After the early years of transplantation, with the availability of crossmatch testing, antibody-mediated graft injury was not considered to be an important issue in kidney transplantation, and T-cell-mediated rejection (TCMR) became the center of attention . With the availability of cyclosporine and later tacrolimus and mycophenolate mofetil the rate of TCMR significantly dropped and early graft outcomes considerably improved, with 1-year graft survival surpassing 90–95%. More than two decades ago, the role of the anti-human leukocyte antigen (HLA) antibody response and the resulting pattern of graft injury was reintroduced by Halloran et al.[2,3]. Shortly thereafter Bohmig et al. developed the C4d staining in kidney biopsies that became a unique marker of alloantibody-induced tissue injury. During the subsequent 2 decades we have witnessed an acceleration of research on the mechanisms, recognition, and treatment of antibody-mediated rejection (AMR).
HLA antigens are the primary targets for the recognition and development of donor-specific antibodies (DSA). We have come a long way from cell-based assays to solid phase assays with higher sensitivity and specificity for detection of DSA. Moving from ELISA to flow cytometry and Luminex technology using single antigen beads (SAB) has increased our ability to identify HLA DSA with high sensitivity and specificity. The detection of HLA DSA before or after kidney transplantation is associated with a higher risk of AMR and graft failure [5–7]. However, detection of DSA does not always predict AMR or poor graft outcome . Differentiating the pathogenic DSA from others, and understanding the factors modulating the effect of antibody on the graft, requires further investigation.
With better understanding of the mechanisms of antibody-mediated graft injury, the histological criteria for the diagnosis of AMR have evolved. It has become clear that the endothelial cells in renal microvasculature are the main targets of the antibody-induced injury, evidenced by peritubular capillaritis and glomerulitis. The use of electron microscopy has revealed the early ultrastructural changes in the glomerular or peritubular capillary (PTC) endothelial cells, thus making earlier diagnosis of AMR possible.
The treatment of AMR as the major cause of late graft failure has not significantly changed over the years. Plasma exchange and IVIg still remain the mainstay of therapy. Use of rituximab, bortezomib, and eculizumab have not significantly improved long-term outcome . Unfortunately, there is no effective treatment for chronic AMR and efforts to identify one have been very limited.
In this article, we will review the recent developments in the AMR research related to its pathogenesis and diagnosis, and discuss the newer therapeutic options that may prove to be well tolerated and effective.
DONOR-SPECIFIC ANTIBODIES INTERPRETATION
As previously noted, several studies have shown that preformed or de-novo DSA formation is associated with a higher risk of AMR and worse graft function and survival [6,10]. However, it is not clear whether the DSA detected by SAB assays [particularly with a low mean fluorescence intensity (MFI)] represents true donor-directed anti-HLA antibodies, and, if so, it is not possible to predict which DSA specificity will cause graft injury and which ones can be simply watched. Here we will review some of the recent studies that help differentiating between the two.
The HLA molecules attached to solid phase beads are not in their native environment and can be denatured during the tagging process. For class I HLA antigens, β2-microglobulin can dissociate from the α-chain that carries the polymorphic residues, causing conformational changes in the molecule and its epitope composition. The binding of HLA antigens to beads can also induce a change in their tertiary structure, leading to the failure in recognizing the presence of anti-HLA antibodies [11▪]. Antidenatured (d) HLA antibody is found in 39% of sensitized kidney transplant candidates with class I HLA antibody, with a low probability of causing crossmatch positivity [12,13▪]. AntidHLA DSA was generally of low-MFI (500–1000) and not associated with AMR during the first year or the 5-year graft survival . Furthermore, some antidHLA antibodies bind native (n) HLA on lymphocytes and some antinHLAs bind to denatured epitopes . Not differentiating between these two types of antibodies could limit the number of acceptable HLA mismatched organs using the virtual crossmatch.
