title: Increased expression of cytotoxic effector molecules: different interpretations for steroid-based and steroid-free immunosuppression.
abstract: Cytotoxic T lymphocyte (CTL) effector molecules have been studied as markers of acute rejection in renal allograft recipients on steroid-based immunosuppression. We hypothesized that basal CTL gene expression may vary with time post-transplantation as well as with different immunosuppression protocols (steroid-based or steroid-free). Variations in CTL gene expression may thus impact on the ability to predict acute allograft rejection. We used the non-invasive method of quantitative competitive-reverse transcription-polymerase chain reaction (QC-RT-PCR) to quantify the amounts of CTL effector molecules (granulysin, GL; perforin, P; granzyme B, GB) in serial peripheral blood lymphocyte (PBL) samples from steroid-free and steroid-based adult and pediatric renal allograft recipients. Patients on both protocols were clinically monitored by protocol biopsies at 1, 3, 6, and 12 months post-transplantation and for graft function at 1 yr post-transplantation in a separate clinical study. Steroid-free patients with stable graft function showed an increase in GL, P, and GB gene expression over time post-transplantation with the increase being seen largely by the first post-transplant month. A further increase in GL expression was noted at the end of the first post-transplant year in the absence of acute rejection, whereas GB and P levels were unchanged. At comparative time-points post-transplantation, CTL genes were found to be higher in steroid-free patients with stable graft function, compared to steroid-based recipients with either clinically stable graft function or acute rejection. This study suggests that levels of CTL gene expression, although important in a steroid-based regimen to monitor the risk of acute rejection, may not be similarly applied in patients on steroid-free immunosuppression. The early increase in levels seen in steroid-free patients appears to correlate with the total absence of steroids. As steroid-free patients seem to have a lower incidence of acute rejection and better long-term graft function at 1 yr, the early increase in CTL genes in the absence of acute rejection may suggest an early adaptive immune activation response, promoting early graft acceptance in this protocol.
authors.affiliation: Department of Pediatrics, Stanford University School of Medicine, 269 Campus Drive, CCSR, Stanford, California 94305, USA.
authors.forename: Thomas
authors.initials: T
authors.lastname: Satterwhite
authors.forename: Mei-Sze
authors.initials: MS
authors.lastname: Chua
authors.forename: Szu-Chuan
authors.initials: SC
authors.lastname: Hsieh
authors.forename: Stella
authors.initials: S
authors.lastname: Chang
authors.forename: John
authors.initials: J
authors.lastname: Scandling
authors.forename: Oscar
authors.initials: O
authors.lastname: Salvatierra
authors.forename: Minnie M
authors.initials: MM
authors.lastname: Sarwal
mesh_terms: D000328:Adult; D000911:Antibodies, Monoclonal / Q000494:pharmacology; D061067:Antibodies, Monoclonal, Humanized; D000945:Antigens, Differentiation, T-Lymphocyte / Q000235:genetics / Q000378:metabolism; D002648:Child; D003602:Cytotoxicity, Immunologic; D000077561:Daclizumab; D015870:Gene Expression / Q000187:drug effects; D006084:Graft Rejection / Q000378:metabolism; D053804:Granzymes; D006801:Humans; D007074:Immunoglobulin G / Q000494:pharmacology; D007166:Immunosuppressive Agents / Q000494:pharmacology*; D016030:Kidney Transplantation; D008562:Membrane Glycoproteins / Q000235:genetics / Q000378:metabolism; D009173:Mycophenolic Acid / Q000031:analogs & derivatives / Q000494:pharmacology; D054353:Perforin; D052899:Pore Forming Cytotoxic Proteins; D020133:Reverse Transcriptase Polymerase Chain Reaction; D012697:Serine Endopeptidases / Q000235:genetics / Q000378:metabolism*; D013602:T-Lymphocytes, Cytotoxic / Q000187:drug effects / Q000276:immunology* / Q000378:metabolism; D016559:Tacrolimus / Q000494:pharmacology
chemical_list: D000911:Antibodies, Monoclonal; D061067:Antibodies, Monoclonal, Humanized; D000945:Antigens, Differentiation, T-Lymphocyte; C075005:GNLY protein, human; D007074:Immunoglobulin G; D007166:Immunosuppressive Agents; D008562:Membrane Glycoproteins; D052899:Pore Forming Cytotoxic Proteins; D054353:Perforin; D000077561:Daclizumab; C509213:GZMB protein, human; D053804:Granzymes; D012697:Serine Endopeptidases; D009173:Mycophenolic Acid; D016559:Tacrolimus