Immune complex handling in transplantation: central roles for complement factor H, animal models, and translational implications.

Immune complexes (ICs) are increasingly recognized as dynamic regulators of graft injury in solid organ transplantation. Beyond their formation, the biological impact of ICs is determined by how they are handled, trafficked, and cleared. Complement plays a central role in this process, functioning not only as an effector system but as a context-dependent regulator of IC fate. Classical pathway activation initiates complement deposition on ICs, while the alternative pathway amplifies these signals, with regulatory proteins constraining excessive activation. Complement factor H (CFH), the principal regulator of the alternative pathway, emerges as a key determinant of IC handling by modulating complement amplification and directing ICs toward non-inflammatory clearance pathways. This review integrates mechanistic insights into IC biology with clinical observations across kidney, heart, and lung transplantation. We highlight species-specific differences in IC clearance, examine how complement-targeted therapies intersect with IC biology, and address ongoing controversies regarding complement as a marker versus driver of injury. Collectively, these concepts position IC handling, not merely for IC formation, but as a central determinant of transplant outcomes.