Immunoregulatory Sertoli Cell Allografts Engineered to Express Human Insulin Survive Humoral-Mediated Rejection
An effective treatment and possible cure for type 1 diabetes is transplantation of pancreatic islets. Unfortunately, transplanted islets are rejected by the immune system with humoral-mediated responses being an important part of rejection. Sertoli cells (SC), an immune regulatory cell shown to surv...
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MDPI AG
2022-12-01
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| Series: | International Journal of Molecular Sciences |
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| Online Access: | https://www.mdpi.com/1422-0067/23/24/15894 |
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| author | Rachel L. Washburn Taylor Hibler Gurvinder Kaur Anna Sabu-Kurian Alissa Landefeld Jannette M. Dufour |
| author_facet | Rachel L. Washburn Taylor Hibler Gurvinder Kaur Anna Sabu-Kurian Alissa Landefeld Jannette M. Dufour |
| author_sort | Rachel L. Washburn |
| collection | DOAJ |
| description | An effective treatment and possible cure for type 1 diabetes is transplantation of pancreatic islets. Unfortunately, transplanted islets are rejected by the immune system with humoral-mediated responses being an important part of rejection. Sertoli cells (SC), an immune regulatory cell shown to survive as allografts long-term without immunosuppressants, have the potential to be used as a cell-based gene therapy vehicle to deliver endogenous insulin—a possible alternative to islets. Previously, we transduced a mouse SC line to produce human insulin. After transplantation into diabetic mice, these cells consistently produced low levels of insulin with graft survival of 75% at 50 days post-transplantation. The object of this study was to assess humoral immune regulation by these engineered SC. Both nontransduced and transduced SC survived exposure to human serum with complement in vitro. Analysis of allografts in vivo at 20 and 50 days post-transplantation revealed that despite IgG antibody detection, complement factor deposition was low and grafts survived through 50 days post-transplantation. Furthermore, the transduced SC secreted elevated levels of the complement inhibitor C1q binding protein. Overall, this suggests SC genetically engineered to express insulin maintain their ability to prevent complement-mediated killing. Since inhibiting complement-mediated rejection is important for graft survival, further studies of how SC modifies the immune response could be utilized to advance the use of genetically engineered SC or to prolong islet allograft survival to improve the treatment of diabetes. |
| first_indexed | 2024-03-09T16:19:03Z |
| format | Article |
| id | doaj.art-b210276f59004a8daecf64d9544ded11 |
| institution | Directory Open Access Journal |
| issn | 1661-6596 1422-0067 |
| language | English |
| last_indexed | 2024-03-09T16:19:03Z |
| publishDate | 2022-12-01 |
| publisher | MDPI AG |
| record_format | Article |
| series | International Journal of Molecular Sciences |
| spelling | doaj.art-b210276f59004a8daecf64d9544ded112023-11-24T15:29:59ZengMDPI AGInternational Journal of Molecular Sciences1661-65961422-00672022-12-0123241589410.3390/ijms232415894Immunoregulatory Sertoli Cell Allografts Engineered to Express Human Insulin Survive Humoral-Mediated RejectionRachel L. Washburn0Taylor Hibler1Gurvinder Kaur2Anna Sabu-Kurian3Alissa Landefeld4Jannette M. Dufour5Department of Cell Biology and Biochemistry, School of Medicine, Texas Tech University Health Sciences Center, Lubbock, TX 79430, USADepartment of Cell Biology and Biochemistry, School of Medicine, Texas Tech University Health Sciences Center, Lubbock, TX 79430, USADepartment of Cell Biology and Biochemistry, School of Medicine, Texas Tech University Health Sciences Center, Lubbock, TX 79430, USADepartment of Cell Biology and Biochemistry, School of Medicine, Texas Tech University Health Sciences Center, Lubbock, TX 79430, USADepartment of Cell Biology and Biochemistry, School of Medicine, Texas Tech University Health Sciences Center, Lubbock, TX 79430, USADepartment of Cell Biology and Biochemistry, School of Medicine, Texas Tech University Health Sciences Center, Lubbock, TX 79430, USAAn effective treatment and possible cure for type 1 diabetes is transplantation of pancreatic islets. Unfortunately, transplanted islets are rejected by the immune system with humoral-mediated responses being an important part of rejection. Sertoli cells (SC), an immune regulatory cell shown to survive as allografts long-term without immunosuppressants, have the potential to be used as a cell-based gene therapy vehicle to deliver endogenous insulin—a possible alternative to islets. Previously, we transduced a mouse SC line to produce human insulin. After transplantation into diabetic mice, these cells consistently produced low levels of insulin with graft survival of 75% at 50 days post-transplantation. The object of this study was to assess humoral immune regulation by these engineered SC. Both nontransduced and transduced SC survived exposure to human serum with complement in vitro. Analysis of allografts in vivo at 20 and 50 days post-transplantation revealed that despite IgG antibody detection, complement factor deposition was low and grafts survived through 50 days post-transplantation. Furthermore, the transduced SC secreted elevated levels of the complement inhibitor C1q binding protein. Overall, this suggests SC genetically engineered to express insulin maintain their ability to prevent complement-mediated killing. Since inhibiting complement-mediated rejection is important for graft survival, further studies of how SC modifies the immune response could be utilized to advance the use of genetically engineered SC or to prolong islet allograft survival to improve the treatment of diabetes.https://www.mdpi.com/1422-0067/23/24/15894diabetesinsulinSertoli cellscomplementgenetic engineeringtransplantation |
| spellingShingle | Rachel L. Washburn Taylor Hibler Gurvinder Kaur Anna Sabu-Kurian Alissa Landefeld Jannette M. Dufour Immunoregulatory Sertoli Cell Allografts Engineered to Express Human Insulin Survive Humoral-Mediated Rejection International Journal of Molecular Sciences diabetes insulin Sertoli cells complement genetic engineering transplantation |
| title | Immunoregulatory Sertoli Cell Allografts Engineered to Express Human Insulin Survive Humoral-Mediated Rejection |
| title_full | Immunoregulatory Sertoli Cell Allografts Engineered to Express Human Insulin Survive Humoral-Mediated Rejection |
| title_fullStr | Immunoregulatory Sertoli Cell Allografts Engineered to Express Human Insulin Survive Humoral-Mediated Rejection |
| title_full_unstemmed | Immunoregulatory Sertoli Cell Allografts Engineered to Express Human Insulin Survive Humoral-Mediated Rejection |
| title_short | Immunoregulatory Sertoli Cell Allografts Engineered to Express Human Insulin Survive Humoral-Mediated Rejection |
| title_sort | immunoregulatory sertoli cell allografts engineered to express human insulin survive humoral mediated rejection |
| topic | diabetes insulin Sertoli cells complement genetic engineering transplantation |
| url | https://www.mdpi.com/1422-0067/23/24/15894 |
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