A Comprehensive Overview of the Clinical Relevance and Treatment Options for Antibody-mediated Rejection Associated With Non-HLA Antibodies

Abstract

Although solid organ transplant results have improved significantly in recent decades, a pivotal cause of impaired long-term outcome is the development of antibody-mediated rejection (AMR), a condition characterized by the presence of donor-specific antibodies to HLA or non-HLA antigens. Highly HLA-sensitized recipients are treated with desensitization protocols to rescue the transplantation. These and other therapies are also applied for the treatment of AMR. Therapeutic protocols include removal of antibodies, depletion of plasma and B cells, inhibition of the complement cascade, and suppression of the T-cell–dependent antibody response. As mounting evidence illustrates the importance of non-HLA antibodies in transplant outcome, there is a need to evaluate the efficacy of treatment protocols on non-HLA antibody levels and graft function. Many reviews have been recently published that provide an overview of the literature describing the association of non-HLA antibodies with rejection in transplantation, whereas an overview of the treatment options for non-HLA AMR is still lacking. In this review, we will therefore provide such an overview. Most reports showed positive effects of non-HLA antibody clearance on graft function. However, monitoring non-HLA antibody levels after treatment along with standardization of therapies is needed to optimally treat solid organ transplant recipients.

Poor Outcomes in Patients With Transplant Glomerulopathy Independent of Banff Categorization or Therapeutic Interventions

“…In our study iTG was observed in 47.5% of indication biopsies without signs for AMR, and we could not detect significant differences in outcomes among iTG, cAMR and cAAMR during a 5-year follow-up. HLA-DSA negative TG may also be caused by antibodies against non-HLA targets including non-HLA antibodies (e.g., against minor histocompatibility antigens) or other targets such as endothelial antigens or vimentin ( 53 ) and the failure to demonstrate DSA in iTG cases does not rule out the contribution of other antibodies in the pathophysiology of TG ( 54 ). Alternatively, the absorption of low antibody levels by the allograft may result in a lack of circulating DSA ( 55 ).…”

Microvascular Inflammation of the Renal Allograft: A Reappraisal of the Underlying Mechanisms

“…As mentioned above, ABMRh without detectable circulating HLA-DSAs suggests the involvement of antibodies directed against non-HLA antigens called minor histocompatibility antigens. Despite the fact that the presence of these antibodies is now increasingly accepted ( 56 – 61 ), the real issue is whether these antibodies can cause endothelial damage on their own or whether they are biomarkers of previous/ongoing injury ( 62 ). Two categories of non-HLA antibodies have been identified.…”

“…In transplant contexts, AT1R- and ETAR-specific antibodies could play a role in liver, heart and lung transplantation ( 61 ). AT1R and ETAR were also found in nontransplant patients and associated with cardiovascular disease, preeclampsia, cancer and autoimmune disease ( 77 ).…”

“…In recent decades, many antigens have been identified as potential mediators of allograft rejection not only in kidney transplantation but also in heart, lung and liver transplantation. We recommend the review by Kardol-Hoefnagel and Otten, which provides an overview of non-HLA antibodies and their clinical impact on solid organ transplantation ( 61 ). What we should remember is that non-HLA antibodies are organ dependent and that each kind of antibody may have a different mechanism of action.…”

NK cells in antibody‐mediated rejection – Key effector cells in microvascular graft damage

“…There are several aspects of ABMR not discussed in this manuscript; including non‐HLA antibodies, NK cell‐derived extracellular vesicles, and immunosuppression impact on NK cell function. Non‐HLA antibodies were recently reviewed by Kardol‐Hoefnagel and Otten (Kardol‐Hoefnagel & Otten, 2020). Multiple interesting articles published recently address the exciting new area of extracellular vesicles from immune cells, including NK cells, involved in immune modulation and the impact this presents to transplanted organs (Federici et al., 2020; Itabashi et al., 2020; Quaglia et al., 2020; Xu et al., 2020).…”