An ex vivo model of tolerance vs. rejection: comparison of different signal transducers and activators of transcription, STAT1, STAT4, STAT5 and STAT6.

An ideal for clinical organ transplantation is for the recipient to develop graft-specific immune tolerance. Although tolerance may occur, there is no way of identifying those recipients who are tolerant vs. those still capable of rejecting their graft. Thus immunosuppressive therapy is normally continued throughout life with the attendant risks of infection, neoplasia, and unwanted side effects of the immunosuppressive drugs. A surrogate marker of specific immune non-responsiveness would permit identification of graft-tolerant individuals who may then be weaned off all immunosuppression. Here we present a model which characterises discrete components of a tolerant, vs. aggressive, immune response. In rodents, new populations of tolerant, regulatory cells can be generated for a foreign graft if first exposure of the T cell receptor (TCR) to graft antigen coincides with blockade of the CD4 and CD8 co-receptors of the TCR. Once established, this type of peripheral tolerance is very robust. We have exploited an ex vivo model to compare in vivo-derived allo-tolerant lymphocytes with their counterpart which have been primed to reject the same allo-antigen. The model has revealed differential STAT (Signal Transducers and Activators of Transcription) responses associated with tolerance, vs. rejection, which have not been previously described. This approach will identify candidate surrogate markers of immune response status for potential clinical application.