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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Autores principales:	Priscila Keiko Matsumoto Martin, Roberta Sessa Stilhano, Vivian Yochiko Samoto, Christina Maeda Takiya, Giovani Bravin Peres, Yara Maria Correa da Silva Michelacci, Flavia Helena da Silva, Vanessa Gonçalves Pereira, Vânia D'Almeida, Fabio Luiz Navarro Marques, Andreia Hanada Otake, Roger Chammas, Sang Won Han
Formato:	article
Lenguaje:	EN
Publicado:	Public Library of Science (PLoS) 2014
Materias:	Medicine R Science Q
Acceso en línea:	https://doaj.org/article/1a7cce9dd89d4272a2ff63e581f5f0dc
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spelling	oai:doaj.org-article:1a7cce9dd89d4272a2ff63e581f5f0dc2021-11-18T08:27:37ZMesenchymal stem cells do not prevent antibody responses against human α-L-iduronidase when used to treat mucopolysaccharidosis type I.1932-620310.1371/journal.pone.0092420https://doaj.org/article/1a7cce9dd89d4272a2ff63e581f5f0dc2014-01-01T00:00:00Zhttps://www.ncbi.nlm.nih.gov/pmc/articles/pmid/24642723/pdf/?tool=EBIhttps://doaj.org/toc/1932-6203Mucopolysaccharidosis 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.Priscila Keiko Matsumoto MartinRoberta Sessa StilhanoVivian Yochiko SamotoChristina Maeda TakiyaGiovani Bravin PeresYara Maria Correa da Silva MichelacciFlavia Helena da SilvaVanessa Gonçalves PereiraVânia D'AlmeidaFabio Luiz Navarro MarquesAndreia Hanada OtakeRoger ChammasSang Won HanPublic Library of Science (PLoS)articleMedicineRScienceQENPLoS ONE, Vol 9, Iss 3, p e92420 (2014)
institution	DOAJ
collection	DOAJ
language	EN
topic	Medicine R Science Q
spellingShingle	Medicine R Science Q Priscila Keiko Matsumoto Martin Roberta Sessa Stilhano Vivian Yochiko Samoto Christina Maeda Takiya Giovani Bravin Peres Yara Maria Correa da Silva Michelacci Flavia Helena da Silva Vanessa Gonçalves Pereira Vânia D'Almeida Fabio Luiz Navarro Marques Andreia Hanada Otake Roger Chammas Sang Won Han Mesenchymal stem cells do not prevent antibody responses against human α-L-iduronidase when used to treat mucopolysaccharidosis type I.
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.
format	article
author	Priscila Keiko Matsumoto Martin Roberta Sessa Stilhano Vivian Yochiko Samoto Christina Maeda Takiya Giovani Bravin Peres Yara Maria Correa da Silva Michelacci Flavia Helena da Silva Vanessa Gonçalves Pereira Vânia D'Almeida Fabio Luiz Navarro Marques Andreia Hanada Otake Roger Chammas Sang Won Han
author_facet	Priscila Keiko Matsumoto Martin Roberta Sessa Stilhano Vivian Yochiko Samoto Christina Maeda Takiya Giovani Bravin Peres Yara Maria Correa da Silva Michelacci Flavia Helena da Silva Vanessa Gonçalves Pereira Vânia D'Almeida Fabio Luiz Navarro Marques Andreia Hanada Otake Roger Chammas Sang Won Han
author_sort	Priscila Keiko Matsumoto Martin
title	Mesenchymal stem cells do not prevent antibody responses against human α-L-iduronidase when used to treat mucopolysaccharidosis type I.
title_short	Mesenchymal stem cells do not prevent antibody responses against human α-L-iduronidase when used to treat mucopolysaccharidosis type I.
title_full	Mesenchymal stem cells do not prevent antibody responses against human α-L-iduronidase when used to treat mucopolysaccharidosis type I.
title_fullStr	Mesenchymal stem cells do not prevent antibody responses against human α-L-iduronidase when used to treat mucopolysaccharidosis type I.
title_full_unstemmed	Mesenchymal stem cells do not prevent antibody responses against human α-L-iduronidase when used to treat mucopolysaccharidosis type I.
title_sort	mesenchymal stem cells do not prevent antibody responses against human α-l-iduronidase when used to treat mucopolysaccharidosis type i.
publisher	Public Library of Science (PLoS)
publishDate	2014
url	https://doaj.org/article/1a7cce9dd89d4272a2ff63e581f5f0dc
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Mesenchymal stem cells do not prevent antibody responses against human α-L-iduronidase when used to treat mucopolysaccharidosis type I.

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