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It is well known that adoptive transfer of donor‐derived tolerogenic dendritic cells (DC) helps to reduce acute allograft rejection. However, this method cannot effectively prevent grafts from infiltration of inflammatory cells and fibrosis, and thus has minimal effect on chronic allograft rejection. In this study, we used mitomycin C (MMC) to generate tolerogenic DC and demonstrated that donor (Balb/c)‐derived MMC‐DC could induce hyporesponsiveness of recipient (C57BL/6) T cells in vitro, potentially by inducing T‐cell apoptosis, decreasing IL‐2 and IL‐12 secretion, and increasing regulatory T‐cell numbers and IL‐10 secretion. Furthermore, anti‐CD154 monoclonal antibody (mAb) treatment combined with donor‐derived MMC‐DC prolonged the survival of the allografts in vivo. The mechanisms were similar to those in vitro. Impressively, both acute and chronic rejection were prevented when donor and F1 generation (Balb/c × C57BL/6) derived MMC‐DC were injected together with anti‐CD154 mAb into recipients before heart allotransplantation. In summary, we showed that donor and F1‐derived tolerogenic DC have a synergistic effect on induction and maintenance of T‐cell regulation and the secretion of immunosuppressive cytokines. Moreover, adoptive transfer of these two types of DC could inhibit both acute and chronic transplant rejection in mice.

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Memory cells are currently thought to be a major barrier to tolerance induction in transplantation. However, whether alloreactive memory cells resulting from a primary transplant have cross‐reactivity in a second transplant is unclear. Here, we used skin transplantation from BALB/c mice donors to presensitize C57BL/6 (B6) mice. One month later, several strains of mice (including BALB/c, DBA/2, NOD, C3H and B6 mice) were chosen as donors to construct a memory model of heterotopic cardiac transplantation. The higher degree of major histocompatibility complex (MHC) mismatch to sensitizing MHC resulted in longer median survival times (MSTs, BALB/c 3.63 days versus C3H 6.08 days). After 3.5 days of cardiac transplantation, compared with the BALB/c and DBA/2 groups, in the groups of NOD and C3H, the infiltration of inflammatory cells in the grafts, the proportion and proliferation of memory cells in spleens and the function of allogeneic antibodies decreased significantly. The varying degrees of MHC mismatch between the primary and secondary donors influenced the intensity of alloreactive memory cell function, the higher degree of MHC mismatch resulted in better tolerance during secondary transplantation, and these may be related to the changed activation, proliferation and function of the alloreactive memory cells.