Complement—here, there and everywhere, but what about the transplanted organ?

Abstract

The part of the innate immune system that communicates and effectively primes the adaptive immune system was termed "complement" by Ehrlich to reflect its complementarity to antibodies having previously been described as "alexine" (i.e protective component of serum) by Buchner and Bordet. It has been established that complement is not solely produced systemically but may have origin in different tissues where it can influence organ specific functions that may affect the outcome of transplanted organs. This review looks at the role of complement in particular to kidney transplantation. We look at current literature to determine whether blockade of the peripheral or central compartments of complement production may prevent ischaemic reperfusion injury or rejection in the transplanted organ.We also review new therapeutics that have been developed to inhibit components of the complement cascade with varying degrees of success leading to an increase in our understanding of the multiple triggers of this complex system. In addition, we consider whether biomarkers in this field are effective markers of disease or treatment. Word count 169

Effect of the Anti-C1s Humanized Antibody TNT009 and Its Parental Mouse Variant TNT003 on HLA Antibody–Induced Complement Activation—A Preclinical In Vitro Study

“…Immunoglobulin binding to target antigens is a major trigger of the CP, which is critical in the defense against pathogens and the physiologic clearance of immune complexes, but may also cause tissue injury in a variety of disease states (1,2). The CP is recognized as being involved also in antibody-mediated rejection (AMR) of organ transplants (3,4). This type of rejection is an important cause of transplant injury, significantly contributing to inferior graft function and survival (5).…”

Complement Polymorphisms in Kidney Transplantation: Critical in Graft Rejection?

“…The complement system plays a pivotal role in innate immunity following kidney transplantation . However, the balance between desirable effects such as protection against infections and the clearance of apoptotic cells and destructive complement‐mediated inflammation following, for instance, antibody binding to the allograft is delicate .…”

“…Functional complement polymorphisms may be less relevant in recipients of a living kidney donor as these transplantations are associated with less vigorous complement activation . Furthermore, polymorphisms in the classical pathway or downstream in the cascade may primarily influence rejection rate and graft survival in patients with (non‐)HLA antibodies, as these antibodies may evoke strong complement activation upon binding to the allograft .…”

“…It is increasingly being emphasized that innate immunity plays an important role in the initiation of renal transplant rejection . Complement, one of the components of the innate immune system, is not exclusively involved in rejection but also in other complications including ischemia–reperfusion injury (IRI), infections, and recurrence of some primary renal diseases . The complement system constitutes over 30 proteins, both circulating in plasma and membrane‐bound .…”

Human Tamm-Horsfall protein, a renal specific protein, serves as a cofactor in complement 3b degradation

“…Complement activation occurs during ischemia-reperfusion injury (IRI)[22,23] and organ transplantation. [24,25] THP knockout mice were less able to protect their kidneys from tubular damage when subjected to renal IRI than were wild-type mice[26] and during the recovery phase of IRI, THP was redirected to the tubulointerstitium. [27] In liver transplant patients, patients with the lowest pre-surgical urinary THP concentrations were the ones who developed renal insufficiency post-surgically.…”