Antibodies In Solid Organ Transplantation Research Articles

Complement-activating donor-specific anti-HLA antibodies in solid organ transplantation: systematic review, meta-analysis, and critical appraisal.

Several studies have investigated the impact of circulating complement-activating anti-human leukocyte antigen donor-specific antibodies (anti-HLA DSAs) on organ transplant outcomes. However, a critical appraisal of these studies and a demonstration of the prognostic value of complement-activating status over anti-HLA DSA mean fluorescence intensity (MFI) level are lacking. We conducted a systematic review, meta-analysis and critical appraisal evaluating the role of complement-activating anti-HLA DSAs on allograft outcomes in different solid organ transplants. We included studies through Medline, Cochrane, Scopus, and Embase since inception of databases till May 05, 2023. We evaluated allograft loss as the primary outcome, and allograft rejection as the secondary outcome. We used the Newcastle-Ottawa Scale and funnel plots to assess risk of bias and used bias adjustment methods when appropriate. We performed multiple subgroup analyses to account for sources of heterogeneity and studied the added value of complement assays over anti-HLA DSA MFI level. In total, 52 studies were included in the final meta-analysis (11,035 patients). Complement-activating anti-HLA DSAs were associated with an increased risk of allograft loss (HR 2.77; 95% CI 2.33-3.29, p<0.001; I²=46.2%), and allograft rejection (HR 4.98; 95% CI 2.96-8.36, p<0.01; I²=70.9%). These results remained significant after adjustment for potential sources of bias and across multiple subgroup analyses. After adjusting on pan-IgG anti-HLA DSA defined by the MFI levels, complement-activating anti-HLA DSAs were significantly and independently associated with an increased risk of allograft loss. We demonstrated in this systematic review, meta-analysis and critical appraisal the significant deleterious impact and the independent prognostic value of circulating complement-activating anti-HLA DSAs on solid organ transplant risk of allograft loss and rejection.

The role of non-HLA antibodies in solid organ transplantation: a complex deliberation.

There is tremendous interest in understanding when, if, and how non-HLA antibodies contribute to allograft injury. Numerous non-HLA target antigens have been identified and sensitization to these targets have been associated with delayed allograft function, rejection, and allograft failure. This review focuses on the clinical utility of HLA antibody testing, highlighting the strengths and limitations of current clinical studies, and the need for defining characteristics to inform non-HLA antibody pathogenicity. Clinical studies continue to show associations between non-HLA antibodies and rejection and reduced allograft survival across multiple transplanted organ types. The worst clinical outcomes continue to be observed among recipients testing positive for both non-HLA and donor-specific HLA antibodies. Mechanistic insights from both animal and clinical studies support a model in which tissue injury accompanied by an inflammatory environment influence non-HLA antibody formation and pathogenicity. Immune triggers that lead to non-HLA antibody formation and pathogenicity are complex and poorly understood. The ability of non-HLA antibodies to mediate allograft injury may depend upon their affinity and strength (titer), target specificity, density of the target antigen, and synergy with donor-specific HLA antibodies.

Impact and production of Non-HLA-specific antibodies in solid organ transplantation.

Organ transplantation is an effective way to treat end-stage organ disease. Extending the graft survival is one of the major goals in the modern era of organ transplantation. However, long-term graft survival has not significantly improved in recent years despite the improvement of patient management and advancement of immunosuppression regimen. Antibody-mediated rejection is a major obstacle for long-term graft survival. Donor human leucocyte antigen (HLA)-specific antibodies were initially identified as a major cause for antibody-mediated rejection. Recently, with the development of solid-phase-based assay reagents, the contribution of non-HLA antibodies in organ transplantation starts to be appreciated. Here, we review the role of most studied non-HLA antibodies, including angiotensin II type 1 receptor (AT1 R), K-α-tubulin and vimentin antibodies, in the solid organ transplant, and discuss the possible mechanism by which these antibodies are stimulated.

