Has the Time Come for Widespread MHC Class I MICA Genotyping in Solid Organ Transplantation? : Transplantation

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Has the Time Come for Widespread MHC Class I MICA Genotyping in Solid Organ Transplantation?

Schinstock, Carrie A. MD1; Valenzuela, Nicole M. PhD2

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Transplantation 106(12):p 2269-2270, December 2022. | DOI: 10.1097/TP.0000000000004338
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Extending long-term allograft survival has been an elusive goal in all solid organ transplantation. Although the causes of allograft loss are varied, antibody-mediated rejection (AMR) remains a significant contributor to late allograft loss despite advances in HLA testing. A subset of kidney transplant recipients has undetectable HLA donor-specific antibodies (DSA) yet has histologic and even molecular features consistent with AMR. A lack of clarity exists on how to classify these patients while long-term effects are largely unknown. A broad panel of antibodies toward multiple endothelial and nonendothelial antigen targets have been associated with allograft dysfunction and injury. In clinical practice, these antibodies are often not measured and rarely found. Complicating this issue, a debate exists about whether detectable non-HLA antibodies are the cause of antibody-mediated injury or only innocent bystanders. To date, one of the most extensively investigated nonclassical HLA targets is the major histocompatibility complex (MHC) class I chain-related gene A (MICA).1,2 Recently published data substantiated the relevance of this antigenic target, renewing the need to look beyond classical HLA to understand AMR.3

Among a retrospective multicenter French cohort of 1356 kidney transplant recipients with a median follow-up of 6.3 y who had MICA and HLA genotyping, mismatching at MICA was independently associated with inferior allograft survival with an HR 2.12, P < 0.001.3 Five-year allograft survival was 96% in the MICA genotype matched patients compared with 88% among the MICA mismatched cohort.3 Other independent factors associated with reduced allograft survival included age of donor and recipient, duration of dialysis, end-stage renal disease caused by nephropathy likely to recur, absence of induction treatment, depleting induction, and HLA-DQ beta 1 mismatch. In this comprehensive study, a subset of patients also had testing for anti-MICA and HLA DSAs. Donor-specific MICA antibodies identified either pretransplant or posttransplant were strongly associated with AMR (HR 3.79, P < 0.001), and the effect appeared to add to the risk of HLA DSA.3 The hazard ratio for AMR among patients with both MICA and HLA preformed DSA was 25.68, P = 0.002.3 The association between MICA antibody and allograft survival was confirmed in an independent validation cohort of 168 patients with biopsy-proven AMR. In the validation cohort, patients with anti-MICA DSA detected at the time of AMR were at higher risk for graft failure. Like the initial cohort, patients with both anti-MICA and HLA DSA had the lowest allograft survival.

This large retrospective multicenter trial validates multiple previous studies4 but also provides important clarity about the role of MICA independent of HLA. The retrospective, sequence-based genotyping of recipients and donors for MICA was a major accomplishment and has been lacking from prior studies. This additional and critical step allowed the authors to determine the donor specificity of the MICA antibodies. Most prior studies only evaluated the presence or absence of antibodies, and donor specificity was unknown. These findings are particularly relevant in the era of sensitive donor-specific HLA antibody testing and a renewed interest in the role of HLA whole antigen and eplet matching strategies intended to improve long-term allograft survival. Adding MICA genotyping and DSA testing pretransplant and posttransplant could enhance our ability to predict rejection and personalize immunosuppression. The relevance of the findings extends beyond renal transplant as prior studies have also suggested the role of MICA in heart,5 liver, and lung6 rejection.

To understand how MICA can independently result in rejection, it is worthwhile to understand how it differs from classical HLA. Like classical HLA, the MICA gene is part of the MHC class I complex located on chromosome.6 In contrast to classical HLA, the polymorphic MICA molecule is not involved in antigenic peptide presentation and has limited tissue distribution.7 MICA antigens are expressed conditionally on epithelial cells in the gastrointestinal tract, endothelial cells, fibroblasts, monocytes, keratinocytes, and dendritic cells.8 Importantly, MICA is not expressed on resting T or B lymphocytes or upregulated by interferon-gamma. Therefore, traditional T- and B-cell crossmatching does not help with detection.8 MICA molecules play a key role in connecting innate and adaptive immune responses because they activate a C-type lectin-like natural killer (NK) group 2, member D (NKG2D) receptor that is present on NK cells, γδ T cells, and CD8+ αβ T cells.7 The interaction between MICA and the NKG2D receptor leads to antigen-specific cytotoxic T lymphocyte-mediated cytotoxicity, NK cell responses, and cytokine production. Importantly, a major dimorphism exists for MICA alleles (MICA-129) that strongly influences this interaction, and alleles can be classified into one of these two functional groups.8

The authors of the recent study conclude that assessment of MICA matching and antibody detection is warranted to identify patients at elevated risk for rejection. We agree that the findings are valuable and undoubtedly contribute to our understanding of transplant rejection, but widespread MICA genotyping and DSA testing may not be ready for prime time. Several drawbacks warrant additional studies to further bolster the clinical validity and utility of MICA genotyping and antibody testing.

First, assay standardization, validation, and appropriate assignment of antibody positivity are key issues to resolve. Notably, the MFI cutoffs to define positivity for HLA and MICA antibodies, respectively, were very low at 500 and 100 MFI in this study. In fact, the positive cutoff of 500 MFI to define HLA antibody positivity is much lower than typically used or recommended and could have affected the results of this study.9 Furthermore, recipient and donor racial and ethnic breakdowns were not provided. Because of the preponderance of extended haplotypes and MICA alleles combined with differences across individuals with disparate backgrounds, a follow-up validation study in a diverse cohort is needed.

After addressing the laboratory issues, the community needs to understand when MICA should be obtained and how to interpret the results. Currently, MICA antibody testing is infrequently utilized by only a few transplant centers in select circumstances when searching to explain histological features suggestive of AMR when classical HLA antibody is not present. Widespread MICA genotyping and DSA testing would certainly help to further clarify the role of MICA in transplantation, but unintended consequences must be considered. Reducing access to transplantation by overestimating the risk of MICA mismatch and DSA without further data would be inappropriate. The causes of allograft failure are multifactorial, and DSA is only one of the multiple factors to consider.

In conclusion, the evidence is building that the MICA antigen should no longer be ignored in solid organ transplantation. MICA genotype mismatching is associated with reduced kidney allograft survival independent of HLA matching, and future pretransplant workup will likely include MICA genotyping. At the same time, there is, more than ever, a need to standardize, validate, and optimize MICA DSA testing.

Thus, it will need to be determined how to use the information by Carapoito and coworkers with the question remaining of how to incorporate the data provided into practice to improve long-term patient outcomes.


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