates in the renal glomeruli. The spreading of the transplanted MSC into the peritoneum of other organs was confirmed after injection of 111In-labeled MSC. In conclusion, the antibody response against IDUA could not be avoided by MSC. On the contrary, these cells worked as an adjuvant that favored IDUA immunization. Therefore, the humoral immunosuppressant property of MSC is questionable and indicates the danger of using MSC as a source for the production of exogenous proteins to treat monogenic diseases.</description><identifier>ISSN: 1932-6203</identifier><identifier>EISSN: 1932-6203</identifier><identifier>DOI: 10.1371/journal.pone.0092420</identifier><identifier>PMID: 24642723</identifier><language>eng</language><publisher>United States: Public Library of Science</publisher><subject>Animals ; Antibody response ; Autoantibodies - blood ; Biochemistry ; Biology and Life Sciences ; Biophysics ; Bone marrow ; Cells, Cultured ; Combined Modality Therapy ; Cytokines - blood ; Disease ; Electroporation ; Enzyme Replacement Therapy ; Enzymes ; Gene expression ; Gene therapy ; Genetic disorders ; Hazards ; Heparan sulfate ; Human behavior ; Humans ; Hypotheses ; IDUA gene ; Iduronidase - immunology ; Iduronidase - therapeutic use ; Immunization ; Immunogenicity ; Immunoglobulins ; Injections, Intraperitoneal ; L-Iduronidase ; Laboratories ; Lupus ; Medicine and Health Sciences ; Mesenchymal Stem Cell Transplantation ; Mesenchymal stem cells ; Mesenchymal Stromal Cells - physiology ; Mesenchyme ; Metabolic disorders ; Mice ; Mice, Inbred C57BL ; Mice, Knockout ; Mucopolysaccharidosis ; Mucopolysaccharidosis I - blood ; Mucopolysaccharidosis I - immunology ; Mucopolysaccharidosis I - therapy ; Nuclear medicine ; Oncology ; Organs ; Pediatrics ; Peritoneum ; Plasmids ; Production capacity ; Proteins ; Research and Analysis Methods ; Stem cell transplantation ; Stem cells ; Tissue Distribution ; Transplantation ; Tumor necrosis factor-α</subject><ispartof>PloS one, 2014-03, Vol.9 (3), p.e92420</ispartof><rights>2014 Martin et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License: http://creativecommons.org/licenses/by/4.0/ (the “License”), which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. Notwithstanding the ProQuest Terms and Conditions, you may use this content in accordance with the terms of the License.</rights><rights>2014 Martin et al 2014 Martin et al</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c596t-98425c324339dce3fda0c2ad84e3c41873875d15f2ad59235d00a715e9dce5f03</citedby><cites>FETCH-LOGICAL-c596t-98425c324339dce3fda0c2ad84e3c41873875d15f2ad59235d00a715e9dce5f03</cites></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktopdf>$$Uhttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC3958533/pdf/$$EPDF$$P50$$Gpubmedcentral$$Hfree_for_read</linktopdf><linktohtml>$$Uhttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC3958533/$$EHTML$$P50$$Gpubmedcentral$$Hfree_for_read</linktohtml><link.rule.ids>230,314,723,776,780,860,881,2096,2915,23845,27901,27902,53766,53768,79342,79343</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/24642723$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Martin, Priscila Keiko Matsumoto</creatorcontrib><creatorcontrib>Stilhano, Roberta Sessa</creatorcontrib><creatorcontrib>Samoto, Vivian Yochiko</creatorcontrib><creatorcontrib>Takiya, Christina Maeda</creatorcontrib><creatorcontrib>Peres, Giovani Bravin</creatorcontrib><creatorcontrib>da Silva Michelacci, Yara Maria Correa</creatorcontrib><creatorcontrib>da Silva, Flavia Helena</creatorcontrib><creatorcontrib>Pereira, Vanessa Gonçalves</creatorcontrib><creatorcontrib>D'Almeida, Vânia</creatorcontrib><creatorcontrib>Marques, Fabio Luiz Navarro</creatorcontrib><creatorcontrib>Otake, Andreia Hanada</creatorcontrib><creatorcontrib>Chammas, Roger</creatorcontrib><creatorcontrib>Han, Sang Won</creatorcontrib><title>Mesenchymal stem cells do not prevent antibody responses against human α-L-iduronidase when used to treat mucopolysaccharidosis type I</title><title>PloS one</title><addtitle>PLoS One</addtitle><description>Mucopolysaccharidosis type I (MPSI) is an autosomal recessive disease that leads to systemic lysosomal storage, which is caused by the absence of α-L-iduronidase (IDUA). Enzyme replacement therapy is recognized as the best therapeutic option for MPSI; however, high titers of anti-IDUA antibody have frequently been observed. Due to the immunosuppressant properties of MSC, we hypothesized that MSC modified with the IDUA gene would be able to produce IDUA for a long period of time. Sleeping Beauty transposon vectors were used