Assessment of cytotoxic lymphocyte gene expression in the peripheral blood of human islet allograft recipients: Elevation precedes clinical evidence of rejection

Dongmei Han, Xiumin Xu, David Baidal, Jenifer Leith, Camillo Ricordi, Rodolfo Alejandro, Norma S Kenyon

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Abstract

Studies in nonliuman primates have demonstrated that elevation of the cytotoxic lymphocyte (CL) genes granzyme B, perforin, and Fas ligand in peripheral blood precedes islet allograft rejection. The purpose of this study was to determine whether this approach has utility for prediction of human islet allograft loss. We studied 13 patients who had long-term type 1 diabetes and were treated with steroid-free immunosuppression and given sequential islet cell infusions. All recipients became insulin independent, and eight of them experienced deterioration in glycemic control, followed by reinitiation of insulin therapy. Frequent peripheral blood samples were collected to monitor CL gene mRNA levels with real-time PCR. For the eight back-to-insulin patients, there was a clear elevation of CL gene mRNA levels 25-203 days before the onset of frequent hyperglycemia. Granzyme B was the most reliable indicator of ongoing graft loss. Additional correlations with infection were noted; however, evidence of sensitization in antidonor mixed lymphocyte reaction was observed in seven of eight patients who experienced partial graft loss, whereas this was not seen when upregulated CL gene expression was associated with infection. The results suggest that, when taken into consideration with other clinical parameters, elevated CL gene levels may enable prediction of islet allograft loss.

Original languageEnglish
Pages (from-to)2281-2290
Number of pages10
JournalDiabetes
Volume53
Issue number9
DOIs
StatePublished - Sep 1 2004

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Allografts
Lymphocytes
Gene Expression
Insulin
Genes
Transplants
Granzymes
Messenger RNA
Mixed Lymphocyte Culture Test
Fas Ligand Protein
Infection
Type 1 Diabetes Mellitus
Islets of Langerhans
Hyperglycemia
Immunosuppression
Primates
Real-Time Polymerase Chain Reaction
Steroids
Therapeutics

ASJC Scopus subject areas

  • Internal Medicine
  • Endocrinology, Diabetes and Metabolism

Cite this

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abstract = "Studies in nonliuman primates have demonstrated that elevation of the cytotoxic lymphocyte (CL) genes granzyme B, perforin, and Fas ligand in peripheral blood precedes islet allograft rejection. The purpose of this study was to determine whether this approach has utility for prediction of human islet allograft loss. We studied 13 patients who had long-term type 1 diabetes and were treated with steroid-free immunosuppression and given sequential islet cell infusions. All recipients became insulin independent, and eight of them experienced deterioration in glycemic control, followed by reinitiation of insulin therapy. Frequent peripheral blood samples were collected to monitor CL gene mRNA levels with real-time PCR. For the eight back-to-insulin patients, there was a clear elevation of CL gene mRNA levels 25-203 days before the onset of frequent hyperglycemia. Granzyme B was the most reliable indicator of ongoing graft loss. Additional correlations with infection were noted; however, evidence of sensitization in antidonor mixed lymphocyte reaction was observed in seven of eight patients who experienced partial graft loss, whereas this was not seen when upregulated CL gene expression was associated with infection. The results suggest that, when taken into consideration with other clinical parameters, elevated CL gene levels may enable prediction of islet allograft loss.",
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AU - Xu, Xiumin

AU - Baidal, David

AU - Leith, Jenifer

AU - Ricordi, Camillo

AU - Alejandro, Rodolfo

AU - Kenyon, Norma S

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