Characteristics of donor-specific anti-HLA antibodies in renal transplant recipients

Afucosylation of HLA-specific IgG1 as a potential predictor of antibody pathogenicity in kidney transplantation

“…To this end, the antibody effector functions that may be responsible for AMR are influenced not solely by titer, but by affinity, antigen availability and epitope, and antibody isotype, subclass, and glycosylation (12,(26)(27)(28)(29)(30)(31). In other disease settings, systematic tools for surveillance of this spectrum of serum antibody features and their associated effector functions have identified reliable associations and begun to support robust predictions of disease outcomes (32)(33)(34)(35)(36)(37)(38)(39).…”

“…Solid phase assays using purified HLA antigens (Luminex® single bead antigen assays) have significantly improved stratification and categorization of transplant candidates, because they can detect very low levels of DSAs due to their high sensitivity. While this technique has been used to update organ allocation and desensitization protocols, it has led to minimal benefits to improvement in rejection treatment, as the presence and levels of DSA are not a reliable predictor of transplant outcome (9)(10)(11)(12)(13). While graft survival is clearly poorer for individuals sensitized against donor organ antigens (1, 2, 14-17), several studies have shown that not all DSAs carry the same risk of allograft rejection, as they have been associated with a wide spectrum of effects ranging from a complete absence of graft injury to the most severe form of AMR (18).…”

“…In other disease settings, systematic tools for surveillance of this spectrum of serum antibody features and their associated effector functions have identified reliable associations and begun to support robust predictions of disease outcomes (32)(33)(34)(35)(36)(37)(38)(39). While prior research on the role of antibodies in transplant rejection was predominantly focused on estimation and retrospective correlation of titer to better predict transplant outcomes (16,17,(40)(41)(42), recent studies have begun to interrogate other important factors governing antibody functionality, such as subclass distribution and complement fixing ability (12,27,28,(43)(44)(45)(46)(47)(48)(49)(50)(51), and the evolution of these features with the progression of disease (13,48,(52)(53)(54)(55)(56)(57).…”

Afucosylation of HLA-specific IgG1 as a potential predictor of antibody pathogenicity in kidney transplantation

“…While this technique has been used to update organ allocation and desensitization protocols, it has led to minimal benefits to improvement in rejection treatment as the presence and levels of DSAs are not a reliable predictor of transplant outcome. 9 , 10 , 11 , 12 , 13 While graft survival is clearly poorer for individuals sensitized against donor organ antigens, 1 , 2 , 14 , 15 , 16 , 17 several studies have shown that not all DSAs carry the same risk of allograft rejection, as they have been associated with a wide spectrum of effects ranging from a complete absence of graft injury to the most severe form of AMR. 18 Similarly, appearance of de novo DSAs implies the risk of graft deterioration but provides little to no information on their actual pathogenic activities.…”

“…To this end, the antibody effector functions, such as antibody-dependent cellular cytotoxicity (ADCC), complement-dependent cytotoxicity (CDC), phagocytosis, and induction of inflammatory response mediators that may be responsible for AMR are influenced not solely by titer but by affinity, antigen availability and epitope, and antibody isotype, subclass, and glycosylation. 12 , 26 , 27 , 28 , 29 , 30 , 31 Among these traits, antibody Fc domain glycosylation is perhaps the least frequently characterized, despite relationships between the extent of fucosylation in modifying natural killer (NK)-cell-mediated cytotoxicity, galactose in modifying CDC, and sialylation having been associated with immunomodulatory effects. 32 , 33 , 34 , 35 , 36 , 37 In other disease settings, systematic tools for surveillance of this spectrum of serum antibody features and their associated effector functions have identified reliable associations and begun to support robust predictions of disease outcomes.…”