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Introduction
Xenotransplantation is one of the most attractive strategies to overcome the shortage of organ donors. α1,3-galactosyltransferase gene-deficient-knockout (αGalTKO) pigs have been produced to provide sufficient protection against hyper acute rejection, which is mediated by natural antibodies to xenogeneic antigens and complements (1-4). The expression of complement regulatory proteins, such as C1 esterase inhibitors, decay accelerating factors, and membrane cofactor proteins on porcine cells, downregulates complement-mediated cytotoxicity (5-8). However, a limited number of studies have been conducted on cellular xenogeneic rejection (CXR). Histopathological studies have demonstrated that the mechanisms involved in xenogeneic graft rejection are significantly different from those associated with allogeneic graft rejection. In allograft rejections, cytotoxic T lymphocytes are the main infiltrating cells, while xenografts mainly induce the infiltration of neutrophils, NK cells, and macrophages (9-11). CXR with innate immune cells particularly causes severe rejection in xenotransplantation. Macrophages are activated under xenogeneic conditions through both antibody-dependent and -independent mechanisms. Immunocomplexes of porcine cells with xenogeneic antigen bind to the Fc gamma receptor on macrophages and activate macrophages (12,13). Macrophages are also activated by interaction with neutrophils, NK cells, and Th1 cells in an antibody-independent manner (14,15). Furthermore, damage-associated molecular patterns (DAMPs) from dead porcine cells activate macrophages in an antibody-independent manner (16). Martin et al demonstrated that the infiltration of neutrophils and macrophages in αGalTKO islets was not different from that in wild-type islets in a dual islet transplantation model, suggesting that antibody-independent mechanisms are important in CXR (17). Thus, it is important to develop strategies to suppress the action of innate immune cells, such as macrophages and neutrophils, for successful clinical application of xenotransplantation (18-24).
Surfactant protein-A (SP-A) and SP-D are epithelial cell-derived immune modulators that are C-type collagen-like lectins. SP-A and SP-D can be detected in the mucosal surfaces of various organs, and both proteins play important roles in immune responses (25-29). While ligation of N-terminal collagen domains with the calreticulin/CD91 receptor complex induces pro-inflammatory responses, binding of the carbohydrate recognition domain (CRD) to signal inhibitory regulatory protein α (SIRPα) prevents inflammation (30). We have previously reported the preparation of cDNA for the membrane-type protein, collectin placenta 1 (CL-P1), with the CRD of SP-D (CL-SPD) and its transfection into swine endothelial cells (SECs). The hybrid molecule significantly suppresses macrophage-mediated cytotoxicity in...