Approaches to the clinical application of donor-specific tolerance in living donor organ transplantation.

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(1)Alloantigen or allopeptide can induce hyporesponsiveness to fully mismatched cardiac allografts when delivered intratracheally or orally.(2)Alloantigen or allopeptide can generate regulatory cells when delivered intratracheally.(3)The population of regulatory cells contains regulatory T cells and regulatory dendritic cells.(4)The regulatory T cells and regulatory dendritic cells can suppress rejection of allogeneic heart grafts.(5)The suppression by regulatory T cells and regulatory dendritic cells is donor specific.(6)Intratracheal delivery of alloantigen combined with anti-CD4 mAb or anti-CD40L mAb induces operational tolerance to fully allogeneic cardiac allografts.(7)CD80/86 pathway, signals of THF-family and PD-1 signal are necessary for induction of regulatory cells by intratracheal delivery of alloantigen, individually.(8)IL-10 is essential for induction of regulatory cells by intratracheal delivery of alloantigen.(9)Mycophenolate mofetil and Rapamycin work synergistically for induction of regulatory cells, although high dose of Tacrolimus, Azathioprine and Cyclosporine prevent generating regulatory cells.(10)Histamine 2 receptor antagonist, serotonin receptor antagonist, ursodeoxycholic acid, MCI-186 (free radical scavenger) and anti-thrombin III can generate regulatory cells.(11)The fraction of regulatory T cells is CD4^+CD25^+CTLA4^+ in our model.(12)The number of CD4^+CD25^+CTLA4^+ cells decreased before rejection episode in preliminary clinical study.