Role of Heme Oxygenase-1 in Murine Renal Allograft Acceptance
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Date
2006-06
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The Ohio State University
Abstract
The acceptance of renal grafts in mice seems to be strain specific. While a kidney transplant between MHC disparate Balb/C and C57/B6 mice is rapidly rejected, a DBA kidney transplanted into a B6 mouse is spontaneously accepted and the acceptance is long term. Examination of sera from the B6 recipient demonstrates graft reactive antibodies suggesting an immune response being mounted. Yet the graft remains functioning suggesting that a state of tolerance has developed.
Many theories as to the mode of immune regulation have been proposed including the presence of regulatory cytokines (IL-10 and TGFbeta), and the presence of regulatory T-cells. Regulatory T-cells (Tregs) can be identified by the expression of the forkhead transcription factor foxP3, but the mechanism by which these Tregs down regulate the immune response remains to be determined. One theory is that foxP3 up-regulates the expression of the enzyme heme oxygenase-1 and this molecule produces physiological levels of carbon monoxide which has been shown to down regulate the activity of graft reactive T-cells. Therefore, we hypothesize that the regulation of the accepted grafts act through the presence of FoxP3 positive regulatory T-cells acting through up-regulation of heme oxygenase-1.
To test this hypothesis we isolated RNA from accepted DBA to B6 renal allografts at various time points (day 0, 30, 60, 150). After reverse transcribing the RNA and using a polymerase chain reaction to clone heme oxygenase-1, expression of the gene was compared to expression of heme oxygenase-1 in B6 to B6 murine renal isografts taken at the same time points using gel electrophoresis. The expression of FoxP3 was also measured using the same procedure as stated above. This study is important because the DBA to B6 model seems to mimic the human condition, as patients have been seen that express enough antibody to warrant rejection but are not rejecting their renal grafts after transplantation.
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Keywords
Heme oxygenase-1, FoxP3, allograft acceptance, accommodation