Local cytotoxic T-lymphocyte-associated antigen-4 immunoglobulin inhibition of rejection response is dependent on indoleamine 2,3-dioxygenase activities in the allograft

Abstract

A previous study showed that local gene transfer of cytotoxic T-lymphocyte-associated antigen-4 immunoglobulin (CTLA4Ig) significantly prolonged the survival time of rat flap allografts. However, the underlying mechanism is not fully understood. Indoleamine 2,3-dioxygenase (IDO) is considered to be able to modulate the unresponsiveness state of allografts. In this study, we tested the expression of the CD80 molecule, IDO mRNA, and the level of the tryptophan metabolite kynurenine with or without the application of the IDO blocker 1-methyl-tryptophan (1-MT) in a rat composite tissue allotransplantation model. CD80 expression could be detected in the allograft. The ration of IDO mRNA/glyceraldehyde 3-phosphate dehydrogenase (GAPDH) mRNA and the level of kynurenine were both enhanced (46.3 ± 8.8 versus 4.6 ± 1.8 and 18.9 ± 1.3 μmol/L versus 2.1 ± 0.2 μmol/L separately) after adenovirus-mediated CTLA4Ig (AdCTLA4Ig) transduction. When 1-MT was applied to the AdCTLA4Ig perfusion recipients, the ration of IDO mRNA/GAPDH mRNA (5.2 ± 2.9) and the level of kynurenine (0.8 ± 0.5 μmol/L) were significantly reduced. Moreover, the allograft survival time was greatly reduced when 1-MT was applied to AdCTLA4Ig perfusion recipients compared to single AdCTLA4Ig perfusion therapy recipients (7.2 days versus 13.6 days). We showed that the inhibitory effect of locally delivered CTLA4Ig is dependent on IDO activities within the allograft.