Donor-specific HLA Antibodies in Solid Organ Transplantation: Clinical Relevance and Debates

Early outcomes following solid organ transplantation have markedly improved in recent years. Antibody-mediated rejection caused by donor specific anti-human leukocyte antigen antibodies (HLA-DSA) is widely recognized to be a risk factor for rejection episode, graft loss and decreased graft survival. The presence of HLA-DSA before transplantation and the appearance of these antibodies after transplantation can induce a wide spectrum of allograft injuries, ranging from the absence of allograft lesions with normal biopsy histopathologies to indolent subclinical processes to acute rejection with early allograft loss. However, the interpretation of the current DSA results is not easy and has led to many discussions and controversies. Current challenges exist in identification of pathologic DSA, monitoring and diagnostic algorithms, appropriate risk stratification, minimization for preformed or de novo DSA by proper use of immunosuppression. This article summarizes recent advances concerning the impact of preformed and de novo DSA in solid organ transplantation, with a focus on the clinical significance of DSA and available treatment modalities. Areas requiring further investigation are also identified.

Anticorps non-HLA et transplantation d’organe : une vision critique

In solid organ transplantation, the deleterious effect of antibodies directed against donor HLA antigens, whether preformed or de novo, is well established. Anti-HLA antibodies have been associated not only with the risk of antibody-mediated rejection but also with late graft dysfunction and are now considered to be the leading cause of allograft loss after renal transplantation. In addition to HLA antibodies, the possible involvement of non-HLA antibodies targeting donor endothelial cells has long been the subject of intense research. The purpose of this review is to discuss current knowledge and remaining issues related to the involvement of non-HLA antibodies in solid organ transplantation. More specifically, the clinical data underlying the hypothesis of the role of non-HLA antibodies will be discussed, as well as the different techniques for antibody detection, their clinical relevance and their antigenic targets.

Human Leukocyte Antigen Sensitization in Solid Organ Transplantation: A Primer on Terminology, Testing, and Clinical Significance for the Apheresis Practitioner.

The human leukocyte antigen (HLA) system is an important immunologic barrier that must be considered for successful solid organ transplantation. Formation of donor-specific HLA antibodies in solid organ transplantation is an important cause of allograft injury and may contribute to recipient morbidity and mortality. Therapeutic plasma exchange is often requested to lower HLA antibody levels prior to or after transplantation and for management of HLA antibodies in the context of organ rejection. In this review, we summarize the current terminology, laboratory testing, and clinical significance of HLA sensitization in the solid organ transplant population. Furthermore, to illustrate applications of HLA testing in clinical practice, we summarize our own lung and kidney institutional protocols for managing HLA antibodies in the peri-transplant setting.

Clinical and immunological relevance of antibodies in solid organ transplantation.

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.

Antibody-mediated rejection: analyzing the risk, proposing solutions.

Antibody-mediated rejection: analyzing the risk, proposing solutions.

Identification of Specific and Non-Specific HLA Class II Antibodies in Solid Organ Transplantation.

Identification of Specific and Non-Specific HLA Class II Antibodies in Solid Organ Transplantation.

Role of MICA antibodies in solid organ transplantation

As a potential transplant antigen, major histocompatibility complex class I chain-related gene A (MICA) antigen, has attracted increased attention because of its possible role in solid organ transplantation. There are two MICA forms, and MICA antibodies and soluble MICA (sMICA) have been found in the serum of transplant recipients. We searched MEDLINE, EMBASE, and the Cochrane Library for original reports of clinical studies involving the effect of MICA on outcomes of renal, heart, lung, and liver transplantation. In addition to the human leukocyte antigen antigens, which elicit a strong immune response, the polymorphic MICA antigens induce production of MICA antibodies and sMICA. A number of clinical studies have shown that MICA antibodies correlate with an increased incidence of rejection and a decreased allograft survival rate following renal or heart transplantation. Although it is clearly associated with chronic rejection of lung allografts, no such correlation was found for liver transplantation. Moreover, sMICA showed a negative association with acute rejection (AR) and may be a good predictor of heart transplant outcomes. These data suggest MICA expression patterns and regulatory function may be tissue specific and that different transplants have different organ-specific outcomes.

