Activation of counter-regulatory mechanisms in a rat renal acute rejection model.
BACKGROUND
Microarray analysis provides a powerful approach to identify gene expression alterations following transplantation. In patients the heterogeneity of graft specimens, co-morbidity, co-medications and the challenges in sample collection and preparation complicate conclusions regarding the underlying mechanisms of graft injury, rejection and immune regulation.


RESULTS
We used a rat kidney transplantation model with strict transplant and sample preparation procedures to analyze genome wide changes in gene expression four days after syngeneic and allogeneic transplantation. Both interventions were associated with substantial changes in gene expression. After allogeneic transplantation, genes and pathways related to transport and metabolism were predominantly down-regulated consistent with rejection-mediated graft injury and dysfunction. Up-regulated genes were primarily related to the acute immune response including antigen presentation, T-cell receptor signaling, apoptosis, interferon signaling and complement cascades. We observed a cytokine and chemokine expression profile consistent with activation of a Th1-cell response. A novel finding was up-regulation of several regulatory and protective genes after allogeneic transplantation, specifically IL10, Bcl2a1, C4bpa, Ctla4, HO-1 and the SOCS family.


CONCLUSIONS
Our data indicate that in parallel with the predicted activation of immune response and tissue injury pathways, there is simultaneous activation of pathways for counter regulatory and protective mechanisms that would balance and limit the ongoing inflammatory/immune responses. The pathophysiological mechanisms behind and the clinical consequences of alterations in expression of these gene classes in acute rejection, injury and dysfunction vs. protection and immunoregulation, prompt further analyses and open new aspects for therapeutic approaches.
Edemir
Bayram
B
Experimentelle Nephrologie, Medizinische Klinik und Poliklinik D, Universitätsklinikum Münster, Germany. edemir@uni-muenster.de
Kurian
Sunil M
SM
Eisenacher
Martin
M
Lang
Detlef
D
Müller-Tidow
Carsten
C
Gabriëls
Gert
G
Salomon
Daniel R
DR
Schlatter
Eberhard
E
D000208:Acute Disease; D000818:Animals; D017951:Antigen Presentation / Q000235:genetics; D018925:Chemokines / Q000235:genetics; D003167:Complement Activation / Q000235:genetics; D016207:Cytokines / Q000235:genetics; D020869:Gene Expression Profiling; D005802:Genes, MHC Class II; D005819:Genetic Markers; D006084:Graft Rejection / Q000235:genetics* / Q000276:immunology*; D007372:Interferons / Q000235:genetics; D016030:Kidney Transplantation / Q000009:adverse effects* / Q000276:immunology*; D008297:Male; D020411:Oligonucleotide Array Sequence Analysis; D051381:Rats; D011914:Rats, Inbred BN; D011917:Rats, Inbred Lew; D015398:Signal Transduction / Q000235:genetics; D018417:Th1 Cells / Q000276:immunology; D014184:Transplantation, Homologous; D014185:Transplantation, Isogeneic
D018925:Chemokines; D016207:Cytokines; D005819:Genetic Markers; D007372:Interferons