Tribbles-1 as a novel biomarker of chronic antibody-mediated rejection.

Diagnosis of the specific cause of late allograft injury is necessary if more personalized and efficient immunosuppressive regimens are to be introduced. This study sought previously unrecognized biomarkers for specific histologic diagnoses of late graft scarring by comparison of gene sets from published microarray studies. Tribbles-1 (TRIB1), a human homolog of Drosophila tribbles, was identified to be a potentially informative biomarker. For testing this, mRNA expression in 76 graft biopsies, 71 blood samples, and 11 urine samples were profiled from independent cohorts of renal transplant patients with different histologic diagnoses recruited at two European centers. TRIB1 but not TRIB2 or TRIB3 was found to be a potential blood and tissue biomarker of chronic antibody-mediated rejection, an active immune-mediated form of chronic allograft failure associated with a poor prognosis. TRIB1 mRNA levels in peripheral blood mononuclear cells discriminated patients with chronic antibody-mediated rejection from those with other types of late allograft injury with high sensitivity and specificity. TRIB1 was also upregulated in a rodent model of chronic cardiac vasculopathy, suggesting that this biomarker may be useful in other solid-organ transplants and across species. It was determined that TRIB1 is expressed primarily by antigen-presenting cells and activated endothelial cells. Overall, these data support the potential use of TRIB1 as a biomarker of chronic antibody-mediated allograft failure.

[1]  A. Scherer,et al.  Early prognosis of the development of renal chronic allograft rejection by gene expression profiling of human protocol biopsies , 2003, Transplantation.

[2]  R. Colvin.  Antibody-mediated renal allograft rejection: diagnosis and pathogenesis. , 2007, Journal of the American Society of Nephrology : JASN.

[3]  Anke Schwarz,et al.  Safety and Adequacy of Renal Transplant Protocol Biopsies , 2005, American journal of transplantation : official journal of the American Society of Transplantation and the American Society of Transplant Surgeons.

[4]  J. Stockman.  Messenger RNA for FOXP3 in the Urine of Renal-Allograft Recipients , 2007 .

[5]  E. Wieschaus,et al.  A Genetic Link between Morphogenesis and Cell Division during Formation of the Ventral Furrow in Drosophila , 2000, Cell.

[6]  S. Brouard,et al.  Functional Compartmentalization Following Induction of Long‐Term Graft Survival with Pregraft Donor‐Specific Transfusion , 2007, American journal of transplantation : official journal of the American Society of Transplantation and the American Society of Transplant Surgeons.

[7]  M. Kretzler,et al.  Differential Expression of Profibrotic and Growth Factors in Chronic Allograft Nephropathy , 2006, Transplantation.

[8]  Fadi G Lakkis,et al.  Lymphoid Neogenesis in Murine Cardiac Allografts Undergoing Chronic Rejection , 2005, American journal of transplantation : official journal of the American Society of Transplantation and the American Society of Transplant Surgeons.

[9]  M. Suthanthiran,et al.  Noninvasive diagnosis of renal-allograft rejection by measurement of messenger RNA for perforin and granzyme B in urine. , 2001, The New England journal of medicine.

[10]  T. Klingler,et al.  Noninvasive Discrimination of Rejection in Cardiac Allograft Recipients Using Gene Expression Profiling , 2006, American journal of transplantation : official journal of the American Society of Transplantation and the American Society of Transplant Surgeons.

[11]  S. Brouard,et al.  Contrasting CD25hiCD4+T Cells/FOXP3 Patterns in Chronic Rejection and Operational Drug-Free Tolerance , 2006, Transplantation.

[12]  M. Haubitz,et al.  ELEVATED NUMBERS OF CIRCULATING ENDOTHELIAL CELLS IN RENAL TRANSPLANT RECIPIENTS , 2003, Transplantation.

[13]  D. Wishart,et al.  Transplant Glomerulopathy, Late Antibody‐Mediated Rejection and the ABCD Tetrad in Kidney Allograft Biopsies for Cause , 2006, American journal of transplantation : official journal of the American Society of Transplantation and the American Society of Transplant Surgeons.

[14]  M. Leptin,et al.  Tribbles, a cell-cycle brake that coordinates proliferation and morphogenesis during Drosophila gastrulation , 2000, Current Biology.

[15]  S. Dower,et al.  Human Tribbles, a Protein Family Controlling Mitogen-activated Protein Kinase Cascades* , 2004, Journal of Biological Chemistry.

[16]  T. Theruvath,et al.  Strategies to improve long-term outcomes after renal transplantation. , 2002, The New England journal of medicine.

[17]  E. Kiss-Toth,et al.  Tribbles: a family of kinase-like proteins with potent signalling regulatory function. , 2007, Cellular signalling.

[18]  J. Ashton-Chess,et al.  An in vitro evaluation of the potential suitability of peripheral blood CD14(+) and bone marrow CD34(+)-derived dendritic cells for a tolerance inducing regimen in the primate. , 2005, Journal of immunological methods.

[19]  S. Head,et al.  De Novo Kidney Transplantation Without Use of Calcineurin Inhibitors Preserves Renal Structure and Function at Two Years , 2004, American journal of transplantation : official journal of the American Society of Transplantation and the American Society of Transplant Surgeons.