After the initial report by Yabu et al., Loupy et al. observed that complement binding DSA, assessed by C1q-Luminex assay, was associated with a 4.78 fold adjusted increase in the risk of graft loss (over 5 years compared with those with no DSA or with noncomplement binding DSA) and an increased risk of AMR with a more severe histological injury pattern. C1q-binding de-novo DSA at 2 years has been associated with a worse 5-year graft failure risk compared with DSA-negative or C1q-nonbinding DSA. However, the latter predicted higher failure rate at 10 years compared with non-DSA . Interestingly in this study, no class I de-novo DSA was C1q+, and an MFI threshold of 6237 was predictive of C1q+ de-novo DSA. Examining patients with renal graft failure, C1q+ HLA antibody (DSA or non-DSA) was present in 43% and none of the matched controls . Yell et al.[20▪] reported an association between C1q+ DSA with risk of AMR (53% with AMR and 13% among no-AMR). However, there was a correlation between the presence of C1q+ DSA and DSA MFI, with higher sensitivity for the prediction of AMR for DSA with an MFI of more than 7000 (74%) versus C1q+ DSA (53%), albeit with lower specificity (73 versus 87%). Moreover, there was no difference between C1q+ and C1q- DSA regarding the relative abundance of complement-fixing IgG isotypes.
In a cohort of kidney transplant recipients who received alemtuzumab induction and maintained on tacrolimus monotherapy, 19% had C4-binding DSA with AMR among 70%, as compared with 19% in the C4d- DSA group . Sicard et al.[22▪] studied patients who experienced AMR and found that C3d-binding DSA was an independent predictor of graft loss, with a higher sensitivity and specificity compared with C1q-binding DSA. Although, the C3d-binding capacity significantly correlated with the number and MFI of DSA, even with a low MFI (<3500) C3d+ DSA was associated with a worse graft survival.
Kannabhiran et al. reported that the sum of all DSA MFIs more than 6000 and the presence of both class I and class II DSA were independent predictors of one-year AMR. Malheiro et al. reported that among patients with preformed DSA, only an MFI of more than 3000 was associated with AMR [an MFI > 4900 in the highest DSA bead had a high sensitivity (85.7%) and sum of MFIs > 11000 had a high specificity (94.9%) for predicting AMR].
The HLA molecule density on a SAB is high, therefore C1q binding to IgG HLA antibodies on a SAB depends on the density of bound antibodies and their IgG subclass. The density of bound antibodies in turn is related to their amount, avidity, and specificity . In a study by Schaub et al. 36% of the samples were positive using IgGpan assay (detecting all subtypes of IgG), 22% of them were C1q binding with MFI of more than 500. Only 5% of the samples consisted of isolated weak or no complement binding antibodies (IgG2/IgG4). They observed a strong association between C1q binding capacity and IgGpan MFI (r2 = 0.74), with a lower threshold for class I than class II DSA for predicting C1q positivity. IgGpan MFI was the strongest independent predictor of C1q binding capacity [odds ratio (OR): 9.96; P < 0.0001], better than IgG1 (OR: 5.52; P = 0.0001), and IgG3 MFI (OR: 2.64; P = 0.004). Interestingly, 93% of the C1q- antibodies contained IgG1 and IgG3 subclasses.
It is important to point out that the deposition of complement activation products (C1q, C4, or C3) on the SAB can cause steric interference with the binding of the secondary anti-IgG antibody, hence causing a false-negative DSA assay (prozone effect) . Schwaiger et al. reported prozone effect in 11% of the samples in sera from HLA class I sensitized transplant candidates, and demonstrated that this was due to deposition of the C1q, C3, or C4 split products on the beads.
A review of these studies suggests that using modified SAB assays, looking for C1q, C4d, or C3d binding capacity of DSA may be helpful in some but not all patients with DSA. It seems that the complement component binding capacity of DSA correlates with the MFI value of the standard SAB assay; therefore may not provide an additional predictive value in the majority of the cases. Currently, considering the cost-effectiveness of these newer assays, their universal use cannot be justified or recommended. It is of note that the difficulty of attributing prognostic value to the DSA detected by SAB assay is to some extent related to a lack of standardized interpretation due to variation in the density of antigens on the beads, threshold of MFI value used for detection of DSA and nonnative conformation of HLA molecules on the beads.
