4. General discussion
4.1 Minor antigens in renal transplantation
Several years ago, a possible role of non-HLA immunity in allograft injury has been suggested after data from The Collaborative Transplant Study showed an unexpected negative effect of PRA on graft survival in HLA-identical sibling transplants (182). The effect of PRA was apparent only beyond one year post- transplantation and progressed slowly over time in that population in comparison with deceased donor patients who were subjected to earlier graft loss. A possible explanation was that antibodies to minor histocompatibility antigens occurred frequently with anti-HLA antibodies or cross-reacted with epitopes shared by HLA antibodies. However, the finding that a substantial proportion of sibling transplants failed even in the absence of any detectable antibody reactivity suggested that non-HLA immunity could contribute significantly to graft loss.
Antibodies to non-HLA antigens have been pointed out as likely to be involved in renal allograft rejection and graft loss throughout associative studies. The most abundant literature in that field undoubtedly relates to MICA antibodies followed by antibodies to AT1R and antibodies to vimentin or agrin. However, no experimental model was able to demonstrate at the present time a real pathogenicity of those antibodies, especially as a substantial proportion of them has been reported to be auto-antibodies and therefore, might be simple artefacts due to cross-reactivity with epitopes from infectious agents for example.
Since MICA had appeared in recent years as a non-HLA antigenic target in renal
transplantation, we decided to start a research in 2008 because little was actually
known in that field at that time, especially with regard to epidemiology, risk factors for sensitization and the autologuous or allogeneic nature of MICA antibodies. By a happy coincidence, we received support from a firm that aimed to market a new kit for identifying MICA antibodies by Luminex technology.
4.2 Epidemiology of MICA antibodies and risk factors for MICA sensitization Our work showed that MICA sensitization was 4-fold higher among CKD patients than in healthy volunteers. Unexpectedly, the prevalence of MICA antibodies was also found to be 2 fold higher among males as compared to females while we could identify pregnancy as an independent risk factor for MICA sensitization.
The origin of the influence of male gender on the presence of MICA antibodies has not been investigated yet but mechanisms controlling MICA expression might be related to sex. The other routes for MICA allo-immunisation were mainly those involved in HLA immunization: previous graft and blood transfusions. In addition, uremia “per se” also appeared as an independent risk factor for the development of MICA antibodies. Nevertheless, the presence of MICA antibodies among controls suggested that other possible routes for MICA sensitization might exist. A possible explanation might be cross-reactivity against epitopes shared by for example, both microbial agents and MICA antigens.
Since MICA is a cell-surface stress-inducible glycoprotein expressed on ECs, the high prevalence of MICA antibodies among CKD patients might be related to the
“chronic microinflammatory state” of such patients. This “microinflammatory
state” relates to an increased percentage of CD14+/CD16+ monocytes in
peripheral blood that promote endothelial injury through the release of pro-
inflammatory cytokines and to patient-related factors, such as underlying disease, comorbidity, oxidative stress, infectious, genetic and immunologic factors, as well as those arising from dialysis treatment itself, mainly membrane and dialysate biocompatibility (317). Indeed, chronically haemodialyzed patients were recently shown to exhibit a profound decrease in NKG2D bearing cells within both the CD8+ T cell and NK cell populations, and conversely, both increased membrane-bound MICA on monocytes and soluble MICA levels, possibly leading to the induction of MICA antibodies (318).
4.3 Impact of MICA antibodies on graft survival
Since 5 years approximately, several groups reported an association of MICA
antibodies with lower graft survival or rejection (290, 291, 300, 304). However,
those previous publications showed a crude univariate analysis of the
relationship between MICA antibodies and graft outcomes without investigating
the impact of possible confounding factors likely to influence graft loss. Until now,
no study in renal transplantation gave the formal proof of neither the
pathogenicity of such antibodies nor that those possibly deleterious antibodies
were DSA. Moreover, positive MICA reactivity had not been confirmed on MICA
expressing cell lines. Up to now, 2 studies tried to demonstrate the donor
specificity of MICA antibodies. The first was performed in heart transplant
recipients and it concluded to a lack of a deleterious impact of MICA antibodies
whether they were DSA or NDSA (294). The second aimed to address the effect
of MICA mismatching on the development of MICA antibodies but did not focus
on graft loss (306).