52-P: DE NOVO DEVELOPMENT OF DONOR SPECIFIC HLA ANTIBODIES IS STRONGLY ASSOCIATED WITH ANTIBODY MEDIATED REJECTION FOLLOWING LIVE DONOR RENAL TRANSPLANTATION

The harmful effects of preformed and de novo development of donor specific anti HLA antibodies in solid organ transplantation have been extensively reviewed and are found to be associated with allograft dysfunction. The spectrum of antibody mediated insult ranges from hyperacute rejection to chronic antibody mediated rejection (AMR) leading ultimately to graft loss. With the advent of solid phase assays, the sensitivity and specificity of antibody detection have increased. We studied 105 renal transplant recipients who had undergone live donor renal transplantation at this hospital. None of the recipients were sensitized. The recipients were longitudinally followed-up for a period of 60 months after transplantation. Serum samples collected serially at pre-transplant, at least one time during the post-transplant period and at the time of rejection were analyzed by the solid-phase immunoassay system on a Luminex 200 Platform using OneLambda SAB kits. Of the total patients, 79 did not show any evidence of AMR. The remaining 26 (24.7%) recipients had evidence of AMR as characterized by donor specific antibodies, histopathological changes and C4D staining on biopsy as per the Banff 2007 criteria. Luminex SAB analysis revealed that out of the 26 patients experiencing AMR, 80.7% had DSA compared to recipients who had no evidence of AMR (12.6%). The study highlights the relevance of de novo development of donor specific HLA antibodies with AMR in the renal allograft recipients.

Non-HLA antibodies in solid organ transplantation

Humoral responses beyond major histocompatibility antigens continue to receive the attention of the transplantation community. We report on clinical studies testing clinical relevance of non-human leukocyte antigen (HLA) antigens in solid organ transplantation and provide an update on novel experimental findings. A conceptual framework on the role of graft microenvironment during initiation of non-HLA-related humoral immunity is addressed as well. Clinical relevance of antibodies targeting angiotensin type 1 receptor (AT1R-Abs) is broadly confirmed in renal and cardiac transplantation, where in addition antibodies against endothelin type A receptor (ETAR-Abs) were found. Obliterative lesions in lung allografts occur more commonly in the presence of antibodies directed against K-α 1 tubulin and collagen-V. Anti-perlecan antibodies are newly identified as accelerators of obliterative vascular lesions. Changes in the intragraft microenvironment, ischemia and alloimmunity seem to represent important permissive factors for non-HLA antibody responses. Confirmed clinical relevance of non-HLA humoral responses in solid organ transplantation emphasizes the need for revision of classical diagnostic approaches based solely on detection of HLA-donor-specific antibodies (DSA). A better understanding of intersections of HLA- and non-HLA-related mechanisms and identification of common effector mechanisms would represent an important step towards targeted therapies.

Role of angiotensin II type 1 receptor-activating antibodies in solid organ transplantation

Angiotensin type I receptor (AT1R) mediates physiologic and pathophysiologic actions of its ligand, angiotensin II. Overactivity of the AT1R and angiotensin II interaction results in hypertension and vascular remodeling. Antibodies to AT1R have been implicated in several vascular pathologies. In renal transplantation, elevated levels of anti-AT1R antibodies have been associated with antibody mediated rejection (AMR) in the absence of donor HLA specific antibodies. In heart transplantation, increased levels of anti-AT1R antibodies have been associated with cellular and AMR as well as an early onset of microvasculopathy. This review summarizes the current investigations regarding the impact of anti-AT1R antibodies in solid organ transplantation and provides insight into the humoral response in the presence of non-HLA and HLA specific antibodies.

Consensus Guidelines on the Testing and Clinical Management Issues Associated With HLA and Non-HLA Antibodies in Transplantation