MOLECULAR METHODS IN ANTIBODY-MEDIATED REJECTION DIAGNOSIS
The histological diagnostic criteria for AMR have evolved over the years. It has become clear that microvascular inflammation is the main feature and PTC C4d deposition is no longer a requirement for the diagnosis . However, AMR is a more complex process than that defined by our standard criteria, and quite often the biopsy does not portray the full classical features of AMR in the setting of a detectable DSA and compatible clinical picture. Therefore, different investigators have tried to develop more sensitive and specific tests, to at least supplement the standard histologic features. The University of Alberta group has attempted to validate the use of gene expression profiling in biopsy specimens to diagnose different histological entities including AMR . Although identifying gene sets that are either upregulated or downregulated in the presence of AMR may increase the sensitivity or specificity of detecting the disease process, it is still not ready to be used as the diagnostic gold standard.
Venner et al., using pattern of AMR-selective transcripts, proposed a model involving injury-repair in the endothelium, angiogenesis, and natural killer (NK) cell-mediated cytotoxicity resulting from engagement of CD16α Fc receptor and release of interferon (INF)γ. Sellares et al. showed that using this microarray-based method, the previously defined AMR Molecular Score and endothelial DSA-selective transcripts  were independently predictive of graft loss in patients who experienced AMR during the first-year posttransplant, and adding them to traditional-risk models, including histologic features (g + ptc + cg + v + C4d), improved prediction of graft loss . More recently, Halloran et al.[34▪] studied 703 for cause biopsies and observed that molecular assessment strongly agreed with conventional diagnosis, with 91% accuracy for TCMR and 83% for AMR, with incremental increase in AMR score predictive of stepwise increase in risk of graft failure. Adding AMR scores to conventional assessment enhanced the 3-year graft survival prediction by 23% (confidence interval: 10–36%, P < 0.001). Beyond 10.2 years posttransplant AMR activity was frequent but no TCMR activity was detected. They concluded that in late biopsies the majority of conventionally diagnosed mixed rejections may be incorrect, as tubulitis and arteritis can also be seen with pure AMR.
Xu-Dubois et al.[35▪] reported increased expression of the markers of endothelial-to-mesenchymal transition (EndMT), including fascin1, vimentin, and heat shock protein 47 in glomerular and PTC endothelial cells in 53 renal biopsy specimens with AMR. EndMT markers were more specific than capillaritis for diagnosis of AMR and the best independent predictor of poor graft function at 4 years, in addition, they were able to detect AMR at an early stage. In a validation set these markers had a sensitivity of 100% and specificity of 85% for AMR diagnosis.
Kamal et al.[36▪] studied 52 patients with transplant glomerulopathy. Although clinical and histological features, including microcirculation inflammation and PTC C4d scores, were similar between patients who lost their grafts (n = 17) and those with functioning grafts, microarray analysis showed upregulation of 86 genes in the former group, including endothelial cell-associated transcripts, gene transcripts associated with complement cascade, interleukins, and their receptors and granulysin.
Urinary chemokine CXCL10 has a significant correlation with microvascular inflammation, and an independent association with graft loss and PTC score . Urinary CXCL10 to creatinine ratio, when used in combination with immunodominant DSA improved the prediction of AMR.
Examination of the RNA profiles of peripheral mononuclear cells in patients with chronic AMR, has shown upregulated genes involved in type I interferon signaling and a decrease in circulating BDCA2+ dendritic cells that produce type I interferon, and their recruitment into the graft . Dominy et al.[39▪] used quantitative real time PCR to assess the expression of 11 genes previously reported as elevated in AMR and found that NK cell markers were associated with microcirculatory inflammation and graft survival to a greater extent than endothelial-cell markers. Furthermore, the expression of two genes, SH2D1b and MYBL1, correlated with microvascular inflammation score and, in predictive modeling, these genes provided 66.7% sensitivity and 89.7% specificity for graft loss.
The ongoing research on the ‘molecular microscope’ and on circulating or urinary biomarkers is very exciting, provides a great insight into the mechanisms of injury in AMR and offers tools to improve the diagnostic and prognostic value of the standard histological variables.
