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Introduction: The adaptive immune system is both necessary and suffi cient for the acute and chronic rejection of solid organ allografts. Little is known, however, about how the innate immune system triggers and perpetuates allograft rejection. Methods: Using Rag -/mice, which are devoid of T-and B-cells, we investigated the innate immune response to alloantigen in a footpad and ear swelling experiment analogous to delayed-type hypersensitivity in wild-type mice. We also asked whether the innate immune system is suffi cient to cause chronic rejection in a Rag -/model of heterotopic heart transplantation. Results: One week after priming Balb/c Rag -/mice with allogeneic C57BL/6 (B6) Rag -/splenocytes (allo), rechallenge with allo induced signifi cantly more swelling than challenge with syngeneic Balb/c Rag -/splenocytes (syn), peaking at 6h and gradually declining thereafter (footpad: allo vs. syn: 6h: 0.1 ± 0.02 vs. 0.03 ± 0.01; 12h: 0.08 ± 0.01 vs. 0.01 ± 0.00; 24h: 0.06 ± 0.01 vs. 0.01 ± 0.01; all p<0.001). Challenge of immunized mice 4 weeks after priming also resulted in a signifi cant response to alloantigen (footpad: allo vs. syn: 6h: 0.16 ± 0.02 vs. 0.09 ± 0.01; 12h: 0.1 ± 0.01 vs. 0.05 ± 0.00; 24h: 0.07 ± 0.01 vs. 0.03 ± 0.01; all p<0.05). Challenge without prior sensitization resulted in a signifi cantly weaker response. We also found that the observed response was not NK cell-dependent but that depletion of F4/80 + Gr-1 int macrophages led to an abrogation of the swelling response. All results were comparable between ear and footpad. To test whether suffi cient priming or activation of the innate immune system alone leads to graft pathology, Balb/c Rag -/mice were either left untreated or immunized with allo with or without complete Freund's adjuvant prior to performing an allogeneic B6 Rag -/heart transplantation. Analysis of the functioning hearts 50 days post-transplantation revealed no histopathological evidence of either acute or chronic rejection when compared to syngeneic control allografts.

Background: Immunological status is still one of the key points discussed in the area of composite tissue allotransplantation (CTA) mainly due to the risks of life-long systemic immunosuppression. This study focus on immature dendritic cells (imDCs) and CD4+CD25+Foxp3+ regulatory T cells (Treg) to find their immunoregulatory roles in CTA, and meanwhile to find a mild immunoregulation way with minimal drug side-effects. Methods: Superficial inferior epigastric artery flap fromBrown-Norway (RT1n) was transplanted to Lewis (RT11) rats (day 0). ImDCs were propagated from the recipient (Lewis, RT11) or donor (Brown-Norway, RT1n) bone marrow, stained with CFSE and then topically transfused into allografts through femoral artery pedicle on day 0. Group 1 (control group) did not receive any treatment. Groups 2 received rapamycin (Rapa) at a concentration of 2mg/kg/day on days 0-7 postoperative. Groups 3 received donor imDCs transfusion. Groups 4 received recipient imDCs transfusion. Group 5 received combined treatment with donor imDCs and Rapa (2mg/kg/day, days 0-7). Group 6 received combined treatment with recipient imDCs and Rapa (2mg/kg/day, days 0-7). Graft rejection was defined as epidermolysis/ desquamation/gangrene of the donor skin. Tissue samples were biopsied to analyze the histological changes, and flow cytometry was performed to trace the location of imDCs labeling with CFSE and to quantify the recipient Treg on endpoint of rejection.

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