Effects of immunosuppression on alpha and beta cell renewal in transplanted mouse islets

Aims/hypothesis Immunosuppressive drugs used in human islet transplantation interfere with the balance between beta cell renewal and death, and thus may contribute to progressive graft dysfunction. We analysed the influence of immunosuppressants on the proliferation of transplanted alpha and beta ce...

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Veröffentlicht in:Diabetologia 2013-07, Vol.56 (7), p.1596-1604
Hauptverfasser: Krautz, C., Wolk, S., Steffen, A., Knoch, K.-P., Ceglarek, U., Thiery, J., Bornstein, S., Saeger, H.-D., Solimena, M., Kersting, S.
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container_end_page 1604
container_issue 7
container_start_page 1596
container_title Diabetologia
container_volume 56
creator Krautz, C.
Wolk, S.
Steffen, A.
Knoch, K.-P.
Ceglarek, U.
Thiery, J.
Bornstein, S.
Saeger, H.-D.
Solimena, M.
Kersting, S.
description Aims/hypothesis Immunosuppressive drugs used in human islet transplantation interfere with the balance between beta cell renewal and death, and thus may contribute to progressive graft dysfunction. We analysed the influence of immunosuppressants on the proliferation of transplanted alpha and beta cells after syngeneic islet transplantation in streptozotocin-induced diabetic mice. Methods C57BL/6 diabetic mice were transplanted with syngeneic islets in the liver and simultaneously abdominally implanted with a mini-osmotic pump delivering BrdU alone or together with an immunosuppressant (tacrolimus, sirolimus, everolimus or mycophenolate mofetil [MMF]). Glycaemic control was assessed for 4 weeks. The area and proliferation of transplanted alpha and beta cells were subsequently quantified. Results After 4 weeks, glycaemia was significantly higher in treated mice than in controls. Insulinaemia was significantly lower in mice treated with everolimus, tacrolimus and sirolimus. MMF was the only immunosuppressant that did not significantly reduce beta cell area or proliferation, albeit its levels were in a lower range than those used in clinical settings. Conclusions/interpretation After transplantation in diabetic mice, syngeneic beta cells have a strong capacity for self-renewal. In contrast to other immunosuppressants, MMF neither impaired beta cell proliferation nor adversely affected the fractional beta cell area. Although human beta cells are less prone to proliferate compared with rodent beta cells, the use of MMF may improve the long-term outcome of islet transplantation.
doi_str_mv 10.1007/s00125-013-2895-z
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We analysed the influence of immunosuppressants on the proliferation of transplanted alpha and beta cells after syngeneic islet transplantation in streptozotocin-induced diabetic mice. Methods C57BL/6 diabetic mice were transplanted with syngeneic islets in the liver and simultaneously abdominally implanted with a mini-osmotic pump delivering BrdU alone or together with an immunosuppressant (tacrolimus, sirolimus, everolimus or mycophenolate mofetil [MMF]). Glycaemic control was assessed for 4 weeks. The area and proliferation of transplanted alpha and beta cells were subsequently quantified. Results After 4 weeks, glycaemia was significantly higher in treated mice than in controls. Insulinaemia was significantly lower in mice treated with everolimus, tacrolimus and sirolimus. MMF was the only immunosuppressant that did not significantly reduce beta cell area or proliferation, albeit its levels were in a lower range than those used in clinical settings. Conclusions/interpretation After transplantation in diabetic mice, syngeneic beta cells have a strong capacity for self-renewal. In contrast to other immunosuppressants, MMF neither impaired beta cell proliferation nor adversely affected the fractional beta cell area. Although human beta cells are less prone to proliferate compared with rodent beta cells, the use of MMF may improve the long-term outcome of islet transplantation.</description><identifier>ISSN: 0012-186X</identifier><identifier>EISSN: 1432-0428</identifier><identifier>DOI: 10.1007/s00125-013-2895-z</identifier><identifier>PMID: 23532258</identifier><language>eng</language><publisher>Berlin/Heidelberg: Springer-Verlag</publisher><subject>Animals ; Biological and medical sciences ; Blood Glucose - drug effects ; Cell growth ; Cell Proliferation - drug effects ; Diabetes ; Diabetes. Impaired glucose tolerance ; Endocrine pancreas. Apud cells (diseases) ; Endocrinopathies ; Etiopathogenesis. Screening. Investigations. 