TREATMENT OF ANTIBODY-MEDIATED REJECTION
C1 esterase inhibitor is a serine protease inhibitor of complement activation through both classic and lectin pathways, in addition to major effects on the activation of the coagulation cascade and the regulation of vascular permeability and inflammation. It was initially shown in a nonhuman primate model to be effective in preventing AMR in presensitized recipients . Recently Vo et al.[41▪▪] reported the results of a trial of C1-inhibitor in 20 HLA-sensitized patients who had received desensitization therapy with IVIg, rituximab ± plasma exchange. The patients were randomized to receive human C1 inhibitor intraoperatively and seven doses posttransplant versus placebo. During the 6-month study period none in the former group and two in the placebo group experienced AMR. However, after 6 months two in each group had AMR episodes. In five patients in the treatment group with C1q+ DSA pretransplant, the antibodies were undetectable or reduced after treatment. Montgomery et al. enrolled 18 patients with AMR to receive human C1 inhibitor or placebo. Seventy eight percent of the patients in the treatment group versus 44% in the placebo group had histologic resolution of the rejection. Follow-up biopsies showed transplant glomerulopathy in zero of seven and three of seven, respectively.
Interleukin-6 (IL-6) is an important cytokine with an assortment of effects on the immune response and plays a key role in the survival of long-lived plasma cells in specialized niches in the bone morrow . With the central role of plasma cells in producing DSA, the IL-6 pathway seems to be a potential therapeutic target. Tocilizumab is a humanized IL-6 receptor-inhibiting monoclonal antibody that has been approved for use in rheumatoid arthritis. Vo et al.[44▪▪] reported the results of a phase I/II trial of Tocilizumab and IVIg in 10-sensitized patients who did not respond to desensitization with IVIg and rituximab. Five patients could undergo transplantation 8.1 ± 5.4 months after starting treatment, with significantly reduced or undetectable DSA. There were no AMR cases during the first 6 months while they received monthly tocilizumab. Despite four serious adverse events, the drug use seemed to be well tolerated overall.
Anti-C1 s monoclonal antibody, TNT003, inhibits the deposition of HLA-antibody-mediated complement activation products on cultured human aortic endothelial cells and reduces production of anaphylatoxins, C3a, C4a, and C5a in a concentration-dependent manner . Furthermore, TNT003 was able to block the deposition of C3d on SAB, using anti-HLA antibodies. In a rat kidney transplant model, ixazomib, a proteasome inhibitor, with decreased dose Cyclosporine reduced DSA along with microcirculatory inflammation, PTC C4d deposition, splenic plasma cells, and intragraft transcription of chemokines, HLA class II, and Toll-like receptors, and was effective in reducing the risk of AMR . Using a mouse AMR model it was shown that the use of anti-CD20 monoclonal antibody was effective in prolonging graft survival with low DSA when started prior to transplantation .
Finally, the use of atacicept, a monoclonal antibody targeting B-cell activation/survival factor, in a nonhuman primate AMR model antibody was associated with decreased DSA levels, peripheral B cells, and histological features of AMR . However, the graft survival was just marginally increased (P = 0.11), and there was more TCMR findings in the biopsies.
With the suboptimal therapeutic options that are currently available for the treatment of AMR, the current studies are very encouraging. Targeting complement components, B lymphocytes or plasma cells is expected to be helpful. However, with the complexity of the immune system and the mechanisms of injury, aiming at single targets for treatment is doomed to fail. We need novel approaches that combine multiple pathogenic pathways using effective and well tolerated agents to halt the injury, particularly with chronic AMR.
AMR has been shown to be the major cause of late graft failure. Over the past two decades, we have made great progress in recognizing the patterns of injury and learning about the mechanisms of this process. However, therapeutic options are limited and the results are not encouraging. Advances in the application of molecular methods in recent years have shed light on potential pathways of injury and have shown promise in improving the diagnosis of AMR. Extension of SAB methodology shows some hope in improving the predictive value of DSA detection before or after transplantation. Currently, there are a number of potentially well tolerated and effective therapeutic agents targeting different players in the injury pathways that need to be tested in randomized controlled trials.
The author would like to thank Ms. Tia Paul for her invaluable secretarial assistance.
Financial support and sponsorship
Supported by the Division of Nephrology, University of Maryland school of Medicine funds.
Conflicts of interest
There are no conflicts of interest.
REFERENCES AND RECOMMENDED READING
Papers of particular interest, published within the annual period of review, have been highlighted as:
- ▪ of special interest
- ▪▪ of outstanding interest
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