Elsevier

Human Immunology

Volume 74, Issue 11, November 2013, Pages 1486-1490
Human Immunology

Moving beyond HLA: A review of nHLA antibodies in organ transplantation

https://doi.org/10.1016/j.humimm.2013.07.001Get rights and content

Abstract

Given the finite graft life expectancy of HLA identical organ transplants and the recognition of humoral graft injury in the absence of donor directed anti-HLA antibodies, the clinical impact of antibodies against non-HLA (nHLA) antigens in transplant injury is being increasingly recognized. The recognition of the impact of nHLA antigen discrepancies between donor and recipient on transplant outcomes is timely given the advances in rapid and lower cost sequencing methods that can soon provide complete maps of all recipient and donor HLA and nHLA mismatch data. In this review, we present a summary of recent reports evaluating the role of nHLA antibodies and their relevance to the field of 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)

  • M.J. Acevedo et al.

    Antibodies against heterogeneous nuclear ribonucleoprotein K in patients with cardiac allograft vasculopathy

    J Heart Lung Transplant

    (2011)
  • V. Tiriveedhi et al.

    HIF-1alpha signaling by airway epithelial cell K-alpha1-tubulin: role in fibrosis and chronic rejection of human lung allografts

    Cell Immunol

    (2012)
  • P.P. Wadia et al.

    Antibodies specifically target AML antigen NuSAP1 after allogeneic bone marrow transplantation

    Blood

    (2010)
  • M.M. Sarwal et al.

    Functional proteogenomics-embracing complexity

    Semin Immunol

    (2011)
  • H.G. Otten et al.

    Identification of non-HLA target antigens recognized after lung transplantation

    J Heart Lung Transplant

    (2006)
  • F. Porcheray et al.

    B-cell immunity in the context of T-cell tolerance after combined kidney and bone marrow transplantation in humans

    Am J Transplant

    (2009)
  • B.J. Nankivell et al.

    Rejection of the kidney allograft

    N Engl J Med

    (2010)
  • R. Patel et al.

    Significance of the positive crossmatch test in kidney transplantation

    N Engl J Med

    (1969)
  • P.I. Terasaki

    A personal perspective: 100-year history of the humoral theory of transplantation

    Transplantation

    (2012)
  • A. Zeevi et al.

    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

    (2012)
  • Q. Zhang et al.

    Targets of antibody-mediated rejection in heart transplantation

    Transplantation

    (2011)
  • L. Li et al.

    Compartmental localization and clinical relevance of MICA antibodies after renal transplantation

    Transplantation

    (2010)
  • A.J. Butte et al.

    Protein microarrays discover angiotensinogen and PRKRIP1 as novel targets for autoantibodies in chronic renal disease

    Mol Cell Proteomics

    (2011)
  • L. Li et al.

    Identifying compartment-specific non-HLA targets after renal transplantation by integrating transcriptome and “antibodyome” measures

    Proc Natl Acad Sci USA

    (2009)
  • T.K. Sigdel et al.

    Non-HLA antibodies to immunogenic epitopes predict the evolution of chronic renal allograft injury

    J Am Soc Nephrol

    (2012)
  • L. Li et al.

    Differential immunogenicity and clinical relevance of kidney compartment specific antigens after renal transplantation

    J Proteome Res

    (2010)
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