The introduction of solid-phase immunoassay (SPI) technology for the detection and characterization of human leukocyte antigen (HLA) antibodies in transplantation while providing greater sensitivity than was obtainable by complement-dependent lymphocytotoxicity (CDC) assays has resulted in a new paradigm with respect to the interpretation of donor-specific antibodies (DSA). Although the SPI assay performed on the Luminex instrument (hereafter referred to as the Luminex assay), in particular, has permitted the detection of antibodies not detectable by CDC, the clinical significance of these antibodies is incompletely understood. Nevertheless, the detection of these antibodies has led to changes in the clinical management of sensitized patients. In addition, SPI testing raises technical issues that require resolution and careful consideration when interpreting antibody results. With this background, The Transplantation Society convened a group of laboratory and clinical experts in the field of transplantation to prepare a consensus report and make recommendations on the use of this new technology based on both published evidence and expert opinion. Three working groups were formed to address (a) the technical issues with respect to the use of this technology, (b) the interpretation of pretransplantation antibody testing in the context of various clinical settings and organ transplant types (kidney, heart, lung, liver, pancreas, intestinal, and islet cells), and (c) the application of antibody testing in the posttransplantation setting. The three groups were established in November 2011 and convened for a "Consensus Conference on Antibodies in Transplantation" in Rome, Italy, in May 2012. The deliberations of the three groups meeting independently and then together are the bases for this report. A comprehensive list of recommendations was prepared by each group. A summary of the key recommendations follows. Technical Group: (a) SPI must be used for the detection of pretransplantation HLA antibodies in solid organ transplant recipients and, in particular, the use of the single-antigen bead assay to detect antibodies to HLA loci, such as Cw, DQA, DPA, and DPB, which are not readily detected by other methods. (b) The use of SPI for antibody detection should be supplemented with cell-based assays to examine the correlations between the two types of assays and to establish the likelihood of a positive crossmatch (XM). (c) There must be an awareness of the technical factors that can influence the results and their clinical interpretation when using the Luminex bead technology, such as variation in antigen density and the presence of denatured antigen on the beads. Pretransplantation Group: (a) Risk categories should be established based on the antibody and the XM results obtained. (b) DSA detected by CDC and a positive XM should be avoided due to their strong association with antibody-mediated rejection and graft loss. (c) A renal transplantation can be performed in the absence of a prospective XM if single-antigen bead screening for antibodies to all class I and II HLA loci is negative. This decision, however, needs to be taken in agreement with local clinical programs and the relevant regulatory bodies. (d) The presence of DSA HLA antibodies should be avoided in heart and lung transplantation and considered a risk factor for liver, intestinal, and islet cell transplantation. Posttransplantation Group: (a) High-risk patients (i.e., desensitized or DSA positive/XM negative) should be monitored by measurement of DSA and protocol biopsies in the first 3 months after transplantation. (b) Intermediate-risk patients (history of DSA but currently negative) should be monitored for DSA within the first month. If DSA is present, a biopsy should be performed. (c) Low-risk patients (nonsensitized first transplantation) should be screened for DSA at least once 3 to 12 months after transplantation. If DSA is detected, a biopsy should be performed. In all three categories, the recommendations for subsequent treatment are based on the biopsy results. A comprehensive list of recommendations is provided covering the technical and pretransplantation and posttransplantation monitoring of HLA antibodies in solid organ transplantation. The recommendations are intended to provide state-of-the-art guidance in the use and clinical application of recently developed methods for HLA antibody detection when used in conjunction with traditional methods.

Clinical importance of non-HLA antibodies in solid organ transplantation

Clinical importance of non-HLA antibodies in solid organ transplantation

Potential of Anti-Interleukin-2 Receptor Monoclonal Antibodies in Solid Organ Transplantation

Monoclonal and polyclonal antibody preparations have been used for induction therapy after organ transplantation. Apart from serious adverse effects directly associated with their administration, for example the cytokine release syndrome, the resulting profound and aspecific immunosuppression leads to increased incidences of infections and, in the long term, of malignancies. To avoid the drawbacks of this aselective immunosuppression, monoclonal antibodies (mAbs) against specific T cell activation determinants have been developed. In view of the pivotal role of interleukin-2 in the activation cascade of antigen-stimulated lymphocytes, mAbs directed against the interleukin-2 receptor (IL-2R) are believed to have a strong inhibitory effect only on activated T cells.

Future of monoclonal antibodies in solid organ transplantation

The ultimate objective of immunosuppressive therapy is to block transplant recipient reactivity to allograft incompatibilities while sparing other responses. Increased clarification of rejection mechanisms has made possible the precise suppression of specific elements of the immune response using murine anti-human monoclonal antibodies. In addition, recombinant DNA technology has made available novel agents including "humanized," bispecific, or toxin-conjugated molecules, which avoid some of the limitations of murine reagents. Using such agents, donor-specific tolerance has been induced in experimental models after a limited course of therapy directed against selected effector cell surface-associated molecules such as CD4, CD25, and CD54. It remains to be determined how such observations can be successfully transferred to the human situation. It seems likely, however, that as new molecular agents are developed, increasingly effective suppression of specific cellular targets will become an essential element of clinical protocols. Such agents may provide long-term immunosuppression with limited periods of immunosuppressive agent administration.