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We analysed the influence of immunosuppressants on the proliferation of transplanted alpha and beta cells after syngeneic islet transplantation in streptozotocin-induced diabetic mice. Methods C57BL/6 diabetic mice were transplanted with syngeneic islets in the liver and simultaneously abdominally implanted with a mini-osmotic pump delivering BrdU alone or together with an immunosuppressant (tacrolimus, sirolimus, everolimus or mycophenolate mofetil [MMF]). Glycaemic control was assessed for 4 weeks. The area and proliferation of transplanted alpha and beta cells were subsequently quantified. Results After 4 weeks, glycaemia was significantly higher in treated mice than in controls. Insulinaemia was significantly lower in mice treated with everolimus, tacrolimus and sirolimus. MMF was the only immunosuppressant that did not significantly reduce beta cell area or proliferation, albeit its levels were in a lower range than those used in clinical settings. Conclusions/interpretation After transplantation in diabetic mice, syngeneic beta cells have a strong capacity for self-renewal. In contrast to other immunosuppressants, MMF neither impaired beta cell proliferation nor adversely affected the fractional beta cell area. Although human beta cells are less prone to proliferate compared with rodent beta cells, the use of MMF may improve the long-term outcome of islet transplantation.</description><subject>Animals</subject><subject>Biological and medical sciences</subject><subject>Blood Glucose - drug effects</subject><subject>Cell growth</subject><subject>Cell Proliferation - drug effects</subject><subject>Diabetes</subject><subject>Diabetes. Impaired glucose tolerance</subject><subject>Endocrine pancreas. Apud cells (diseases)</subject><subject>Endocrinopathies</subject><subject>Etiopathogenesis. Screening. Investigations. 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We analysed the influence of immunosuppressants on the proliferation of transplanted alpha and beta cells after syngeneic islet transplantation in streptozotocin-induced diabetic mice. Methods C57BL/6 diabetic mice were transplanted with syngeneic islets in the liver and simultaneously abdominally implanted with a mini-osmotic pump delivering BrdU alone or together with an immunosuppressant (tacrolimus, sirolimus, everolimus or mycophenolate mofetil [MMF]). Glycaemic control was assessed for 4 weeks. The area and proliferation of transplanted alpha and beta cells were subsequently quantified. Results After 4 weeks, glycaemia was significantly higher in treated mice than in controls. Insulinaemia was significantly lower in mice treated with everolimus, tacrolimus and sirolimus. MMF was the only immunosuppressant that did not significantly reduce beta cell area or proliferation, albeit its levels were in a lower range than those used in clinical settings. Conclusions/interpretation After transplantation in diabetic mice, syngeneic beta cells have a strong capacity for self-renewal. In contrast to other immunosuppressants, MMF neither impaired beta cell proliferation nor adversely affected the fractional beta cell area. Although human beta cells are less prone to proliferate compared with rodent beta cells, the use of MMF may improve the long-term outcome of islet transplantation.</abstract><cop>Berlin/Heidelberg</cop><pub>Springer-Verlag</pub><pmid>23532258</pmid><doi>10.1007/s00125-013-2895-z</doi><tpages>9</tpages></addata></record>
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subjects Animals
Biological and medical sciences
Blood Glucose - drug effects
Cell growth
Cell Proliferation - drug effects
Diabetes
Diabetes. Impaired glucose tolerance
Endocrine pancreas. Apud cells (diseases)
Endocrinopathies
Etiopathogenesis. Screening. Investigations. Target tissue resistance
Glucose
Human Physiology
Immunohistochemistry
Immunosuppression - methods
Immunosuppressive agents
Immunosuppressive Agents - pharmacology
Insulin
Insulin-Secreting Cells - drug effects
Internal Medicine
Islets of Langerhans Transplantation
Medical sciences
Medicine
Medicine & Public Health
Metabolic Diseases
Metabolism
Mice
Mice, Inbred C57BL
Surgery
Transplants & implants
Veins & arteries
title Effects of immunosuppression on alpha and beta cell renewal in transplanted mouse islets
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