The complement system paradigm in transplantation: from innate regulator to therapeutic target

The complement system is a pillar component of innate immunity, acting as an enzymatic cascade critical for defending the host and maintaining tissue homeostasis. Once known for quickly clearing pathogens, it is now recognized as a complex network influencing both innate and adaptive immunity, affecting inflammation and T and B cell regulation. Complement dysregulation, whether due to a functional deficit or uncontrolled overactivation, can inflict significant injury to organs and tissues. This understanding is driving robust, expanding agreement on the central role of the complement system within the complex context of transplantation.Transplantation remains a life-saving intervention, yet long-term graft survival is hindered by immune-mediated injury. The complement system has emerged as a critical contributor to both acute cellular and antibody-mediated rejection, and it represents one of the emerging targets for genetic engineering in xenotransplantation. Activation of complement pathways during ischemia reperfusion (I/R) triggers inflammation, endothelial damage, and recruitment of immune cells, leading to delayed graft function (DGF), and ultimately compromising its survival. Complement activation is also involved in Graft-versus-Host Disease (GVHD), a major cause of morbidity and mortality in bone marrow transplant recipients. Despite advances in immunosuppressive therapies, these strategies often fail to fully control complement-driven injury. In this scenario, complement inhibitors, such as C5-blocking agents (e.g., Eculizumab) or C3-targeted drugs, may have the potential for mitigating allograft rejection episodes and improving graft survival. Addressing this goal requires a comprehensive characterization of complement activation across the entire trajectory of transplantation. By bridging immunology and translational medicine, this Research Topic welcomes submissions with the aim of compiling evidence on the following themes:• Novel mechanistic insights of complement-mediated injury in acute and chronic rejection, DGF, disease recurrence and GVHD.• Diagnostic potential of complement activation products in predicting graft failure.• Therapeutic targeting of complement system.• Crosstalk between complement system and T- and B-cell response post-transplant.• Challenges and solutions for complement regulation in cross-species grafts.• Complement genetics and personalized medicine.• Integration of complement modulation with other immunosuppressive regimens. Topic editors: Matteo Stravalaci, Peter F. Zipfel, Giuseppe Castellano Source: https://www.frontiersin.org/research-topics/76440/the-complement-system-paradigm-in-transplantation-from-innate-regulator-to-therapeutic-target