Moving beyond HLA: A review of nHLA antibodies in organ transplantation
Introduction
Early recognition and mitigation of transplant injuries due to immune and non-immune related injuries is a critical unmet need for improving the long-term management of transplant recipients [1]. The injurious role of circulating and graft deposited antibodies is well recognized in the context of donor-specific HLA antigens (DSA), acute humoral rejection and graft vasculopathy. Though most of this literature is in renal transplantation, a similar association has been observed in other solid organ transplants, such as heart, lung and intestine [2], [3], [4], [5], [6]. There has been an increased recognition of a causal and associative role of antibodies against non-HLA (nHLA) antigens such as MICA [7], anti-endothelial cell specific antibodies (AECAs), protein kinase zeta [8], with injury in both native organs and after organ transplantation [7], [9], [10], [11], [12], [13], [14], [15], [16]. Given that organ transplant injury in the form of both acute and chronic rejection can occur in the absence of demonstrable donor specific HLA-antibodies, rejection can also occur in HLA identical transplants, and there is an unmet need to better define immunogenic epitopes other than HLA, that drive the evolution of chronic rejection after organ transplantation, this review discusses recent work in the field of nHLA antibody analysis in organ transplantation. To better understand the causal role of nHLA antibodies in human organ injury, the review also discusses relevant work on mapping of the nHLA antibody repertoire in failing organs, prior to transplantation, to evaluate if the existing repertoire of specific nHLA antibodies in the pre-transplant sera in the recipient could also contribute to post-transplant pathology.
Section snippets
nHLA antibodies in organ transplantation
The finding of nHLA antibodies directed against donor antigens was reported as early as 1995 [17] and subsequent studies suggested that specific nHLA antibodies may bear relevance to transplant injury, irrespective of the impact of donor specific HLA antibodies. In a seminal study by Terasaki et al. [18] UNOS Registry graft survival records were evaluated to assess the percentage of graft failures from immunological or non-immunological factors in HLA identical kidneys and HLA mismatched living
nHLA antibodies and acute transplant rejection
Antibodies against nHLA antigens are involved in hyperacute rejection, most of these inferred to be targeted against the vascular endothelium [27], [28] and called anti-endothelial cell antibodies (AECAs) Vascular endothelial cells are considered as primary targets for allograft injury for both cellular and humoral AR [29]. A recently study by Jackson et al. looked at 60 living-donor kidney transplant patients, by using flow cytometry and solid-phase bead immunoassays on donor-derived
nHLA antibodies and chronic transplant injury: predicting the event before organ engraftment?
nHLA antibodies have also been implicated in chronic transplant injury in various organs. In heart transplant patients, there is a reported association of nHLA antibodies against myosin and vimentin with cardiac allograft vasculopathy (CAV) [38], [39]. In another study of heart transplant recipients, levels of anti-heterogeneous nuclear ribonucleoprotein K antibodies (anti-hnRNP-K antibodies) four years post-transplant were found to be statistically significantly associated with CAV disease [40]
Conclusions
With improvements in immunosuppression and a reduction in the incidence of early acute rejection, and limited improvements in graft life expectancy, attention has turned to nHLA antibodies as unrecognized triggers of acute and more importantly, chronic graft injury. These antibodies have been difficult to identify, given the inherent difficulty of identifying the immunogenic antigens in vivo. Though these have been traditionally identified by flow cytometry and ELISA against selected proteins,
Acknowledgments
Authors would like to Thank Xiaoxiao Gao for the help with literature search and we acknowledge NIH (R01 DK083447-01A2, U01 AI063594-06), and California Pacific Medical Center Research Institute San Francisco, CA for funding support.
References (52)
- et al.
Clinical relevance of preformed HLA donor-specific antibodies in kidney transplantation
Am J Transplant
(2008) - et al.
Protein microarrays identify antibodies to protein kinase Czeta that are associated with a greater risk of allograft loss in pediatric renal transplant recipients
Kidney Int
(2009) Relevance of MICA and other non-HLA antibodies in clinical transplantation
Curr Opin Immunol
(2008)Non-HLA transplantation immunity revealed by lymphocytotoxic antibodies
Lancet
(2005)- et al.
Non-HLA-type endothelial cell reactive alloantibodies in pre-transplant sera of kidney recipients trigger apoptosis
Am J Transplant
(2003) - et al.
Progressive histological damage in renal allografts is associated with expression of innate and adaptive immunity genes
Kidney Int
(2011) - et al.
Complete steroid avoidance is effective and safe in children with renal transplants: a multicenter randomized trial with three-year follow-up
Am J Transplant
(2012) - et al.
