Reversal of naturally occurring diabetes in primates by unmodified islet xenografts without chronic immunosuppression

Francis T. Thomas, Camillo Ricordi, Juan L. Contreras, William J. Hubbard, Xiao Ling Jiang, Devin E. Eckhoff, Samuel Cartner, Guadalupe Bilbao, David M. Neville, Judith M. Thomas

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Abstract

Background. Isolated pancreatic islet transplantation (IPITx) is an attractive alternative for treatment of insulin-dependent diabetes mellitus (IDDM). However, IPITx has been difficult to implement clinically because islets frequently fail to function, have a high incidence of rejection, and are susceptible to autoimmune recurrence and damage by chronic immunosuppressive therapy. Tolerance induction may be a rational approach to resolve several of these limitations. Because anti-CD3 immunotoxin (IT) has been successful in promoting stable primate kidney transplant tolerance in our experience, we considered that tolerance induction with IT might be duplicated in IPITx. Materials and Methods. Three monkeys with spontaneous IDDM (two Macaca fascicularis and one Ceropithecus aethiops) were treated with xenogeneic pancreatic islets (Macaca mulatta). Intrahepatic islet transplantation was performed at a mean of 13136±3860 islet equivalents/kg. Islet xenograft acceptance was accomplished by tolerance induction with two injections of IT given on day 0 at 2 hr before transplantation and on day +1, respectively. IT treatment was supplemented with cyclosporine and steroids administered on days 0 through 4. No additional immunosuppression was given thereafter. Two additional control macaques with spontaneous IDDM received the immunosuppressive protocol without islet infusion. Results. All recipients were restored to stable euglycemia, off exogenous insulin, within 1-2 weeks after transplantation. Glucose tolerance, C-peptide, and glycosylated hemoglobin tests confirmed the restoration of normal glucose homeostasis after islet transplantation. All three islet recipients have remained euglycemic at 410, 255, and 100 days of follow-up despite recovery of peripheral T cells to normal levels. In contrast, none of the controls presented changes in the diabetic status 4 and 8 months after treatment. Conclusions. These results represent the first demonstration in nonhuman primates of stable, long-term acceptance of nonencapsulated xenogeneic islets off all immunosuppression, suggesting operational tolerance. The findings have potential implications for islet transplantation as well as improved and more cost-effective therapy for IDDM.

Original languageEnglish
Pages (from-to)846-854
Number of pages9
JournalTransplantation
Volume67
Issue number6
StatePublished - Mar 27 1999

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Immunotoxins
Islets of Langerhans Transplantation
Heterografts
Immunosuppression
Primates
Type 1 Diabetes Mellitus
Immunosuppressive Agents
Transplantation
Therapeutics
Glucose
Macaca fascicularis
C-Peptide
Glycosylated Hemoglobin A
Macaca
Macaca mulatta
Islets of Langerhans
Cyclosporine
Haplorhini
Homeostasis
Steroids

ASJC Scopus subject areas

  • Immunology
  • Transplantation

Cite this

Thomas, F. T., Ricordi, C., Contreras, J. L., Hubbard, W. J., Jiang, X. L., Eckhoff, D. E., ... Thomas, J. M. (1999). Reversal of naturally occurring diabetes in primates by unmodified islet xenografts without chronic immunosuppression. Transplantation, 67(6), 846-854.

Reversal of naturally occurring diabetes in primates by unmodified islet xenografts without chronic immunosuppression. / Thomas, Francis T.; Ricordi, Camillo; Contreras, Juan L.; Hubbard, William J.; Jiang, Xiao Ling; Eckhoff, Devin E.; Cartner, Samuel; Bilbao, Guadalupe; Neville, David M.; Thomas, Judith M.

In: Transplantation, Vol. 67, No. 6, 27.03.1999, p. 846-854.

Research output: Contribution to journalArticle

Thomas, FT, Ricordi, C, Contreras, JL, Hubbard, WJ, Jiang, XL, Eckhoff, DE, Cartner, S, Bilbao, G, Neville, DM & Thomas, JM 1999, 'Reversal of naturally occurring diabetes in primates by unmodified islet xenografts without chronic immunosuppression', Transplantation, vol. 67, no. 6, pp. 846-854.
Thomas, Francis T. ; Ricordi, Camillo ; Contreras, Juan L. ; Hubbard, William J. ; Jiang, Xiao Ling ; Eckhoff, Devin E. ; Cartner, Samuel ; Bilbao, Guadalupe ; Neville, David M. ; Thomas, Judith M. / Reversal of naturally occurring diabetes in primates by unmodified islet xenografts without chronic immunosuppression. In: Transplantation. 1999 ; Vol. 67, No. 6. pp. 846-854.
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abstract = "Background. Isolated pancreatic islet transplantation (IPITx) is an attractive alternative for treatment of insulin-dependent diabetes mellitus (IDDM). However, IPITx has been difficult to implement clinically because islets frequently fail to function, have a high incidence of rejection, and are susceptible to autoimmune recurrence and damage by chronic immunosuppressive therapy. Tolerance induction may be a rational approach to resolve several of these limitations. Because anti-CD3 immunotoxin (IT) has been successful in promoting stable primate kidney transplant tolerance in our experience, we considered that tolerance induction with IT might be duplicated in IPITx. Materials and Methods. Three monkeys with spontaneous IDDM (two Macaca fascicularis and one Ceropithecus aethiops) were treated with xenogeneic pancreatic islets (Macaca mulatta). Intrahepatic islet transplantation was performed at a mean of 13136±3860 islet equivalents/kg. Islet xenograft acceptance was accomplished by tolerance induction with two injections of IT given on day 0 at 2 hr before transplantation and on day +1, respectively. IT treatment was supplemented with cyclosporine and steroids administered on days 0 through 4. No additional immunosuppression was given thereafter. Two additional control macaques with spontaneous IDDM received the immunosuppressive protocol without islet infusion. Results. All recipients were restored to stable euglycemia, off exogenous insulin, within 1-2 weeks after transplantation. Glucose tolerance, C-peptide, and glycosylated hemoglobin tests confirmed the restoration of normal glucose homeostasis after islet transplantation. All three islet recipients have remained euglycemic at 410, 255, and 100 days of follow-up despite recovery of peripheral T cells to normal levels. In contrast, none of the controls presented changes in the diabetic status 4 and 8 months after treatment. Conclusions. These results represent the first demonstration in nonhuman primates of stable, long-term acceptance of nonencapsulated xenogeneic islets off all immunosuppression, suggesting operational tolerance. The findings have potential implications for islet transplantation as well as improved and more cost-effective therapy for IDDM.",
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T1 - Reversal of naturally occurring diabetes in primates by unmodified islet xenografts without chronic immunosuppression

