Sunil M SM. Kurian, Raymond R. Heilman, Tony S TS. Mondala, Aleksey A. Nakorchevsky, Johannes A JA. Hewel, Daniel D. Campbell, Elizabeth H EH. Robison, Lin L. Wang, Wen W. Lin, Lillian L. Gaber, Kim K. Solez, Hamid H. Shidban, Robert R. Mendez, Randolph L RL. Schaffer, Jonathan S JS. Fisher, Stuart M SM. Flechner, Steve R SR. Head, Steve S. Horvath, John R JR. Yates, Christopher L CL. Marsh, Daniel R DR. Salomon.
2009 Jul; (4):e6212 7
Despite significant improvements in life expectancy of kidney transplant patients due to advances in surgery and immunosuppression, Chronic Allograft Nephropathy (CAN) remains a daunting problem. A complex network of cellular mechanisms in both graft and peripheral immune compartments complicates the non-invasive diagnosis of CAN, which still requires biopsy histology. This is compounded by non-immunological factors contributing to graft injury. There is a pressing need to identify and validate minimally invasive biomarkers for CAN to serve as early predictors of graft loss and as metrics for managing long-term immunosuppression.
Sophie S. Brouard, Elaine E. Mansfield, Christophe C. Braud, Li L. Li, Magali M. Giral, Szu-chuan SC. Hsieh, Dominique D. Baeten, Meixia M. Zhang, Joanna J. Ashton-Chess, Cécile C. Braudeau, Frank F. Hsieh, Alexandre A. Dupont, Annaik A. Pallier, Anne A. Moreau, Stéphanie S. Louis, Catherine C. Ruiz, Oscar O. Salvatierra, Jean-Paul JP. Soulillou, Minnie M. Sarwal.
Proceedings of the National Academy of Sciences of the United States of America
2007 Sep; (104):15448-53 39
Long-term allograft survival generally requires lifelong immunosuppression (IS). Rarely, recipients display spontaneous "operational tolerance" with stable graft function in the absence of IS. The lack of biological markers of this phenomenon precludes identification of potentially tolerant patients in which IS could be tapered and hinders the development of new tolerance-inducing strategies. The objective of this study was to identify minimally invasive blood biomarkers for operational tolerance and use these biomarkers to determine the frequency of this state in immunosuppressed patients with stable graft function. Blood gene expression profiles from 75 renal-transplant patient cohorts (operational tolerance/acute and chronic rejection/stable graft function on IS) and 16 healthy individuals were analyzed. A subset of samples was used for microarray analysis where three-class comparison of the different groups of patients identified a "tolerant footprint" of 49 genes. These biomarkers were applied for prediction of operational tolerance by microarray and real-time PCR in independent test groups. Thirty-three of 49 genes correctly segregated tolerance and chronic rejection phenotypes with 99% and 86% specificity. The signature is shared with 1 of 12 and 5 of 10 stable patients on triple IS and low-dose steroid monotherapy, respectively. The gene signature suggests a pattern of reduced costimulatory signaling, immune quiescence, apoptosis, and memory T cell responses. This study identifies in the blood of kidney recipients a set of genes associated with operational tolerance that may have utility as a minimally invasive monitoring tool for guiding IS titration. Further validation of this tool for safe IS minimization in prospective clinical trials is warranted.
F F. Veronese, S S. Rotman, R N RN. Smith, T D TD. Pelle, M L ML. Farrell, T T. Kawai, A A. Benedict Cosimi, R B RB. Colvin.
American journal of transplantation : official journal of the American Society of Transplantation and the American Society of Transplant Surgeons
2007 Apr; (7):914-22 4
The localization and significance of regulatory T cells (Treg) in allograft rejection is of considerable clinical and immunological interest. We analyzed 80 human renal transplant biopsies (including seven donor biopsies) with a double immunohistochemical marker for the Treg transcription factor FOXP3, combined with a second marker for CD4 or CD8. Quantitative FOXP3 cell counts were performed and analyzed for clinical and pathologic correlates. FOXP3(+) cells were present in the interstitium in acute cellular rejection (ACR) type I and II, at a greater density than in acute humoral rejection or CNI toxicity (p < 0.01). Most FOXP3(+) cells were CD4(+) (96%); a minority expressed CD8. FOXP3(+)CD4(+) cells were concentrated in the tubules (p < 0.001), suggesting a selective attraction or generation at that site. Considering only patients with ACR, a higher density of FOXP3(+) correlated with HLA class II match (p = 0.03), but paradoxically with worse graft survival. We conclude that infiltration of FOXP3(+) cells occurs in ACR to a greater degree than in humoral rejection, however, within the ACR group, no beneficial effect on outcome was evident. Tregs concentrate in tubules, probably contributing to FOXP3 mRNA in urine; the significance and pathogenesis of 'Treg tubulitis' remains to be determined.
Thangamani T. Muthukumar, Darshana D. Dadhania, Ruchuang R. Ding, Catherine C. Snopkowski, Rubina R. Naqvi, Jun B JB. Lee, Choli C. Hartono, Baogui B. Li, Vijay K VK. Sharma, Surya V SV. Seshan, Sandip S. Kapur, Wayne W WW. Hancock, Joseph E JE. Schwartz, Manikkam M. Suthanthiran.
The New England journal of medicine
2005 Dec; (353):2342-51 22
The outcome of renal transplantation after an episode of acute rejection is difficult to predict, even with an allograft biopsy.
Valeria R VR. Mas, Luciana A LA. Mas, Kellie J KJ. Archer, Kenneth K. Yanek, Anne L AL. King, Eric M EM. Gibney, Adrian A. Cotterell, Robert A RA. Fisher, Marc M. Posner, Daniel G DG. Maluf.
Molecular medicine (Cambridge, Mass.)
; (13):315-24 5-6
Non-invasive monitoring may be useful after kidney transplantation (KT), particularly for predicting acute rejection (AR). It is less clear whether chronic allograft nephropathy (CAN) is also associated with changes in urine cells. To identify non-invasive markers of allograft function in kidney transplant patients (KTP), mRNA levels of AGT, TGF-beta1, EGFR, IFN-gamma, TSP-1, and IL-10 in urine (Ur) samples were studied using QRT-PCR. Ninety-five KTP and 111 Ur samples were evaluated. Patients (Pts) were divided as, within six months (N = 31), and with more than six months post-KT (N = 64). KTP with more than six months post-KT were classified as KTP with stable kidney function (SKF) (N = 32), KTP with SKF (creatinine < 2 mg/dL) and proteinuria > 500 mg/24 h (N = 18), and KTP with biopsy proven CAN (N = 14). F-test was used to test for equality of variances between groups. IL-10 mRNA was decreased in Ur samples from KTP with less than six months post-KT (P = 0.005). For KTR groups with more than six months post-KT, AGT and EGFR mRNA were statistically different among KTP with SKF, KTP with SKF and proteinuria, and CAN Pts (P = 0.003, and P = 0.01), with KTP with SKF having higher mean expression. TSP-1 mRNA levels also were significantly different among these three groups (P = 0.04), with higher expression observed in CAN Pts. Using the random forest algorithm, AGT, EGFR, and TGF-beta1 were identified as predictors of CAN, SKF, SKF with proteinuria. A characteristic pattern of mRNA levels in the different KTP groups was observed indicating that the mRNA levels in Ur cells might reflect allograft function.