Assessment of cytotoxic lymphocyte gene expression in the peripheral blood of human islet allograft recipients: elevation precedes clinical evidence of rejection.
Studies in nonhuman 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.
Diabetes Research Institute, University of Miami School of Medicine, 1450 NW 10th Avenue (R-134), Miami, FL 33136, USA. dhan@med.miami.edu
Dongmei
D
Han
Xiumin
X
Xu
David
D
Baidal
Jenifer
J
Leith
Camillo
C
Ricordi
Rodolfo
R
Alejandro
Norma S
NS
Kenyon
D015415:Biomarkers; D053222:Fas Ligand Protein; D015870:Gene Expression; D006084:Graft Rejection / Q000175:diagnosis* / Q000276:immunology / Q000503:physiopathology; D006085:Graft Survival / Q000502:physiology; D053804:Granzymes; D006801:Humans; D007165:Immunosuppression Therapy; D007239:Infections / Q000276:immunology / Q000503:physiopathology; D016381:Islets of Langerhans Transplantation; D007959:Lymphocyte Culture Test, Mixed; D008562:Membrane Glycoproteins / Q000235:genetics*; D054353:Perforin; D052899:Pore Forming Cytotoxic Proteins; D011237:Predictive Value of Tests; D012697:Serine Endopeptidases / Q000235:genetics*; D013602:T-Lymphocytes, Cytotoxic / Q000502:physiology*; D014184:Transplantation, Homologous
D015415:Biomarkers; C505661:FASLG protein, human; D053222:Fas Ligand Protein; D008562:Membrane Glycoproteins; D052899:Pore Forming Cytotoxic Proteins; D054353:Perforin; C509213:GZMB protein, human; D053804:Granzymes; D012697:Serine Endopeptidases