AU - Thomas, Francis T.

AU - Ricordi, Camillo

AU - Contreras, Juan L.

AU - Hubbard, William J.

AU - Jiang, Xiao Ling

AU - Eckhoff, Devin E.

AU - Cartner, Samuel

AU - Bilbao, Guadalupe

AU - Neville, David M.

AU - Thomas, Judith M.

PY - 1999/3/27

Y1 - 1999/3/27

N2 - Background. Isolated pancreatic islet transplantation (IPITx) is an attractive alternative for treatment of insulin-dependent diabetes mellitus (IDDM). However, IPITx has been difficult to implement clinically because islets frequently fail to function, have a high incidence of rejection, and are susceptible to autoimmune recurrence and damage by chronic immunosuppressive therapy. Tolerance induction may be a rational approach to resolve several of these limitations. Because anti-CD3 immunotoxin (IT) has been successful in promoting stable primate kidney transplant tolerance in our experience, we considered that tolerance induction with IT might be duplicated in IPITx. Materials and Methods. Three monkeys with spontaneous IDDM (two Macaca fascicularis and one Ceropithecus aethiops) were treated with xenogeneic pancreatic islets (Macaca mulatta). Intrahepatic islet transplantation was performed at a mean of 13136±3860 islet equivalents/kg. Islet xenograft acceptance was accomplished by tolerance induction with two injections of IT given on day 0 at 2 hr before transplantation and on day +1, respectively. IT treatment was supplemented with cyclosporine and steroids administered on days 0 through 4. No additional immunosuppression was given thereafter. Two additional control macaques with spontaneous IDDM received the immunosuppressive protocol without islet infusion. Results. All recipients were restored to stable euglycemia, off exogenous insulin, within 1-2 weeks after transplantation. Glucose tolerance, C-peptide, and glycosylated hemoglobin tests confirmed the restoration of normal glucose homeostasis after islet transplantation. All three islet recipients have remained euglycemic at 410, 255, and 100 days of follow-up despite recovery of peripheral T cells to normal levels. In contrast, none of the controls presented changes in the diabetic status 4 and 8 months after treatment. Conclusions. These results represent the first demonstration in nonhuman primates of stable, long-term acceptance of nonencapsulated xenogeneic islets off all immunosuppression, suggesting operational tolerance. The findings have potential implications for islet transplantation as well as improved and more cost-effective therapy for IDDM.

AB - Background. Isolated pancreatic islet transplantation (IPITx) is an attractive alternative for treatment of insulin-dependent diabetes mellitus (IDDM). However, IPITx has been difficult to implement clinically because islets frequently fail to function, have a high incidence of rejection, and are susceptible to autoimmune recurrence and damage by chronic immunosuppressive therapy. Tolerance induction may be a rational approach to resolve several of these limitations. Because anti-CD3 immunotoxin (IT) has been successful in promoting stable primate kidney transplant tolerance in our experience, we considered that tolerance induction with IT might be duplicated in IPITx. Materials and Methods. Three monkeys with spontaneous IDDM (two Macaca fascicularis and one Ceropithecus aethiops) were treated with xenogeneic pancreatic islets (Macaca mulatta). Intrahepatic islet transplantation was performed at a mean of 13136±3860 islet equivalents/kg. Islet xenograft acceptance was accomplished by tolerance induction with two injections of IT given on day 0 at 2 hr before transplantation and on day +1, respectively. IT treatment was supplemented with cyclosporine and steroids administered on days 0 through 4. No additional immunosuppression was given thereafter. Two additional control macaques with spontaneous IDDM received the immunosuppressive protocol without islet infusion. Results. All recipients were restored to stable euglycemia, off exogenous insulin, within 1-2 weeks after transplantation. Glucose tolerance, C-peptide, and glycosylated hemoglobin tests confirmed the restoration of normal glucose homeostasis after islet transplantation. All three islet recipients have remained euglycemic at 410, 255, and 100 days of follow-up despite recovery of peripheral T cells to normal levels. In contrast, none of the controls presented changes in the diabetic status 4 and 8 months after treatment. Conclusions. These results represent the first demonstration in nonhuman primates of stable, long-term acceptance of nonencapsulated xenogeneic islets off all immunosuppression, suggesting operational tolerance. The findings have potential implications for islet transplantation as well as improved and more cost-effective therapy for IDDM.

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