title: Mesenchymal stem cells do not prevent antibody responses against human α-L-iduronidase when used to treat mucopolysaccharidosis type I.
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.
authors.affiliation: Research Center for Gene Therapy, Federal University of São Paulo, São Paulo, Brazil; Department of Biophysics, Federal University of São Paulo, São Paulo, Brazil.
authors.forename: Priscila Keiko Matsumoto
authors.initials: PK
authors.lastname: Martin
authors.affiliation: Research Center for Gene Therapy, Federal University of São Paulo, São Paulo, Brazil; Department of Biophysics, Federal University of São Paulo, São Paulo, Brazil.
authors.forename: Roberta Sessa
authors.initials: RS
authors.lastname: Stilhano
authors.affiliation: Carlos Chagas Filho Institute of Biophysics, Federal University of Rio de Janeiro, Rio de Janeiro, Brazil.
authors.forename: Vivian Yochiko
authors.initials: VY
authors.lastname: Samoto
authors.affiliation: Carlos Chagas Filho Institute of Biophysics, Federal University of Rio de Janeiro, Rio de Janeiro, Brazil.
authors.forename: Christina Maeda
authors.initials: CM
authors.lastname: Takiya
authors.affiliation: Department of Biochemistry, Federal University of São Paulo, São Paulo, Brazil.
authors.forename: Giovani Bravin
authors.initials: GB
authors.lastname: Peres
authors.affiliation: Department of Biochemistry, Federal University of São Paulo, São Paulo, Brazil.
authors.forename: Yara Maria Correa
authors.initials: YM
authors.lastname: da Silva Michelacci
authors.affiliation: Research Center for Gene Therapy, Federal University of São Paulo, São Paulo, Brazil; Department of Genetics, Federal University of Rio Grande do Sul, São Paulo, Brazil.
authors.forename: Flavia Helena
authors.initials: FH
authors.lastname: da Silva
authors.affiliation: Department of Pediatrics, Federal University of São Paulo, São Paulo, Brazil.
authors.forename: Vanessa Gonçalves
authors.initials: VG
authors.lastname: Pereira
authors.affiliation: Department of Pediatrics, Federal University of São Paulo, São Paulo, Brazil.
authors.forename: Vânia
authors.initials: V
authors.lastname: D'Almeida
authors.affiliation: Nuclear Medicine Center, University of São Paulo, São Paulo, Brazil.
authors.forename: Fabio Luiz Navarro
authors.initials: FL
authors.lastname: Marques
authors.affiliation: Laboratory of Experimental Oncology, Department of Radiology and Oncology, School of Medicine, São Paulo University, São Paulo, Brazil; Translational Investigation Center of Oncology, Cancer Institute of São Paulo State, São Paulo, Brazil.
authors.forename: Andreia Hanada
authors.initials: AH
authors.lastname: Otake
authors.affiliation: Laboratory of Experimental Oncology, Department of Radiology and Oncology, School of Medicine, São Paulo University, São Paulo, Brazil; Translational Investigation Center of Oncology, Cancer Institute of São Paulo State, São Paulo, Brazil.
authors.forename: Roger
authors.initials: R
authors.lastname: Chammas
authors.affiliation: Research Center for Gene Therapy, Federal University of São Paulo, São Paulo, Brazil; Department of Biophysics, Federal University of São Paulo, São Paulo, Brazil.
authors.forename: Sang Won
authors.initials: SW
authors.lastname: Han
mesh_terms: D000818:Animals; D001323:Autoantibodies / Q000097:blood; D002478:Cells, Cultured; D003131:Combined Modality Therapy; D016207:Cytokines / Q000097:blood; D056947:Enzyme Replacement Therapy; D006801:Humans; D007068:Iduronidase / Q000276:immunology* / Q000627:therapeutic use; D007274:Injections, Intraperitoneal; D045164:Mesenchymal Stem Cell Transplantation; D059630:Mesenchymal Stem Cells / Q000502:physiology*; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008059:Mucopolysaccharidosis I / Q000097:blood / Q000276:immunology / Q000628:therapy*; D014018:Tissue Distribution
chemical_list: D001323:Autoantibodies; D016207:Cytokines; D007068:Iduronidase