Clinical and immunological relevance of antibodies in solid organ transplantation

Abstract

The two important issues affecting recipients of solid organ transplants and of importance to immunologists are (i) sensitization of the recipient to HLA antigens and the resultant humoral immune response leading to the development of anti-HLA antibodies; and ii) development of robust assays for early detection of humoral rejection post-transplant. Evidence from several studies clearly indicates that presence of circulating anti-HLA antibodies especially donor specific leads to early graft loss and high titres of DSA may even lead to hyperacute or accelerated acute rejection. Long-term graft survival too is adversely affected by the presence of either pre- or post-transplant DSA. HLA matching status of the recipient - donor pair - is an important factor in the modulation of humoral response following transplantation and in a way affects de novo development of DSA. Data collected over the past decade clearly indicate significantly lower level of DSAs in optimally matched donor-recipient pairs. HLA mismatches especially those on HLA-DR and HLA-C loci have wider implications on post-transplant graft survival. The presence of circulating anti-HLA antibodies leads to endothelial damage in the newly grafted organ through complement dependent or independent pathways. Although detection of C4d deposition in renal biopsies serves as an important indicator of humoral rejection, its absence does not preclude the presence of DSAs and humoral rejection, and hence, it cannot be relied upon in every case. The emergence of epitope-based screening for anti-HLA antibodies on Luminex platform with high degree of sensitivity has revolutionized the screening for anti-HLA antibodies and DSAs. Studies indicate that humoral response to non-HLA antigens might also have a detrimental effect on allograft survival. High titres of such circulating antibodies may even lead to hyperacute rejection. Pre-emptive testing of solid organ recipients, especially kidney transplant recipients for anti-HLA and non-HLA antibodies and aggressive post-transplant monitoring of allograft function to detect DSAs using Luminex-based tests, is highly recommended.

Impact of HLA compatibility in recipients of kidneys from expanded criteria donors: A Collaborative Transplant Study Report

“…A high degree of HLA incompatibility between donor and recipient has been shown to predispose to development of de novo donor‐specific HLA antibodies (DSAs) as well as to reactivation of preformed DSAs (Dreyer & de Fijter, 2020; Foroutan et al., 2019; Mohan et al., 2012). This may lead to antibody‐mediated rejection and subsequently impair long‐term allograft survival (Mehra & Baranwal, 2016; Slavcev, 2013). However, there are special immunological aspects to consider among the elderly—both in transplant recipients and donors.…”

“…A high degree of HLA incompatibility between donor and recipient has been shown to predispose to development of de novo donor-specific HLA antibodies (DSAs) as well as to reactivation of preformed DSAs (Dreyer & de Fijter, 2020;Foroutan et al, 2019;Mohan et al, 2012). This may lead to antibody-mediated rejection and subsequently impair long-term allograft survival (Mehra & Baranwal, 2016;Slavcev, 2013 (Aw, Silva, & Palmer, 2007;Heinbokel et al, 2013). In consequence, elderly kidney transplant recipients have been shown to experience less acute rejection episodes than younger recipients (Noble, Jouve, Malvezzi, Susal, & Rostaing, 2019;Rana et al, 2017).…”

The impact of donor/recipient age difference and HLA mismatch on graft outcome in pediatric kidney transplantation

“…While the importance of HLA matching has been postulated to be less important in the current era of more powerful immunosuppression, it has emerged again more recently as a potentially important factor influencing long‐term graft survival . Poor HLA matching is associated with the development of DSA and can lead to chronic antibody‐mediated rejection, the main cause of long‐term graft loss . A number of recent adult studies have demonstrated decreased graft survival associated with poor HLA matching .…”

Impact of C1q fixing donor‐specific antibodies on renal transplant outcome

“…Anti‐HLA antibodies, particularly those directed against donor‐specific antigens, irrespective of whether appearing at pretransplant stage or develop de novo following transplantation are associated with adverse renal allograft outcome 1‐7 . However, not all DSAs are deleterious to the allograft.…”