Identification of Gene Markers for the Prediction of Allograft Rejection or Permanent Acceptance

• Published in: American journal of transplantation Vol. 7; no. 5; pp. 1091 - 1102
• Main Authors: Sawitzki, B., Bushell, A., Steger, U., Jones, N., Risch, K., Siepert, A., Lehmann, M., Schmitt‐Knosalla, I., Vogt, K., Gebuhr, I., Wood, K., Volk, H.‐D.
• Format: Journal Article
• Language: English
• Published: Oxford, UK Blackwell Publishing Ltd 01.05.2007; Blackwell
• Subjects: Animals; Biological and medical sciences; CD3 Complex - genetics; CD3 Complex - physiology; Gene expression; Gene Expression Regulation - physiology; Genetic Markers - genetics; Genetic Markers - physiology; Graft Rejection - genetics; Graft Rejection - immunology; Graft Rejection - physiopathology; Graft Survival - genetics; Graft Survival - immunology; Graft Survival - physiology; Heart Transplantation - physiology; Kidney Transplantation - physiology; Leukocytes - metabolism; Male; Mannosidases - genetics; Mannosidases - metabolism; Medical sciences; Membrane Glycoproteins - genetics; Membrane Glycoproteins - physiology; Mice; Mice, Inbred C57BL; Mice, Inbred CBA; Perforin; Pore Forming Cytotoxic Proteins - genetics; Pore Forming Cytotoxic Proteins - physiology; Predictive Value of Tests; Rats; Rats, Inbred Lew; Rats, Inbred Strains; rejection; RNA, Messenger - genetics; RNA, Messenger - metabolism; Surgery (general aspects). Transplantations, organ and tissue grafts. Graft diseases; T cell; tolerance; transplantation; Transplantation, Homologous; Graft(material); Genetic marker; T cell; Prediction; Identification; Transplantation; Gene expression; Homotransplantation; Rejection; toler ance; Treatment; Surgery; Immune tolerance; T-Lymphocyte; Graft; Predictive factor
• ISSN: 1600-6135; 1600-6143
• DOI: 10.1111/j.1600-6143.2007.01768.x

The clinical success of new treatment strategies aiming on inducing permanent graft acceptance will rely on the ability to determine whether specific unresponsiveness to donor alloantigens has developed and for how long it is maintained. To identify markers for such posttransplant monitoring, genes differentially expressed by graft infiltrating leukocytes during tolerance induction or rejection after kidney transplantation in rats were compared. A subsequently performed full kinetic analysis in two different transplant models, kidney and heart, in two species, rat and mouse identified two markers (TOAG‐1, α‐1,2‐mannosidase) with high specificity and reproducibility, which are highly expressed during induction and maintenance of acceptance, and downregulated during rejection. Expression level of these markers showed a strong positive correlation with graft function. In addition, expression of both genes was downregulated in the peripheral blood and the graft prior to rejection, suggesting that these markers may be useful for monitoring in clinical transplantation where peripheral blood is the most easily accessible patient sample. Interestingly, downregulation of TOAG‐1 and α‐1,2‐mannosidase expression occurred in graft infiltrating cells and expression of both genes was also downregulated after T‐cell activation in vitro. Gene expression profiling of intragraft and peripheral blood samples in experimental transplant and autoimmune models identified two genes whose expression is associated with tolerance.