Mechanisms involved in antibody- and complement-mediated allograft rejection

Abstract

Antibody-mediated rejection has become critical clinically because this form of rejection is usually unresponsive to conventional anti-rejection therapy, and therefore, it has been recognized as a major cause of allograft loss. Our group developed experimental animal models of vascularized organ transplantation to study pathogenesis of antibody- and complement-mediated endothelial cell injury leading to graft rejection. In this review, we discuss mechanisms of antibody-mediated graft rejection resulting from activation of complement by C1q- and MBL (mannose-binding lectin)-dependent pathways and interactions with a variety of effector cells, including macrophages and monocytes through Fcγ receptors and complement receptors.

Inflammation in Myocardial Diseases

“…180 -182 There are 3 major pathways of complement activation: classical, alternative, and mannosebinding lectin (MBL)-dependent pathways. 181,183 The classical pathway is thought to be triggered by binding of immunoglobulin immunoglobulin M (IgM; and certain classes of immunoglobulin G [IgG]) to the foreign antigens), whereas the alternative and MBL-dependent pathways involve recognition of foreign surfaces and binding of MBL to foreign microbes, respectively. 181,183 Despite the difference in the initiating factors, all 3 pathways share the central process of complement component C3 activation, which can lead to the generation of (1i) C3a and C5a, which can act as inflammatory mediators, (2) C3b can mediate the opsonisation and engulfment of foreign material by phagocytes, and ultimately, (3) terminal complement components that together form the C5b-9 membrane attack complex can trigger subsequent damage and destruction of the targeted (foreign) cells, eg, myocytes of the cardiac allograft.…”

“…181,183 Despite the difference in the initiating factors, all 3 pathways share the central process of complement component C3 activation, which can lead to the generation of (1i) C3a and C5a, which can act as inflammatory mediators, (2) C3b can mediate the opsonisation and engulfment of foreign material by phagocytes, and ultimately, (3) terminal complement components that together form the C5b-9 membrane attack complex can trigger subsequent damage and destruction of the targeted (foreign) cells, eg, myocytes of the cardiac allograft. 181,183,184 …”

Non-canonical activity of the podosomal formin FMNL1γ supports immune cell migration

“…Unwarranted macrophage activation and infiltration of tissues has been implicated in a number of diseases, including diabetes, rheumatoid arthritis (RA), organ transplant rejection, atherosclerosis and cancer progression (Cookson, 1971;Coussens and Werb, 2002;Davies et al, 2013;Lech et al, 2012;Mantovani et al, 2013;Sebbag et al, 1997;Steinman and Cohn, 1973;Wasowska, 2010;Weisberg et al, 2003;Xu et al, 2003). Macrophages are capable of both amoeboid and mesenchymal migratory phenotypes (Van Goethem et al, 2010).…”

Pathologic diagnosis of antibody-mediated rejection in endomyocardial biopsy after heart transplantation based on renewed International Society for Heart and Lung Transplantation criteria

“…Hyperacute rejection occurs within minutes to hours of the blood flow being reestablished and is caused by preformed antibodies to ABO blood group antigens, HLA, or endothelial antigens. Antibodies in the blood of the recipient bind to the vascular endothelium of the transplant and activate complement, which results in neutrophil infiltration, vascular disruption, hemorrhage, fibrin deposition and platelet aggregation [10]. It is rare owing to tests for DSAs [11].…”

“…According to published data [24,25] it is most probable that MBL correlates positively with C4d deposition. Wasowska et al [10] suggested combine mechanism of MBL depending on both complement-activating and non-activating antibodies. Nonetheless, further studies are needed within this pathway.…”