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T cells play a critical role in acute allograft rejection. TGF-β/Smad3 signaling is a key pathway in regulating T cell development. We report here that Smad3 is a key transcriptional factor of TGF-β signaling that differentially regulates T cell immune responses in a mouse model of cardiac allograft rejection in which donor hearts from BALB/c mice were transplanted into Smad3 knockout (KO) and wild type (WT) mice. Results showed that the cardiac allograft survival was prolonged in Smad3 KO recipients. This allograft protection was associated with a significant inhibition of proinflammatory cytokines (IL-1β, TNF-α, and MCP-1) and infiltration of neutrophils, CD3+ T cells, and F4/80+ macrophages. Importantly, deletion of Smad3 markedly suppressed T-bet and IFN-γ while enhancing GATA3 and IL-4 expression, resulting in a shift from the Th1 to Th2 immune responses. Furthermore, mice lacking Smad3 were also protected from the Th17-mediated cardiac injury, although the regulatory T cell (Treg) response was also suppressed. In conclusion, Smad3 is an immune regulator in T cell-mediated cardiac allograft rejection. Loss of Smad3 results in a shift from Th1 to Th2 but suppressing Th17 immune responses. Thus, modulation of TGF-β/Smad3 signaling may be a novel therapy for acute allograft rejection.

Background: Effective non-invasive monitoring method to tell histopathology is a big challenge in renal transplantation., Methods: We used 70-mer long oligonucleotide array with 449 immune related genes to determine gene expression profiles of peripheral blood mononuclear cells (PBMCs) under different immune status including stable renal function (TX), acute tubular necrosis (ATN), biopsy conformed acute rejection (AR), clinical rejection with pathology of borderline changes (BL), clinical rejection without biopsy proven/presumed rejection (PR) and renal dysfunction without rejection (NR)., Results: Distinct molecular expression signatures in each group were found to correlate with histopathology. And we concluded that B cell chemokine CXCL13 and mast cell may play a role in renal allograft rejection through significant difference analysis and functional pathway analysis., Conclusions: It provides a potential non-invasive method for monitoring renal allograft function and immune status of renal transplant recipients., (Copyright © 2010 Elsevier B.V. All rights reserved.)

Aims: Acute allograft rejection is one of the important complications after renal transplantation, and it is a deleterious factor for long-term graft survival. Rejection is a complex pathophysiologic process, which has been explained by transcriptome and proteome in RNA transcripts and proteins level respectively. How are serum metabolite levels in response to acute rejection? Can metabolite levels in serum be used to diagnose and explain acute renal allograft rejection?, Methods: Gas chromatograph-mass spectrometry (GC-MS) was used to analyze serum metabolome in 22 recipients of acute rejection and 15 stable renal transplant recipients., Results: 46 endogenous metabolites included amino acid, fatty acid, carbohydrate and other intermediate metabolites were identified in 37 recipients. Principal component analysis based on these metabolites discriminated acute rejection group from stable recipients. Among these metabolites, the levels of 17 metabolites were significant higher in rejection group than those in stable group. These included amino acid (phenylalanine, serine, glycine, threonine, valine), carbohydrate (galactose oxime, glycose, fructose), carboxylic acid, lipids and other metabolite such as lactate, urea and myo-inositol. The levels of 5 metabolites of alanine, lysine, leucine, aminomalonic acid and tetradecanoic acid were low in rejection group compared to stable group. The prediction accuracy of acute rejection was 77.3% and stable function was 100% by supervised clustering based on these 22 metabolites., Conclusions: This study demonstrated that metabolic profile was changed in response to rejection process and renal function can be reflected by serum metabolite levels. This study showed potential capability to diagnose acute rejection by metabolome analysis.