[20]  D. Gjertson,et al.  Noninvasive diagnosis of cellular and antibody-mediated rejection by perforin and granzyme B in renal allografts. , 2006, Human immunology.

[21]  B. Charreau,et al.  The Adaptor Molecule Lnk Negatively Regulates Tumor Necrosis Factor-α-dependent VCAM-1 Expression in Endothelial Cells through Inhibition of the ERK1 and -2 Pathways* , 2006, Journal of Biological Chemistry.

[22]  Osamu Takeuchi,et al.  Enhanced TLR-mediated NF-IL6–dependent gene expression by Trib1 deficiency , 2007, The Journal of experimental medicine.

[23]  H. Volk,et al.  Heightened Expression of the Cytotoxicity Receptor NKG2D Correlates with Acute and Chronic Nephropathy After Kidney Transplantation , 2007, American journal of transplantation : official journal of the American Society of Transplantation and the American Society of Transplant Surgeons.

[24]  R. Colvin,et al.  Banff '05 Meeting Report: Differential Diagnosis of Chronic Allograft Injury and Elimination of Chronic Allograft Nephropathy (‘CAN’) , 2007, American journal of transplantation : official journal of the American Society of Transplantation and the American Society of Transplant Surgeons.

[25]  Juan Mata,et al.  Tribbles Coordinates Mitosis and Morphogenesis in Drosophila by Regulating String/CDC25 Proteolysis , 2000, Cell.

[26]  F. Delmonico,et al.  Prevalence and significance of anti‐HLA and donor‐specific antibodies long‐term after renal transplantation , 2005, Transplant international : official journal of the European Society for Organ Transplantation.

[27]  E. Chiffoleau,et al.  New Evidence for a Role of Allograft Accommodation in Long-Term Tolerance , 2006, Transplantation.

[28]  J. Chapman,et al.  Calcineurin Inhibitor Nephrotoxicity: Longitudinal Assessment by Protocol Histology , 2004, Transplantation.

[29]  E. Kiss-Toth,et al.  Tribbles: novel regulators of cell function; evolutionary aspects , 2006, Cellular and Molecular Life Sciences CMLS.

[30]  R. Fisher,et al.  Establishing the Molecular Pathways Involved in Chronic Allograft Nephropathy for Testing New Noninvasive Diagnostic Markers , 2007, Transplantation.

[31]  D. Crossman,et al.  Human Tribbles-1 Controls Proliferation and Chemotaxis of Smooth Muscle Cells via MAPK Signaling Pathways* , 2007, Journal of Biological Chemistry.

[32]  A. Schwarz,et al.  Risk factors for chronic allograft nephropathy after renal transplantation: a protocol biopsy study. , 2005, Kidney international.

[33]  J. Chapman,et al.  The natural history of chronic allograft nephropathy. , 2003, The New England journal of medicine.

[34]  J. Timmer,et al.  Expression profiling on chronically rejected transplant kidneys. , 2003, Transplantation.

[35]  D. Kerjaschki,et al.  The Cellular Lesion of Humoral Rejection: Predominant Recruitment of Monocytes to Peritubular and Glomerular Capillaries , 2007, American journal of transplantation : official journal of the American Society of Transplantation and the American Society of Transplant Surgeons.

[36]  T. Larson,et al.  Transplant Glomerulopathy: Subclinical Incidence and Association with Alloantibody , 2007, American journal of transplantation : official journal of the American Society of Transplantation and the American Society of Transplant Surgeons.

[37]  Thomas D. Schmittgen,et al.  Analysis of relative gene expression data using real-time quantitative PCR and the 2(-Delta Delta C(T)) Method. , 2001, Methods.

[38]  M. Giral,et al.  Impact of graft mass on the clinical outcome of kidney transplants. , 2004, Journal of the American Society of Nephrology : JASN.

[39]  C. Usal,et al.  Induction of Donor‐Specific Allograft Tolerance by Short‐Term Treatment with LF15‐0195 After Transplantation. Evidence for a Direct Effect on T‐Cell Differentiation , 2002, American journal of transplantation : official journal of the American Society of Transplantation and the American Society of Transplant Surgeons.

[40]  Markus Exner,et al.  Capillary deposition of complement split product C4d in renal allografts is associated with basement membrane injury in peritubular and glomerular capillaries: a contribution of humoral immunity to chronic allograft rejection. , 2002, Journal of the American Society of Nephrology : JASN.

[41]  J. Soulillou,et al.  Genetics of the blood transfusion effect on heart allografts in rats. , 1984, Transplantation.

[42]  A. Magil,et al.  Monocytes and peritubular capillary C4d deposition in acute renal allograft rejection. , 2003, Kidney international.

[43]  R. Colvin,et al.  Chronic humoral rejection: identification of antibody-mediated chronic renal allograft rejection by C4d deposits in peritubular capillaries. , 2001, Journal of the American Society of Nephrology : JASN.

[44]  M. Fishbein,et al.  Antibody‐Mediated Rejection Criteria – an Addition to the Banff ′97 Classification of Renal Allograft Rejection , 2003, American journal of transplantation : official journal of the American Society of Transplantation and the American Society of Transplant Surgeons.