The Innate Cellular Immune Response in Xenotransplantation

Abstract

Xenotransplantation is very attractive strategy for addressing the shortage of donors. While hyper acute rejection (HAR) caused by natural antibodies and complement has been well defined, this is not the case for innate cellular xenogeneic rejection. An increasing body of evidence suggests that innate cellular immune responses contribute to xenogeneic rejection. Various molecular incompatibilities between receptors and their ligands across different species typically have an impact on graft outcome. NK cells are activated by direct interaction as well as by antigen dependent cellular cytotoxicity (ADCC) mechanisms. Macrophages are activated through various mechanisms in xenogeneic conditions. Macrophages recognize CD47 as a "marker of self" through binding to SIRPα. A number of studies have shown that incompatibility of porcine CD47 against human SIRPα contributes to the rejection of xenogeneic target cells by macrophages. Neutrophils are an early responder cell that infiltrates xenogeneic grafts. It has also been reported that neutrophil extracellular traps (NETs) activate macrophages as damage-associated pattern molecules (DAMPs). In this review, we summarize recent insights into innate cellular xenogeneic rejection.

Keywords: ITIMs; NETosis; innate cellular response; macrophage-mediated xenogeneic rejection; xenotransplantation.

Figure 1

Crosstalk between macrophages and other innate immune cells in xenograft. The immunocomplex of porcine cells and natural antibodies against porcine antigens binds to Fc receptors (FcRs) on macrophages and NK cell. Activated NK cell and macrophage induce antibody-dependent cellular cytotoxicity (ADCC) against porcine cells. Furthermore, incompatibility between SLA1 and NK receptors (NKRs) causes macrophage and NK cell activation because of lack of inhibitory signals. Macrophages were activated by the binding of DAMPs from dead cells to toll-like receptors (TLRs), receptor for advanced glycation end-products (RAGE) and macrophage-inducible C-type lectin (Mincle). Activation signals were induced and various pro-inflammatory cytokines are released from macrophages. These cytokines activate neutrophils and promote NETosis. Especially, IL-8 contributes to the neutrophil recruitment and IL-1β enhances NETosis formation in neutrophils. In addition, NETs from neutrophils also activate macrophages as DAMPs. Macrophages can activate NK cells and IFN-γ from activated NK cells was known to activates both macrophage and neutrophil. CD11a and CD11b on neutrophils bind to iC3b deposits on porcine cells, suggesting that neutrophils can recognize porcine target cells via binding of CD11a,b and iC3b. CD154 on NK cells enhances NK cytotoxicity to CD40 positive target cells.

Figure 2

Strategies for innate cellular xenogeneic rejection. Both HLA-E and G1 on porcine endothelial cells suppress NK and macrophage-mediated xenogeneic rejection. The transgenic expression of human CD47, SP-D and CD200 on porcine cells results in the suppression of macrophage-mediated cytotoxicity and inflammation. Human CD31 inhibits NETosis in neutrophils via the homophilic binding to CD31 on neutrophils. Both Tofacitinib (JAK inhibitor) and PQA-18 (PAK2 inhibitor) have been reported to suppress macrophage-mediated cytotoxicity and differentiation of macrophages. Anti-CD154 Ab suppress NK cytotoxicity against CD40⁺ target cells. Cp40 (C3 inhibitor) suppress CD11b expression, resulting in suppression of neutrophil adhesion to porcine cell. Y shows an inhibitory intracellular signaling motif of inhibitory receptors.