Transplantation of Cultured Islets from Two-Layer Preserved Pancreases in Type 1 Diabetes with Anti-CD3 Antibody

Bernhard J. Hering, Raja Kandaswamy, James V. Harmon, Jeffrey D. Ansite, Sue M. Clemmings, Tetsuya Sakai, Stephen Paraskevas, Peter M. Eckman, Junichiro Sageshima, Masahiko Nakanoa, Toshiya Sawada, Ippei Matsumotoa, Hui J. Zhang, David E.R. Sutherland, Jeffrey A. Bluestone

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Abstract

We sought to determine whether or not optimizing pancreas preservation, islet processing, and induction immunosuppression would facilitate sustained diabetes reversal after single-donor islet transplants. Islets were isolated from two-layer preserved pancreata, purified, cultured for 2 days; and transplanted into six C-peptide-negative, nonuremic, type 1 diabetic patients with hypoglycemia unawareness. Induction immunosuppression, which began 2 days pretransplant, included the Fc receptor nonbinding humanized anti-CD3 monoclonal antibody hOKT3γ 1 (Ala-Ala) and sirolimus. Immunosuppression was maintained with sirolimus and reduced-dose tacrolimus. Of our six recipients, four achieved and maintained insulin independence with normal HbA1c levels and freedom from hypoglycemia; one had partial islet graft function; and one lost islet graft function 2 weeks post-transplant. The four insulin-independent patients showed prolonged CD4+ T-cell lymphocytopenia; inverted CD4:CD8 ratios; and increases in the percentage of CD4+CD25+ T cells. These cells suppressed the in-vitro proliferative response to donor cells and, to a lesser extent, to third-party cells. Severe adverse events were limited to a transient rash in one recipient and to temporary neutropenia in three. Our preliminary results thus suggest that a combination of maximized viable islet yield, pretransplant islet culture, and preemptive immunosuppression can result in successful single-donor islet transplants.

Original languageEnglish (US)
Pages (from-to)390-401
Number of pages12
JournalAmerican Journal of Transplantation
Volume4
Issue number3
DOIs
StatePublished - Mar 1 2004

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Keywords

  • Autoimmunity
  • CD4CD25 T cells
  • Diabetes mellitus
  • HOKT3γ 1 (Ala-Ala)
  • Humanized OKT3
  • Hypoglycemia
  • Immunosuppression
  • Insulin independence
  • Islet culture
  • Islet transplants
  • Perfluorocarbon
  • Perfluorodecalin
  • Rapamycin
  • Single-donor

Cite this

Hering, B. J., Kandaswamy, R., Harmon, J. V., Ansite, J. D., Clemmings, S. M., Sakai, T., Paraskevas, S., Eckman, P. M., Sageshima, J., Nakanoa, M., Sawada, T., Matsumotoa, I., Zhang, H. J., Sutherland, D. E. R., & Bluestone, J. A. (2004). Transplantation of Cultured Islets from Two-Layer Preserved Pancreases in Type 1 Diabetes with Anti-CD3 Antibody. American Journal of Transplantation, 4(3), 390-401. https://doi.org/10.1046/j.1600-6143.2003.00351.x