The innate immune response to allotransplants: mechanisms and therapeutic potentials

Abstract

Surgical trauma and ischemia reperfusion injury (IRI) are unavoidable aspects of any solid organ transplant procedure. They trigger a multifactorial antigen-independent inflammatory process that profoundly affects both the early and long-term outcomes of the transplanted organ. The injury associated with donor organ procurement, storage, and engraftment triggers innate immune activation that inevitably results in cell death, which may occur in many different forms. Dying cells in donor grafts release damage-associated molecular patterns (DAMPs), which alert recipient innate cells, including macrophages and dendritic cells (DCs), through the activation of the complement cascade and toll-like receptors (TLRs). The long-term effect of inflammation on innate immune cells is associated with changes in cellular metabolism that skew the cells towards aerobic glycolysis, resulting in innate immune cell activation and inflammatory cytokine production. The different roles of proinflammatory cytokines in innate immune activation have been described, and these cytokines also stimulate optimal T-cell expansion during allograft rejection. Therefore, early innate immune events after organ transplantation determine the fate of the adaptive immune response. In this review, we summarize the contributions of innate immunity to allograft rejection and discuss recent studies and emerging concepts in the targeted delivery of therapeutics to modulate the innate immune system to enhance allograft survival.

Fig. 1

Pathways linking transplantation-associated tissue damage to graft inflammation. Transplantation-associated ischemia reperfusion injury (IRI) causes inflammatory cell death (e.g., ferroptosis) in host and donor cells, leading to the release of damage-associated molecular patterns (DAMPs). DAMPs bind to Toll-like receptors (TLRs) or activate the complement cascade by creating products that bind to complement receptors (CR), resulting in the activation of inflammatory functions in macrophages. In addition, bacteria that translocate into the tissue during surgery and release pathogen-associated molecular patterns (PAMPs) or alloantibodies, activating the complement system, can also activate macrophages. Inhibitors of this multistep process are described in red. Ex vivo lung perfusion (EVLP) attenuates the inflammatory response to IRI. Ferrostatin-1 (Fer-1) and desferrioxamine (DFO) inhibit ferroptosis. Dexmedetomidine increases cell survival. Xenon gas inhibits the release of DAMPs. Monoclonal antibodies (Abs) specific for PAMPs or DAMPs prevent binding to TLRs. Soluble complement receptor 1 (sCR1) or siRNA decrease the expression of complement factors or receptors, and eculizumab interferes with the complement cascade. Eritoran is a TLR4 antagonist

Fig. 2

Targeting immunometabolism in macrophages to prevent graft rejection. Monocytes from the circulation enter a transplant and acquire either proinflammatory functions (M1) that contribute to graft rejection or immunoregulatory functions (M2) that promote graft tolerance. M2 macrophages generate energy mainly through oxidative phosphorylation (OxPhos) and glutamine metabolism, while M1 macrophages increase metabolic flux through the pentose phosphate pathway (PPP) and glycolysis. HIF-1α and Akt increase glycolysis by upregulating the expression of glycolytic enzymes and the glucose transporter GLUT1, respectively. The cholesterol pathway intermediate mevalonate, which can be blocked using statins, is involved in the epigenetic fixation of the proinflammatory phenotype. Itaconate is an anti-inflammatory metabolite whose expression is upregulated upon macrophage activation