Antibody-mediated rejection despite inhibition of terminal complement

Abstract

Summary Terminal complement blockade has been shown to decrease the incidence of early acute antibody‐mediated rejection (eAMR) in the first month after positive cross‐match kidney transplant recipients, yet some patients still develop eAMR. The current study investigated possible mechanisms of eAMR despite eculizumab treatment. Of the 26 patients treated with eculizumab, two developed clinical eAMR and another patient developed histologic signs of eAMR without graft dysfunction (‘subclinical eAMR’). Twenty‐three did not have histologic injury on early surveillance biopsies. All 26 patients had therapeutic levels of eculizumab and showed complete blockade of complement in hemolytic assays. High levels of donor‐specific alloantibody (DSA) including total IgG, IgG3, and C1q+ DSA were present in patients with and without eAMR, and none correlated well with eAMR. In contrast, IgM DSA was present in only four patients after transplantation: the two patients with clinical eAMR, one patient with subclinical AMR, and one patient without eAMR (P = 0.006 correlation with eAMR). Both clinical eAMR episodes were easily treated with plasma exchange which removed IgM more completely and rapidly than IgG, resulting in normalization of function and histology. These data suggest a possible role of antidonor IgM DSA in the pathogenesis of eAMR in patients treated with terminal complement blockade (ClinicalTrials.gov Identifier: NCT00670774).

Monocyte Recruitment by HLA IgG-Activated Endothelium: The Relationship Between IgG Subclass and FcγRIIa Polymorphisms

“…There is experimental evidence to support both that subclass is important for injury in murine allograft models (91, 92), and conversely that all HLA antibodies have potentially detrimental effects (10, 13, 15, 93). Clinical studies focusing on in vitro complement fixing capacity suggest but do not definitively demonstrate that complement activation is important for outcome (24, 27, 29, 32, 36, 94). …”

“…In transplant waitlist candidates and recipients, all subclasses of HLA antibodies have been reported, with IgG1 most frequently found (24–31). However, initial studies have not yielded a consensus regarding which are most detrimental to graft outcome (3, 24–27, 29, 32, 33). Further, complement is involved in but not absolutely required for clinical and experimental AMR (27, 32, 34–39), and it is likely that other Fc-dependent and Fc-independent mechanisms are at play.…”

IFN-γ Production by Memory Helper T Cells Is Required for CD40-Independent Alloantibody Responses

“…While memory CD4 T cells increased anti-donor IgM responses in CD40−/− recipients, the numbers of donor-reactive IgM secreting cells under CD40-deficient conditions were consistently 6–8 fold lower than those in WT recipients regardless of IFNγ neutralization (data not shown). In addition, the pathogenic role of anti-donor IgM alloAb in allograft rejection remains controversial (60–65). Therefore, our future studies will initially focus on donor-reactive IgG alloAb.…”

Antibody-mediated rejection across solid organ transplants: manifestations, mechanisms, and therapies

“…jci.org Volume 127 Number 7 July 2017 tion (108,109). These findings suggest that upstream complement activation and/or non-complement-mediated effector functions mediate allograft damage.…”