title: Identification of a novel biomarker gene set with sensitivity and specificity for distinguishing between allograft rejection and tolerance.
abstract: Here we examined whether the expression of a novel immunoregulatory gene set could be used to predict outcomes in murine models of rapamycin-induced cardiac tolerance, spontaneous hepatic tolerance, and cardiac rejection. The expression of the immunoregulatory gene set was assessed with the GeXP multiplex reverse-transcription polymerase chain reaction (RT-PCR) analysis system, and it was correlated to the pathological and biochemical parameters of the allografts. In rejecting cardiac grafts, the increased expression of an inflammatory set of genes, which included CD45, CD4, CD25, suppressor of cytokine signaling 2, cytotoxic T lymphocyte-associated protein 4 (CTLA4), selectin lymphocyte, interferon-γ (IFN-γ), programmed cell death 1 (Pdcd1), and granzyme B (Gzmb), was seen 8 days after transplantation along with histological evidence of severe allograft rejection. In tolerant cardiac allografts, the expression of fibrinogen-like protein 2 (Fgl2), Pdcd1, killer cell lectin-like receptor G1 (Klrg1), CTLA4, and lymphocyte-activation gene 3 was associated with tolerance. In a model of liver allograft tolerance, the increased expression of lectin galactose-binding soluble 1, Fgl2, CD39, phosphodiesterase 3B, Klrg1, forkhead box P3 (Foxp3), and transforming growth factor β as well as the inflammatory set of genes was observed 8 to 14 days after transplantation (ie, when there was severe inflammatory injury). At a later time when the liver allografts had been fully accepted and were histologically normal, the expression of the inflammatory set of genes returned to the baseline, but the expression of the tolerogenic set of genes was still increased. Genes that were expressed in tolerant cardiac and liver allografts included Fgl2, Klrg1, and Foxp3, whereas genes associated with rejection included CD25, Gzmb, and IFN-γ. Our data indicate that monitoring the graft expression of a novel biomarker gene set with the GeXP multiplex RT-PCR analysis system may allow differentiation between rejection and tolerance.
authors.affiliation: Division of Radiation Safety and Immune Tolerance, National Research Institute for Child Health and Development, Tokyo, Japan.
authors.forename: Lin
authors.initials: L
authors.lastname: Xie
authors.forename: Naotsugu
authors.initials: N
authors.lastname: Ichimaru
authors.forename: Miwa
authors.initials: M
authors.lastname: Morita
authors.forename: Jiajie
authors.initials: J
authors.lastname: Chen
authors.forename: Ping
authors.initials: P
authors.lastname: Zhu
authors.forename: Jihong
authors.initials: J
authors.lastname: Wang
authors.forename: Peter
authors.initials: P
authors.lastname: Urbanellis
authors.forename: Itay
authors.initials: I
authors.lastname: Shalev
authors.forename: Shizuko
authors.initials: S
authors.lastname: Nagao
authors.forename: Atsushi
authors.initials: A
authors.lastname: Sugioka
authors.forename: Liang
authors.initials: L
authors.lastname: Zhong
authors.forename: Norio
authors.initials: N
authors.lastname: Nonomura
authors.forename: Shiro
authors.initials: S
authors.lastname: Takahara
authors.forename: Gary A
authors.initials: GA
authors.lastname: Levy
authors.forename: Xiao-Kang
authors.initials: XK
authors.lastname: Li
mesh_terms: D000818:Animals; D020869:Gene Expression Profiling / Q000379:methods; D005819:Genetic Markers; D006084:Graft Rejection / Q000235:genetics* / Q000276:immunology / Q000473:pathology / Q000517:prevention & control; D006085:Graft Survival / Q000235:genetics*; D016027:Heart Transplantation / Q000276:immunology*; D007166:Immunosuppressive Agents / Q000494:pharmacology; D007249:Inflammation / Q000235:genetics / Q000276:immunology; D018836:Inflammation Mediators / Q000378:metabolism; D016031:Liver Transplantation / Q000276:immunology*; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D008809:Mice, Inbred C3H; D008810:Mice, Inbred C57BL; D008808:Mice, Inbred CBA; D015203:Reproducibility of Results; D020133:Reverse Transcriptase Polymerase Chain Reaction; D012680:Sensitivity and Specificity; D020123:Sirolimus / Q000494:pharmacology; D013997:Time Factors; D023001:Transplantation Tolerance / Q000235:genetics*; D016896:Treatment Outcome
chemical_list: D005819:Genetic Markers; D007166:Immunosuppressive Agents; D018836:Inflammation Mediators; D020123:Sirolimus