Role of complement and NK cells in antibody mediated rejection

Abstract

Despite extensive research on T cells and potent immunosuppressive regimens that target cellular mediated rejection, few regimens have been proved to be effective on antibody-mediated rejection (AMR), particularly in the chronic setting. C4d deposition in the graft has been proved to be a useful marker for AMR; however, there is an imperfect association between C4d and AMR. While complement has been considered as the main player in acute AMR, the effector mechanisms in chronic AMR are still debated. Recent studies support the role of NK cells and direct effects of antibody on endothelium cells in a mechanism suggesting the presence of a complement-independent pathway. Here, we review the history, currently available systems and progress in experimental animal research. Although there are consistent findings from human and animal research, transposing the experimental results from rodent to human has been hampered by the differences in endothelial functions between species. We briefly describe the findings from patients and compare them with results from animals, to propose a combined perspective.

New insights regarding chronic antibody-mediated rejection and its progression to transplant glomerulopathy

“…in direct endothelial cell activation and the recruitment of secondary effector mechanisms, including natural killer (NK) cells, macrophages, and complement system activation [21] (Fig. 3).…”

“…Biopsies with transplant glomerulopathy are infiltrated with monocytes and NK cells adherent to capillary endothelial cell [26]. These cells, particularly NK cells through their activation by Fc receptors, are likely important in the development of transplant glomerulopathy independent of complement [21]. NK cells are known for their direct cytotoxicity as part of innate immunity and are likely important in the development of transplant glomerulopathy [21].…”

“…These cells, particularly NK cells through their activation by Fc receptors, are likely important in the development of transplant glomerulopathy independent of complement [21]. NK cells are known for their direct cytotoxicity as part of innate immunity and are likely important in the development of transplant glomerulopathy [21]. Both monocytes and NK cells are major producers of multiple cytokines including interferon gamma (INF-g) and tumor necrosis factor alpha (TNF-a), which are also independently associated with transplant glomerulopathy [27,35,36].…”

Lessons and Limits of Mouse Models

“…Colvin and colleagues developed a model of chronic cardiac allograft vasculopathy by the repeated transfer over 28 days of either complement-fixing IgG2a or non-complement-fixing anti-MHC class I mAb into B6.Rag1 2/2 mice recipients of B10.BR hearts (for review, see Akiyoshi et al 2012). Importantly, antibody to class I MHC antigens did not require complement deposition in the graft to induce antibody-mediated rejection, whereas Fc-and NK-dependent events were necessary.…”

Histopathological diagnosis of acute and chronic rejection in pediatric kidney transplantation

“…AMR contributes to both early and in particular late graft loss [48,49]. Antibodies can cause tissue injury through three main pathways: the classical activation of complement, via direct activation of the antigen-expressing target endothelial cell, and through cell-mediated cytotoxicity after binding to Fc receptors of neutrophils, macrophages, and NK cells [52][53][54]. Since donor HLA is widely expressed in the microcirculation of the allograft, these pathways can all culminate in endothelial injury.…”