To date, how MICA antigens might be deleterious to the graft remains unclearly understood. Especially, the possibility that MICA and HLA antibodies could act in concert to allograft injury is not determined.
Unlike Zou’s and Terasaki’s studies, our findings showed a clear lack of effect of either pre- or post-transplant MICA antibodies on renal graft outcomes. This discrepancy might be explained by differences in immunosuppressive regimen given to patients. In our 2 studies, patients received a higher overall amount of immunosuppression, probably modulating the allo-immune response to the graft and therefore, benefiting graft outcome. Indeed, our patients received more frequently tacrolimus and MPA as maintenance therapy rather than cyclosporine and azathioprine in Zou’s and Terasaki’s reports. Likewise, induction therapy was also more prevalent among our patients. Moreover, authors do not give information about the possible discontinuation of the corticoids therapy in the post-transplant setting. In our cohort, 70% of patients still had corticoids at 1y post-transplantation. No data about the incidence, the severity of AR and recovery of renal graft function were reported in Zou’s and Terasaki’s studies while they may affect the graft survival (319).
4.4 How to provide evidence of a possible pathogenicity of MICA antibodies towards the renal graft?
Undoubtedly, to design a study enable to answer to the question whether MICA
antibodies are pathogenic will face the difficulty to clearly isolate the effect of
MICA antibodies on graft outcome as MICA and HLA sensitization are closely
linked. This link has been reflected in all the previous publications related on
MICA (see annexes). As reported in our second article, preliminary statistical calculations were performed in order to determine the sample size needed to detect a difference of death-censored graft survival of at least 5% 3 years after MICA testing considering a prevalence of MICA antibodies of about 10%, as showed by Terasaki (291). These analyses revealed that to avoid the possible confounding impact of anti-HLA antibodies on survival, at least 3500 patients should have been included to reach ± 170 patients who were HLA-/MICA+.
However, the prevalence of post-transplant MICA antibodies reached about 5%
in our cohort making it should have required 7000 patients to test our hypothesis.
Therefore, we considered such a study unrealistic because it would have involved huge logistics and financial support.
To design an animal model would also not be devoid of some pitfalls. A major one would be that mice lack MICA expression. Nevertheless, some might imagine creating a transgenic mice model since the coding regions for the human MICA gene are known and could be cloned. Kidneys from transgenic mice could be transplanted in wild type mice previously immunized with recombinant MICA antigens and parameters such as albuminuria/creatininuria ratio in daily urine samples could be screened until sacrifice.
Another mean, but expensive, to study the relationship between MICA antibodies
and graft failure could be the use of a non-human primate model. For example,
monkey donor and recipient pairs should be selected for ABO and HLA
compatibility but MICA mismatching. Recipients should be submitted to
chimerism protocols such as nonlethal total body irradiation, local thymic
irradiation followed by the infusion of ATG and intravenous donor bone marrow transplantation before heterotopic renal transplantation and bilateral native binephrectomy. For example, cyclosprorine administered at day 0 would be progressively tapered to finally be discontinued. Serum samples would be tested for anti-donor MICA antibodies, anti-HLA antibodies and creatinine. Renal graft biopsies would be performed at regular intervals when creatinine is stable and in addition, when creatinine is rising. We might follow the development of MICA antibodies in monkeys that remained negative for anti-HLA antibodies and the appearance of allograft injury.
Just imagine money is not an obstacle and we have huge logistic means such as a large staff and platforms dedicated to research and highly sophisticated equipment, we could set up a prospective study through a large collaborative network that would allow for the recruitment of a huge amount of patients with available clinical and histological data. Patients should be donor HLA full- matched and mismatched for MICA with no pre-transplant HLA or MICA antibodies detected by single antigen flow beads assays. They should receive a standardized induction and immunosuppressive therapy with clear protocols for reduction of immunosuppression, especially in cases of infection or cancer.
Patients should undergo routine blood tests every 3 months to assess HLA and
MICA status and renal graft biopsies at Day 0, Month 3, Month 6 and yearly
thereafter, until 10 yr post-transplantation. Only the patients who never
developed HLA antibodies would be kept for analysis. Sera positive for MICA
antibodies should be controlled for cytotoxicity on cell lines expressing a single MICA antigen.
