Long-term functional islet mass and metabolic function after xenoislet transplantation in primates

Juan L. Contreras, Devin E. Eckhoff, Samuel Cartner, Guadalupe Bilbao, Camillo Ricordi, David M. Neville, Francis T. Thomas, Judith M. Thomas

Research output: Contribution to journalArticle

34 Citations (Scopus)

Abstract

Background. Pancreatic islet transplantation (PIT) is an attractive alternative for patients with type I diabetes mellitus. PIT is not yet an effective clinical reality due in part to the high incidence of rejection and early loss of functional islet mass. In addition, current immunosuppressive drugs have toxic effects on islets and increase the risk of morbidity and mortality. In the present study, the effects of PIT on glycemic parameters were assessed in spontaneously diabetic primates. Methods. Five insulinopenic nonhuman primates (three Macacca fascicularis, one Ceropithecus aethiops, and one Macacca mulatta) were studied. All required twice-daily treatment with 4- 10 U of insulin. For immunosuppression, the animals received anti-CD3- immunotoxin (100 μg/kg/initially infused 2 hr before transplantation and again on day +1), cyclosporine (CsA) (20 mg/kg/i.v./2 hr before transplantation), cyclosporine microemulsion (Neoral) 50 mg/kg/b.i.d. on days +1 to +3 with dose adjusted by blood levels, and methylprednisolone (15 mg/kg day 0 to +3). Three recipients were given islets from a single donor (M mulatta). The islets were prepared by a semiautomated technique using Liberase. A mean of 13,136 islet equivalents/kg was infused into the portal vein. Two animals (M fascicularis and M mulatta) were used as a diabetic, nontransplanted control. Several metabolic parameters were evaluated. Results. All monkeys that underwent transplantation experienced reversal of diabetes mellitus with normalization of all diabetic glycemic parameters. In the nontransplanted primates given the same immunosuppression but no PIT, diabetic metabolic parameters were unchanged after 9 months of follow-up. In contrast, all three PIT recipients established fasting and nonfasting euglycemia within 1-2 weeks, and none required exogenous insulin after day 10. Normal intravenous glucose tolerance tests were observed at day 15, and no significant differences in the glucose disappearance rate (Kg) were observed at days 15, 45, 190, and 365 days after transplantation. The acute insulin response to glucose indicated no significant reduction of functional islet mass. Conclusions. PIT in severely insulinopenic type I diabetes mellitus primates resulted in restoration of normal glycemic parameters and durable islet mass. Operational tolerance was achieved with only 4 days of drug administration, sparing the animals from chronic exposure to potentially diabetogenic immunosuppressive drugs. These results offer an exciting new potential for type I diabetes mellitus treatment.

Original languageEnglish
Pages (from-to)195-201
Number of pages7
JournalTransplantation
Volume69
Issue number2
StatePublished - Jan 27 2000

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Islets of Langerhans Transplantation
Primates
Transplantation
Type 1 Diabetes Mellitus
Cyclosporine
Insulin
Immunosuppressive Agents
Immunosuppression
Pharmaceutical Preparations
Immunotoxins
Glucose
Poisons
Methylprednisolone
Glucose Tolerance Test
Portal Vein
Haplorhini
Fasting
Diabetes Mellitus
Tissue Donors
Morbidity

ASJC Scopus subject areas

  • Transplantation
  • Immunology

Cite this

Contreras, J. L., Eckhoff, D. E., Cartner, S., Bilbao, G., Ricordi, C., Neville, D. M., ... Thomas, J. M. (2000). Long-term functional islet mass and metabolic function after xenoislet transplantation in primates. Transplantation, 69(2), 195-201.

Long-term functional islet mass and metabolic function after xenoislet transplantation in primates. / Contreras, Juan L.; Eckhoff, Devin E.; Cartner, Samuel; Bilbao, Guadalupe; Ricordi, Camillo; Neville, David M.; Thomas, Francis T.; Thomas, Judith M.

In: Transplantation, Vol. 69, No. 2, 27.01.2000, p. 195-201.

Research output: Contribution to journalArticle

Contreras, JL, Eckhoff, DE, Cartner, S, Bilbao, G, Ricordi, C, Neville, DM, Thomas, FT & Thomas, JM 2000, 'Long-term functional islet mass and metabolic function after xenoislet transplantation in primates', Transplantation, vol. 69, no. 2, pp. 195-201.
Contreras JL, Eckhoff DE, Cartner S, Bilbao G, Ricordi C, Neville DM et al. Long-term functional islet mass and metabolic function after xenoislet transplantation in primates. Transplantation. 2000 Jan 27;69(2):195-201.
Contreras, Juan L. ; Eckhoff, Devin E. ; Cartner, Samuel ; Bilbao, Guadalupe ; Ricordi, Camillo ; Neville, David M. ; Thomas, Francis T. ; Thomas, Judith M. / Long-term functional islet mass and metabolic function after xenoislet transplantation in primates. In: Transplantation. 2000 ; Vol. 69, No. 2. pp. 195-201.
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