to modify MSC because these are basically less-immunogenic plasmids. For cell transplantation, 4×10(6) MSC-KO-IDUA cells (MSC from KO mice modified with IDUA) were injected into the peritoneum of KO-mice three times over intervals of more than one month. The total IDUA activities from MSC-KO-IDUA before cell transplantation were 9.6, 120 and 179 U for the first, second and third injections, respectively. Only after the second cell transplantation, more than one unit of IDUA activity was detected in the blood of 3 mice for 2 days. After the third cell transplantation, a high titer of anti-IDUA antibody was detected in all of the treated mice. Anti-IDUA antibody response was also detected in C57Bl/6 mice treated with MSC-WT-IDUA. The antibody titers were high and comparable to mice that were immunized by electroporation. MSC-transplanted mice had high levels of TNF-alpha and infiltrates in the renal glomeruli. The spreading of the transplanted MSC into the peritoneum of other organs was confirmed after injection of 111In-labeled MSC. In conclusion, the antibody response against IDUA could not be avoided by MSC. On the contrary, these cells worked as an adjuvant that favored IDUA immunization. Therefore, the humoral immunosuppressant property of MSC is questionable and indicates the danger of using MSC as a source for the production of exogenous proteins to treat monogenic diseases.</description><subject>Animals</subject><subject>Antibody response</subject><subject>Autoantibodies - blood</subject><subject>Biochemistry</subject><subject>Biology and Life Sciences</subject><subject>Biophysics</subject><subject>Bone marrow</subject><subject>Cells, Cultured</subject><subject>Combined Modality Therapy</subject><subject>Cytokines - blood</subject><subject>Disease</subject><subject>Electroporation</subject><subject>Enzyme Replacement Therapy</subject><subject>Enzymes</subject><subject>Gene expression</subject><subject>Gene therapy</subject><subject>Genetic disorders</subject><subject>Hazards</subject><subject>Heparan sulfate</subject><subject>Human behavior</subject><subject>Humans</subject><subject>Hypotheses</subject><subject>IDUA gene</subject><subject>Iduronidase - immunology</subject><subject>Iduronidase - therapeutic use</subject><subject>Immunization</subject><subject>Immunogenicity</subject><subject>Immunoglobulins</subject><subject>Injections, Intraperitoneal</subject><subject>L-Iduronidase</subject><subject>Laboratories</subject><subject>Lupus</subject><subject>Medicine and Health Sciences</subject><subject>Mesenchymal Stem Cell Transplantation</subject><subject>Mesenchymal stem cells</subject><subject>Mesenchymal Stromal Cells - physiology</subject><subject>Mesenchyme</subject><subject>Metabolic disorders</subject><subject>Mice</subject><subject>Mice, Inbred C57BL</subject><subject>Mice, Knockout</subject><subject>Mucopolysaccharidosis</subject><subject>Mucopolysaccharidosis I - blood</subject><subject>Mucopolysaccharidosis I - immunology</subject><subject>Mucopolysaccharidosis I - therapy</subject><subject>Nuclear medicine</subject><subject>Oncology</subject><subject>Organs</subject><subject>Pediatrics</subject><subject>Peritoneum</subject><subject>Plasmids</subject><subject>Production capacity</subject><subject>Proteins</subject><subject>Research and Analysis Methods</subject><subject>Stem cell transplantation</subject><subject>Stem cells</subject><subject>Tissue Distribution</subject><subject>Transplantation</subject><subject>Tumor necrosis 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Database</collection><collection>Engineering Database</collection><collection>Nursing & Allied Health Premium</collection><collection>Advanced Technologies & Aerospace Database</collection><collection>ProQuest Advanced Technologies & Aerospace Collection</collection><collection>Biotechnology and BioEngineering Abstracts</collection><collection>Environmental Science Database</collection><collection>Materials Science Collection</collection><collection>Publicly Available Content Database</collection><collection>ProQuest One Academic Eastern Edition (DO NOT USE)</collection><collection>ProQuest One Academic</collection><collection>ProQuest One Academic UKI Edition</collection><collection>ProQuest Central China</collection><collection>Engineering Collection</collection><collection>Environmental Science Collection</collection><collection>Genetics Abstracts</collection><collection>PubMed Central (Full Participant titles)</collection><collection>DOAJ Directory of Open Access Journals</collection><jtitle>PloS one</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Martin, Priscila