To increase the level of evidence for the pathogenicity of MICA antibodies, the following criteria should be present:
i) Good function over time should be associated with patients who do not develop MICA antibodies
ii) The appearance of MICA antibodies should precede immune-mediated graft injury
iii) MICA antibodies should be confirmed as the strongest independent risk factor for immunological graft loss in an appropriate logistic regression model
iv) MICA+ patients whose graft failed from immune-mediated injury compared with MICA+ patients who lost their graft from a non-immunological cause or kept a functioning graft should be confirmed to be DSA
v) MICA+ patients whose graft failed from immune-mediated injury compared with MICA+ patients who lost their graft from a non-immunological cause or kept a functioning graft should have high MICA antibodies titers (dose response effect)
vi) MICA+ patients whose graft failed from immune-mediated injury compared with MICA+ patients who lost their graft from a non-immunological cause should have intra-graft MICA antibodies
The ultimate evidence of the pathogenicity of MICA antibodies should be the
demonstration that eliminating de novo antibodies would result in long-term
survival.
In addition, we may assume that probably MICA antibodies do not act alone but rather exert their effect in concert with antibodies to other minor antigens unexplored so far.
Therefore, another way that should be explored to better understand the possible pathogenic effect of MICA antibodies should be the use of proteogenomics. This approach combines proteomics and genomics. Proteomics is the systematic analysis by chromatography and mass spectrometry of all proteins encoded by the genome in any defined biologic compartment and genomics involves microarrays, which determines gene expression profile (mRNA transcripts) correlated to a corresponding level of protein or other available genomic techniques evolved in recent years such as SNP arrays detecting SNPs of human genome, alterations in gene copy number or alternative RNA splicing.
The proteomic approach has already been used to screen non-HLA antibody response in patients undergoing chronic haemodialysis and awaiting a kidney transplant, to identify compartment-specific non-HLA targets after renal transplantation and recently, to predict the development of chronic allograft injury (320, 321).
The proteogenomic approach might be used in order to better understand the
possible role of minor antigens in rejection. A large multi-centre study could be
set up to compare patterns of proteins and antibodies in both serum and graft
between patients with histological features of humoral AR or CR and patients
with normal biopsy. In the event that a specific pattern emerged, it should be
firstly confirmed in a validation sample set and the second step would be to
identify polymorphisms or aberrations in the genes that encode the selected proteins or alterations in the translation of RNA transcripts. However, the study design would require that patients are matched for donor and recipient demographic characteristics and immunosuppression. Such studies would be very expensive and time consuming requiring high throughput technology and advanced bioinformatics analyses for an uncertain expected benefit.
Until now, proteomics has been used in small patient cohort size with most of the time, the lack of data validation from an independent patient sample set.
Moreover, none of candidate biomarkers identified by proteomics has emerged so far as a reliable clinical tool for the diagnosis of AR or CR (322-324). This seems to be related to the inconsistency in sample handling, and the lack of standardization of experimental design leading to the identification of different discriminatory proteins by different groups. Current proteomic studies suggest that a single biomarker does not provide sufficient specificity to distinguish between diseased and healthy status. Therefore, robust study design with appropriate statistical power, blinding and validation set is crucial to improve the reliability of proteogenomic-driven results, making possible the identification of a panel of candidate markers that will form a signature pattern with sufficient diagnostic performance and good predictive value.
Although our findings suggest that MICA antibodies do not affect renal graft
outcomes, we cannot exclude that high titer and/or cytotoxic MICA antibodies
might be deleterious in rare patients.
Therefore, the question is whether it would be reasonable to incur significant financial and human resources to resolve an issue that concerns finally a low number of patients for an uncertain expected benefit.
Of interest, it is also unclear how long MICA antibodies persist over time.
