Immune Modulatory Cell Therapy for Hemophilia B Based on CD20-Targeted Lentiviral Gene Transfer to Primary B Cells
Gene-modified B cells expressing immunoglobulin G (IgG) fusion proteins have been shown to induce tolerance in several autoimmune and other disease models. However, lack of a vector suitable for gene transfer to human B cells has been an obstacle for translation of this approach. To overcome this hu...
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| Format: | Article |
| Language: | English |
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Elsevier
2017-06-01
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| Series: | Molecular Therapy: Methods & Clinical Development |
| Subjects: | |
| Online Access: | http://www.sciencedirect.com/science/article/pii/S2329050117300505 |
| _version_ | 1818881735017889792 |
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| author | Xiaomei Wang Roland W. Herzog Barry J. Byrne Sandeep R.P. Kumar Qi Zhou Christian J. Buchholz Moanaro Biswas |
| author_facet | Xiaomei Wang Roland W. Herzog Barry J. Byrne Sandeep R.P. Kumar Qi Zhou Christian J. Buchholz Moanaro Biswas |
| author_sort | Xiaomei Wang |
| collection | DOAJ |
| description | Gene-modified B cells expressing immunoglobulin G (IgG) fusion proteins have been shown to induce tolerance in several autoimmune and other disease models. However, lack of a vector suitable for gene transfer to human B cells has been an obstacle for translation of this approach. To overcome this hurdle, we developed an IgG-human factor IX (hFIX) lentiviral fusion construct that was targeted to specifically transduce cells expressing human CD20 (hCD20). Receptor-specific retargeting by mutating envelope glycoproteins of measles virus (MV)-lentiviral vector (LV) and addition of a single-chain variable fragment specific for hCD20 resulted in gene delivery into primary human and transgenic hCD20 mouse B cells with high specificity. Notably, this protocol neither required nor induced activation of the B cells, as confirmed by minimal activation of inflammatory cytokines. Using this strategy, we were able to demonstrate induction of humoral tolerance, resulting in suppression of antibody formation against hFIX in a mouse model of hemophilia B (HB). In conclusion, transduction of receptor-specific retargeted LV into resting B cells is a promising method to develop B cell therapies for antigen-specific tolerance induction in human disease. |
| first_indexed | 2024-12-19T15:06:35Z |
| format | Article |
| id | doaj.art-cbfc10cca4284189aca738ec77b936ec |
| institution | Directory Open Access Journal |
| issn | 2329-0501 |
| language | English |
| last_indexed | 2024-12-19T15:06:35Z |
| publishDate | 2017-06-01 |
| publisher | Elsevier |
| record_format | Article |
| series | Molecular Therapy: Methods & Clinical Development |
| spelling | doaj.art-cbfc10cca4284189aca738ec77b936ec2022-12-21T20:16:25ZengElsevierMolecular Therapy: Methods & Clinical Development2329-05012017-06-015C768210.1016/j.omtm.2017.03.005Immune Modulatory Cell Therapy for Hemophilia B Based on CD20-Targeted Lentiviral Gene Transfer to Primary B CellsXiaomei Wang0Roland W. Herzog1Barry J. Byrne2Sandeep R.P. Kumar3Qi Zhou4Christian J. Buchholz5Moanaro Biswas6Division of Cellular and Molecular Therapy, Department of Pediatrics, University of Florida, Gainesville, FL 32610, USADivision of Cellular and Molecular Therapy, Department of Pediatrics, University of Florida, Gainesville, FL 32610, USAPowell Gene Therapy Center, Department of Pediatrics, University of Florida, Gainesville, FL 32610, USADivision of Cellular and Molecular Therapy, Department of Pediatrics, University of Florida, Gainesville, FL 32610, USAMolecular Biotechnology and Gene Therapy, Paul-Ehrlich-Institut, 63225 Langen, GermanyMolecular Biotechnology and Gene Therapy, Paul-Ehrlich-Institut, 63225 Langen, GermanyDivision of Cellular and Molecular Therapy, Department of Pediatrics, University of Florida, Gainesville, FL 32610, USAGene-modified B cells expressing immunoglobulin G (IgG) fusion proteins have been shown to induce tolerance in several autoimmune and other disease models. However, lack of a vector suitable for gene transfer to human B cells has been an obstacle for translation of this approach. To overcome this hurdle, we developed an IgG-human factor IX (hFIX) lentiviral fusion construct that was targeted to specifically transduce cells expressing human CD20 (hCD20). Receptor-specific retargeting by mutating envelope glycoproteins of measles virus (MV)-lentiviral vector (LV) and addition of a single-chain variable fragment specific for hCD20 resulted in gene delivery into primary human and transgenic hCD20 mouse B cells with high specificity. Notably, this protocol neither required nor induced activation of the B cells, as confirmed by minimal activation of inflammatory cytokines. Using this strategy, we were able to demonstrate induction of humoral tolerance, resulting in suppression of antibody formation against hFIX in a mouse model of hemophilia B (HB). In conclusion, transduction of receptor-specific retargeted LV into resting B cells is a promising method to develop B cell therapies for antigen-specific tolerance induction in human disease.http://www.sciencedirect.com/science/article/pii/S2329050117300505hemophilia BCD20SCFVlentivirusgene transfermeasles viruspsuedotype |
| spellingShingle | Xiaomei Wang Roland W. Herzog Barry J. Byrne Sandeep R.P. Kumar Qi Zhou Christian J. Buchholz Moanaro Biswas Immune Modulatory Cell Therapy for Hemophilia B Based on CD20-Targeted Lentiviral Gene Transfer to Primary B Cells Molecular Therapy: Methods & Clinical Development hemophilia B CD20 SCFV lentivirus gene transfer measles virus psuedotype |
| title | Immune Modulatory Cell Therapy for Hemophilia B Based on CD20-Targeted Lentiviral Gene Transfer to Primary B Cells |
| title_full | Immune Modulatory Cell Therapy for Hemophilia B Based on CD20-Targeted Lentiviral Gene Transfer to Primary B Cells |
| title_fullStr | Immune Modulatory Cell Therapy for Hemophilia B Based on CD20-Targeted Lentiviral Gene Transfer to Primary B Cells |
| title_full_unstemmed | Immune Modulatory Cell Therapy for Hemophilia B Based on CD20-Targeted Lentiviral Gene Transfer to Primary B Cells |
| title_short | Immune Modulatory Cell Therapy for Hemophilia B Based on CD20-Targeted Lentiviral Gene Transfer to Primary B Cells |
| title_sort | immune modulatory cell therapy for hemophilia b based on cd20 targeted lentiviral gene transfer to primary b cells |
| topic | hemophilia B CD20 SCFV lentivirus gene transfer measles virus psuedotype |
| url | http://www.sciencedirect.com/science/article/pii/S2329050117300505 |
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