*Purpose: Induced pluripotent stem cells (iPSCs) is expected to be the source of therapeutic cells in the regenerative medicine. Autologous derivation of iPSCs is the ideal way, but it is not practically and commercially feasible. To overcome these problems, it is beneficial to establish ready-to-use clinically applicable iPSCs, especially, from HLA homozygous donors. This approach not only solve the commercial problems but also reduces the risk of immune rejection. Although HLA-mismatch is the major reason for graft rejection, other antigens (minor antigens) may induce some immune-reactions and rejection. However, the immune-reaction which occurs in iPSCs-based transplantation has not been thoroughly investigated. In this study, we aim to inspect the immune-reaction taking place in MHC homozygous to MHC heterozygous transplantation. Furthermore, it is aimed to develop a control method of the immune-reaction.

*Methods: We used C3H x 129 F1 (H-2k/b) mice as MHC heterozygous recipients because recipient MHC haplotype is heterozygous in most cases. BALB/c (H-2d) mice were used as MHC (major) and minor antigen-mismatched donors, and C57BL/6J (H-2b) mice as MHC (major)-matched but minor antigen-mismatched donors. We performed mouse skin grafting as a model of tissue but not organ transplantation to represent iPSC-based therapy. In addition, we attempted to control rejection by the administration of immunosuppressants, or injection of donor B cells.

*Results: B6 skins, MHC-matched but minor antigen-mismatched grafts, were rejected as early as skins from MHC-mismatched (BALB/c) ones. The magnitude of post-transplant T cell responses varied depending on the donor backgrounds. We observed no anti-donor antibody production when the donor-recipient combination was MHC-matched but minor antigen-mismatched. It was difficult to engraft for a long period both B6 and BALB/c skins by using immunosuppressants. To our surprise, injection of donor B cells induced donor-specific tolerance.

*Conclusions: Our results show an appropriate immune regulation essential for the iPSCs-based transplantation. It is suggested that combination therapy with preconditioning and injection of donor B cells is effective in this setting of transplantation.

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