Hyperacute rejection of living related kidney grafts caused by endothelial cell-specific antibodies: case reports
Transplant Proc
(2008) - et al.
An association between antibodies specific for endothelial cells and renal transplant failure
Transpl Immunol
(1998) - et al.
Characterization of immune responses to cardiac self-antigens myosin and vimentin in human cardiac allograft recipients with antibody-mediated rejection and cardiac allograft vasculopathy
J Heart Lung Transplant
(2010)
Antibodies against heterogeneous nuclear ribonucleoprotein K in patients with cardiac allograft vasculopathy
J Heart Lung Transplant
HIF-1alpha signaling by airway epithelial cell K-alpha1-tubulin: role in fibrosis and chronic rejection of human lung allografts
Cell Immunol
Antibodies specifically target AML antigen NuSAP1 after allogeneic bone marrow transplantation
Blood
Functional proteogenomics-embracing complexity
Semin Immunol
Identification of non-HLA target antigens recognized after lung transplantation
J Heart Lung Transplant
B-cell immunity in the context of T-cell tolerance after combined kidney and bone marrow transplantation in humans
Am J Transplant
Rejection of the kidney allograft
N Engl J Med
Significance of the positive crossmatch test in kidney transplantation
N Engl J Med
A personal perspective: 100-year history of the humoral theory of transplantation
Transplantation
Persistent strong anti-HLA antibody at high titer is complement binding and associated with increased risk of antibody-mediated rejection in heart transplant recipients
J Heart Lung Transplant
Targets of antibody-mediated rejection in heart transplantation
Transplantation
Compartmental localization and clinical relevance of MICA antibodies after renal transplantation
Transplantation
Protein microarrays discover angiotensinogen and PRKRIP1 as novel targets for autoantibodies in chronic renal disease
Mol Cell Proteomics
Identifying compartment-specific non-HLA targets after renal transplantation by integrating transcriptome and “antibodyome” measures
Proc Natl Acad Sci USA
Non-HLA antibodies to immunogenic epitopes predict the evolution of chronic renal allograft injury
J Am Soc Nephrol
Differential immunogenicity and clinical relevance of kidney compartment specific antigens after renal transplantation
J Proteome Res
Cited by (30)
Donor-derived cell-free DNA: An independent biomarker in kidney transplant patients with antibody-mediated rejection
2021, Transplant ImmunologyCitation Excerpt :The current common method for DSA testing is based on HLA antibodies. In addition to HLA-DSA, a number of pathogenic non-HLA DSAs have been identified [18] which may cause a false positive for ABMR. Previous studies have indicated that angiotensin II type 1 receptor antibodies are also independent risk factors for graft loss and can be associated with the lesions of ABMR in the absence of DSA [19,20].
Transplant glomerulopathy
2018, Modern PathologyRenal Transplantation Across HLA and ABO Barriers
2017, Kidney Transplantation, Bioengineering, and Regeneration: Kidney Transplantation in the Regenerative Medicine EraAcute antibody-mediated rejection in kidney transplant recipients
2017, Transplantation ReviewsCitation Excerpt :Indeed, pretransplant epitope matching rather than traditional low-resolution antigen matching may represent a strategy to reduce de novo DSA development [9,10]. In addition to anti-HLA antibodies, a number of potentially pathogenic non-HLA anti-endothelial cell antigenic targets have been identified [11]. Several studies have demonstrated that angiotensin II type 1 receptor antibodies are an independent risk factor for graft loss and can be associated with the histologic lesions of ABMR in absence of DSA [12–15].
Recent advances in heart transplant immunology: The role of antibodies
2016, Progress in Pediatric CardiologyCitation Excerpt :While HLA antibodies are most commonly implicated in AMR and graft dysfunction, other so-called “non-HLA antibodies” may play an important role. Examples of non-HLA antibodies include anti-endothelial cell antibodies and anti-major histocompatibility complex class I chain-related antigens A and B (MICA and MICB antibodies) [18]. Testing for these antibodies is not readily available for clinical use, and is usually done under research protocols; however, non-HLA antibodies may be responsible for AMR without complement deposition, and their presence should be suspected in patients with histologic evidence of AMR without circulating donor-specific anti-HLA antibodies.
Humoral Immune Response and Allograft Function in Kidney Transplantation
2015, American Journal of Kidney DiseasesCitation Excerpt :They may cause injury alone or with anti-HLA antibodies.55 AECA are detected pretransplantation or develop de novo posttransplantation.56 The corresponding antigens are expressed on the allograft endothelium.