Keiko Matsumoto</au><au>Stilhano, Roberta Sessa</au><au>Samoto, Vivian Yochiko</au><au>Takiya, Christina Maeda</au><au>Peres, Giovani Bravin</au><au>da Silva Michelacci, Yara Maria Correa</au><au>da Silva, Flavia Helena</au><au>Pereira, Vanessa Gonçalves</au><au>D'Almeida, Vânia</au><au>Marques, Fabio Luiz Navarro</au><au>Otake, Andreia Hanada</au><au>Chammas, Roger</au><au>Han, Sang Won</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Mesenchymal stem cells do not prevent antibody responses against human α-L-iduronidase when used to treat mucopolysaccharidosis type I</atitle><jtitle>PloS one</jtitle><addtitle>PLoS One</addtitle><date>2014-03-18</date><risdate>2014</risdate><volume>9</volume><issue>3</issue><spage>e92420</spage><pages>e92420-</pages><issn>1932-6203</issn><eissn>1932-6203</eissn><abstract>Mucopolysaccharidosis type I (MPSI) is an autosomal recessive disease that leads to systemic lysosomal storage, which is caused by the absence of α-L-iduronidase (IDUA). Enzyme replacement therapy is recognized as the best therapeutic option for MPSI; however, high titers of anti-IDUA antibody have frequently been observed. Due to the immunosuppressant properties of MSC, we hypothesized that MSC modified with the IDUA gene would be able to produce IDUA for a long period of time. Sleeping Beauty transposon vectors were used to modify MSC because these are basically less-immunogenic plasmids. For cell transplantation, 4×10(6) MSC-KO-IDUA cells (MSC from KO mice modified with IDUA) were injected into the peritoneum of KO-mice three times over intervals of more than one month. The total IDUA activities from MSC-KO-IDUA before cell transplantation were 9.6, 120 and 179 U for the first, second and third injections, respectively. Only after the second cell transplantation, more than one unit of IDUA activity was detected in the blood of 3 mice for 2 days. After the third cell transplantation, a high titer of anti-IDUA antibody was detected in all of the treated mice. Anti-IDUA antibody response was also detected in C57Bl/6 mice treated with MSC-WT-IDUA. The antibody titers were high and comparable to mice that were immunized by electroporation. MSC-transplanted mice had high levels of TNF-alpha and infiltrates in the renal glomeruli. The spreading of the transplanted MSC into the peritoneum of other organs was confirmed after injection of 111In-labeled MSC. In conclusion, the antibody response against IDUA could not be avoided by MSC. On the contrary, these cells worked as an adjuvant that favored IDUA immunization. Therefore, the humoral immunosuppressant property of MSC is questionable and indicates the danger of using MSC as a source for the production of exogenous proteins to treat monogenic diseases.</abstract><cop>United States</cop><pub>Public Library of Science</pub><pmid>24642723</pmid><doi>10.1371/journal.pone.0092420</doi><oa>free_for_read</oa></addata></record> |
| fulltext | fulltext |
| identifier | ISSN: 1932-6203 |
| ispartof | PloS one, 2014-03, Vol.9 (3), p.e92420 |
| issn | 1932-6203 1932-6203 |
| language | eng |
| recordid | cdi_plos_journals_1508464019 |
| source | MEDLINE; DOAJ Directory of Open Access Journals; Elektronische Zeitschriftenbibliothek - Frei zugängliche E-Journals; PubMed Central; Free Full-Text Journals in Chemistry; Public Library of Science (PLoS) |
| subjects | Animals Antibody response Autoantibodies - blood Biochemistry Biology and Life Sciences Biophysics Bone marrow Cells, Cultured Combined Modality Therapy Cytokines - blood Disease Electroporation Enzyme Replacement Therapy Enzymes Gene expression Gene therapy Genetic disorders Hazards Heparan sulfate Human behavior Humans Hypotheses IDUA gene Iduronidase - immunology Iduronidase - therapeutic use Immunization Immunogenicity Immunoglobulins Injections, Intraperitoneal L-Iduronidase Laboratories Lupus Medicine and Health Sciences Mesenchymal Stem Cell Transplantation Mesenchymal stem cells Mesenchymal Stromal Cells - physiology Mesenchyme Metabolic disorders Mice Mice, Inbred C57BL Mice, Knockout Mucopolysaccharidosis Mucopolysaccharidosis I - blood Mucopolysaccharidosis I - immunology Mucopolysaccharidosis I - therapy Nuclear medicine Oncology Organs Pediatrics Peritoneum Plasmids Production capacity Proteins Research and Analysis Methods Stem cell transplantation Stem cells Tissue Distribution Transplantation Tumor necrosis factor-α |
| title | Mesenchymal stem cells do not prevent antibody responses against human α-L-iduronidase when used to treat mucopolysaccharidosis type I |
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