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

https://doi.org/10.1046/j.1600-6143.2003.00351.xGet rights and content
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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 hOKT3γ1 (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.

Key words:

Autoimmunity
CD4+CD25+ T cells
diabetes mellitus
hOKT3γ1 (Ala-Ala)
humanized OKT3
hypoglycemia
immunosuppression
insulin independence
islet culture
islet transplants
perfluorocarbon
perfluorodecalin
rapamycin
single-donor
sirolimus
tacrolimus
two-layer
type 1 diabetes

Abbreviations:

MeSH headings
Islets of Langerhans, islets of Langerhans transplantation, sirolimus, tacrolimus, tissue culture, organ preservation, CD4 lymphocyte count, autoimmunity, fluorocarbons, immunosuppression, hypoglycemia, diabetes mellitus.
ACpR-Arg
acute C-peptide response to arginine
ANC
absolute neutrophil count
AST
aspartate aminotransferase
CFSE
carboxyfluorescein diacetate succinimidyl ester
CMRL
Connaught Medical Research Laboratories
FcR
Fc receptor
HbA1c
hemoglobin A1c
HEPES
N-[2-hydroxy-ethyl]piperzine-N-[2-ethanesulfonic acid
IRI
immunoreactive insulin
LDH
lactate dehydrogenase
PBL
peripheral blood leukocytes.

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