Terasaki and colleagues reported that the frequency of post-transplant MICA antibodies was stable along with time (291). However, nearly two thirds of patients who were sensitized against MICA before transplantation had no more MICA antibodies at 1yr post-transplantation in our cohort (data not shown). This might suggest that MICA antibodies could be absorbed by the graft or MICA sensitization might be a fluctuating phenomenon. Likewise, in our paper dealing with the safety of Influenza A/H1N1 vaccine, MICA antibodies were seen to disappear one month after a positive screening in several kidney transplant patients and in one haemodialysis patient, advocating for the transitory nature of these antibodies. We strongly believe that MICA immunisation is highly influenced by environmental stress and also that immunosuppression modulates the development of MICA antibodies.
4.5 Influenza A/H1N1 vaccination and MICA sensitization
Our research showed that Influenza A/H1N1-adjuvanted vaccine did not trigger either an increased production of anti-HLA or MICA antibodies nor induced AR or a deterioration of renal graft function up to 6 months after vaccination.
Possible MICA sensitization after Influenza A/H1N1 vaccination has also been
recently addressed in cystic fibrosis patients and in lung transplant recipients in
our institution. Analysis of the data confirmed that again transplanted patients
reached lower antibody titres against Influenza A/H1N and had an inferior seroconversion rate compared with cystic fibrosis patients and controls.
Only one lung transplant recipient developed de novo HLA antibodies. No patient produced de novo MICA antibodies or experienced accelerated graft loss.
5. Summary
MICA antibodies are not rare in renal transplantation. Their prevalence is reaching 14% in stage V CKD patients and falls to 5% 1 year after transplantation, possibly due to the modulation of antibody production by immunosuppression.
In the present work, we identified uremia, previous graft, blood transfusion and pregnancy as independent risk factors for MICA allo-sensitization. However, up to 20% of MICA antibodies may also be auto-antibodies, possibly because of cross-reactivity against epitopes shared by both microbial agents and MICA antigens.
Either MICA antibodies had been detected before or after transplantation, our findings suggest a lack of meaningful clinical relevance in renal transplantation.
Rather than pathogenic, MICA antibodies might be simply stress-induced
surrogate markers of high immunological risk, making interest for pre-transplant
screening or post-transplant monitoring by current flow beads assays highly
questionable.
6. Perspectives
The big challenge of renal transplantation is to identify and to validate new pre- and post-transplant biomarkers using patient serum, urines or DNA in order to facilitate personalized transplantation medicine and customization of immunosuppression.
Indeed, the better risk assessment of graft loss in kidney transplant recipients might allow for tailored immunosuppression. This strategy might decrease the risk of AR or CR in patients labelled “at high risk” on the one hand and to avoid immunosuppression-related complications such as renal toxicity, infections and cancers in low risk patients on the other hand. Moreover, the identification of biomarkers might aid the understanding of underlying mechanisms by indicating damage early after transplantation when pathological changes are taking place at the molecular level. This will enable physicians to better predict the likelihood of an individual’s allograft survival and to assist the development of new target drugs. Finally, biomarkers might also allow better matching of donor and recipient and the assessment of an individual’s risk for graft injury. Indeed, while current methods for diagnosing allograft injury require invasive allograft biopsies and detect pathological changes at advanced and often irreversible stages of allograft damage, the use of more sensitive and specific methodologies based on recipient and donor genotyping or transcriptional and proteomic profiling might bridge this gap.
Nowadays, the ongoing biomarker studies increasingly integrate data from
multiple platforms, such as genotype analyses of single nucleotide
polymorphisms, epigenetic studies and analyses of mRNA, miRNA, as well as protein, peptide, antibody and metabolite profiling.
However, the path from discovery and validation of a biomarker towards its approval by clinicians is tortuous. Indeed, the phase of discovery and validation requires high-throughput technologies on multiple molecular platforms and thus, large cohort, large infrastructure, huge logistics means and financial support.
Moreover, replication cohorts are often needed to increase the sensitivity and specificity of the biomarker. Quality control tools have also to be implemented to ensure the comparability of data from different laboratories. Another important step towards confirming the clinic usefulness of a biomarker is to identify and control for experimental confounders including technology bias or patient bias.
At the present time, there is still a long way to go before the identification of biomarkers with high specificity for a defined “disease status” and good predictive value for diagnosis enabling clinicians safely to tailor immunosuppression.
Therefore, it looks that promoting translational research in transplantation units
should be a central concern for clinicians not only to address this issue but also
simply to have a feedback on their own daily practice and to ensure high quality
patient care.
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