Zebularine induces long-term survival of pancreatic islet allotransplants in streptozotocin treated diabetic rats.
Coping with the immune rejection of allotransplants or autologous cells in patients with an active sensitization towards their autoantigens and autoimmunity presently necessitates life-long immune suppressive therapy acting on the immune system as a whole, which makes the patients vulnerable to infe...
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| Format: | Article |
| Language: | English |
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Public Library of Science (PLoS)
2013-01-01
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| Series: | PLoS ONE |
| Online Access: | http://europepmc.org/articles/PMC3753325?pdf=render |
| _version_ | 1818611620416323584 |
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| author | Henrietta Nittby Peter Ericsson Karolina Förnvik Susanne Strömblad Linda Jansson Zhongtian Xue Gunnar Skagerberg Bengt Widegren Hans-Olov Sjögren Leif G Salford |
| author_facet | Henrietta Nittby Peter Ericsson Karolina Förnvik Susanne Strömblad Linda Jansson Zhongtian Xue Gunnar Skagerberg Bengt Widegren Hans-Olov Sjögren Leif G Salford |
| author_sort | Henrietta Nittby |
| collection | DOAJ |
| description | Coping with the immune rejection of allotransplants or autologous cells in patients with an active sensitization towards their autoantigens and autoimmunity presently necessitates life-long immune suppressive therapy acting on the immune system as a whole, which makes the patients vulnerable to infections and increases their risk of developing cancer. New technologies to induce antigen selective long-lasting immunosuppression or immune tolerance are therefore much needed.The DNA demethylating agent Zebularine, previously demonstrated to induce expression of the genes for the immunosuppressive enzymes indolamine-2,3-deoxygenase-1 (IDO1) and kynureninase of the kynurenine pathway, is tested for capacity to suppress rejection of allotransplants. Allogeneic pancreatic islets from Lewis rats were transplanted under the kidney capsule of Fischer rats previously made diabetic by a streptozotocin injection (40 mg/kg). One group was treated with Zebularine (225 mg/kg) daily for 14 days from day 6 or 8 after transplantation, and a control group received no further treatment. Survival of the transplants was monitored by blood sugar measurements. Rats, normoglycemic for 90 days after allografting, were subjected to transplant removal by nephrectomy to confirm whether normoglycemia was indeed due to a surviving insulin producing transplant, or alternatively was a result of recovery of pancreatic insulin production in some toxin-treated rats. Of 9 Zebularine treated rats, 4 were still normoglycemic after 90 days and became hyperglycemic after nephrectomy. The mean length of normoglycemia in the Zebularine group was 67±8 days as compared to 14±3 days in 9 controls. Seven rats (2 controls and 5 Zebularine treated) were normoglycemic at 90 days due to pancreatic recovery as demonstrated by failure of nephrectomy to induce hyperglycemia.Zebularine treatment in vivo induces a long-lasting suppression of the immune destruction of allogeneic pancreatic islets resulting in protection of allograft function for more than 10 weeks after end of treatment. |
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| format | Article |
| id | doaj.art-8aaddacad8aa4c7f800587bd66f8e56b |
| institution | Directory Open Access Journal |
| issn | 1932-6203 |
| language | English |
| last_indexed | 2024-12-16T15:33:13Z |
| publishDate | 2013-01-01 |
| publisher | Public Library of Science (PLoS) |
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| spelling | doaj.art-8aaddacad8aa4c7f800587bd66f8e56b2022-12-21T22:26:17ZengPublic Library of Science (PLoS)PLoS ONE1932-62032013-01-0188e7198110.1371/journal.pone.0071981Zebularine induces long-term survival of pancreatic islet allotransplants in streptozotocin treated diabetic rats.Henrietta NittbyPeter EricssonKarolina FörnvikSusanne StrömbladLinda JanssonZhongtian XueGunnar SkagerbergBengt WidegrenHans-Olov SjögrenLeif G SalfordCoping with the immune rejection of allotransplants or autologous cells in patients with an active sensitization towards their autoantigens and autoimmunity presently necessitates life-long immune suppressive therapy acting on the immune system as a whole, which makes the patients vulnerable to infections and increases their risk of developing cancer. New technologies to induce antigen selective long-lasting immunosuppression or immune tolerance are therefore much needed.The DNA demethylating agent Zebularine, previously demonstrated to induce expression of the genes for the immunosuppressive enzymes indolamine-2,3-deoxygenase-1 (IDO1) and kynureninase of the kynurenine pathway, is tested for capacity to suppress rejection of allotransplants. Allogeneic pancreatic islets from Lewis rats were transplanted under the kidney capsule of Fischer rats previously made diabetic by a streptozotocin injection (40 mg/kg). One group was treated with Zebularine (225 mg/kg) daily for 14 days from day 6 or 8 after transplantation, and a control group received no further treatment. Survival of the transplants was monitored by blood sugar measurements. Rats, normoglycemic for 90 days after allografting, were subjected to transplant removal by nephrectomy to confirm whether normoglycemia was indeed due to a surviving insulin producing transplant, or alternatively was a result of recovery of pancreatic insulin production in some toxin-treated rats. Of 9 Zebularine treated rats, 4 were still normoglycemic after 90 days and became hyperglycemic after nephrectomy. The mean length of normoglycemia in the Zebularine group was 67±8 days as compared to 14±3 days in 9 controls. Seven rats (2 controls and 5 Zebularine treated) were normoglycemic at 90 days due to pancreatic recovery as demonstrated by failure of nephrectomy to induce hyperglycemia.Zebularine treatment in vivo induces a long-lasting suppression of the immune destruction of allogeneic pancreatic islets resulting in protection of allograft function for more than 10 weeks after end of treatment.http://europepmc.org/articles/PMC3753325?pdf=render |
| spellingShingle | Henrietta Nittby Peter Ericsson Karolina Förnvik Susanne Strömblad Linda Jansson Zhongtian Xue Gunnar Skagerberg Bengt Widegren Hans-Olov Sjögren Leif G Salford Zebularine induces long-term survival of pancreatic islet allotransplants in streptozotocin treated diabetic rats. PLoS ONE |
| title | Zebularine induces long-term survival of pancreatic islet allotransplants in streptozotocin treated diabetic rats. |
| title_full | Zebularine induces long-term survival of pancreatic islet allotransplants in streptozotocin treated diabetic rats. |
| title_fullStr | Zebularine induces long-term survival of pancreatic islet allotransplants in streptozotocin treated diabetic rats. |
| title_full_unstemmed | Zebularine induces long-term survival of pancreatic islet allotransplants in streptozotocin treated diabetic rats. |
| title_short | Zebularine induces long-term survival of pancreatic islet allotransplants in streptozotocin treated diabetic rats. |
| title_sort | zebularine induces long term survival of pancreatic islet allotransplants in streptozotocin treated diabetic rats |
| url | http://europepmc.org/articles/PMC3753325?pdf=render |
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