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The MHC class I MICA gene is a histocompatibility antigen in kidney transplantation.

ABSTRACT: The identity of histocompatibility loci, besides human leukocyte antigen (HLA), remains elusive. The major histocompatibility complex (MHC) class I MICA gene is a candidate histocompatibility locus. Here, we investigate its role in a French multicenter cohort of 1,356 kidney transplants. MICA mismatches were associated with decreased graft survival (hazard ratio (HR), 2.12; 95% confidence interval (CI): 1.45-3.11; P < 0.001). Both before and after transplantation anti-MICA donor-specific antibodies (DSA) were strongly associated with increased antibody-mediated rejection (ABMR) (HR, 3.79; 95% CI: 1.94-7.39; P < 0.001; HR, 9.92; 95% CI: 7.43-13.20; P < 0.001, respectively). This effect was synergetic with that of anti-HLA DSA before and after transplantation (HR, 25.68; 95% CI: 3.31-199.41; P = 0.002; HR, 82.67; 95% CI: 33.67-202.97; P < 0.001, respectively). De novo-developed anti-MICA DSA were the most harmful because they were also associated with reduced graft survival (HR, 1.29; 95% CI: 1.05-1.58; P = 0.014). Finally, the damaging effect of anti-MICA DSA on graft survival was confirmed in an independent cohort of 168 patients with ABMR (HR, 1.71; 95% CI: 1.02-2.86; P = 0.041). In conclusion, assessment of MICA matching and immunization for the identification of patients at high risk for transplant rejection and loss is warranted.

SUBMITTER: Carapito R

PROVIDER: S-EPMC9117142 | biostudies-literature | 2022 May

REPOSITORIES: biostudies-literature

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The MHC class I MICA gene is a histocompatibility antigen in kidney transplantation.

Carapito Raphael R Aouadi Ismail I Verniquet Martin M Untrau Meiggie M Pichot Angélique A Beaudrey Thomas T Bassand Xavier X Meyer Sébastien S Faucher Loic L Posson Juliane J Morlon Aurore A Kotova Irina I Delbos Florent F Walencik Alexandre A Aarnink Alice A Kennel Anne A Suberbielle Caroline C Taupin Jean-Luc JL Matern Benedict M BM Spierings Eric E Congy-Jolivet Nicolas N Essaydi Arnaud A Perrin Peggy P Blancher Antoine A Charron Dominique D Cereb Nezih N Maumy-Bertrand Myriam M Bertrand Frédéric F Garrigue Valérie V Pernin Vincent V Weekers Laurent L Naesens Maarten M Kamar Nassim N Legendre Christophe C Glotz Denis D Caillard Sophie S Ladrière Marc M Giral Magali M Anglicheau Dany D Süsal Caner C Bahram Seiamak S

Nature medicine 20220314 5

The identity of histocompatibility loci, besides human leukocyte antigen (HLA), remains elusive. The major histocompatibility complex (MHC) class I MICA gene is a candidate histocompatibility locus. Here, we investigate its role in a French multicenter cohort of 1,356 kidney transplants. MICA mismatches were associated with decreased graft survival (hazard ratio (HR), 2.12; 95% confidence interval (CI): 1.45-3.11; P < 0.001). Both before and after transplantation anti-MICA donor-specific antibod ...[more]

PMID: 35288692

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Project description:An ever growing number of reports on graft rejection and/or failure even with good HLA matches have highlighted an important role of non-HLA antigens in influencing allograft immunity. The list of non-HLA antigens that have been implicated in graft rejection in different types of organ transplantation has already grown long. Of these, the Major Histocompatibility Complex class I chain-related molecule A (MICA) is one of the most polymorphic and extensively studied non-HLA antigenic targets especially in the kidney transplantation. Humoral response to MICA antigens has repeatedly been associated with lower graft survival and an increased risk of acute and chronic rejection following kidney and liver transplantation with few studies showing conflicting results. Although there are clear indications of MICA antibodies being associated with adverse graft outcome, a definitive consensus on this relationship has not been arrived yet. Furthermore, only a few studies have dealt with the impact of MICA donor-specific antibodies as compared to those that are not donor specific on graft outcome. In addition to the membrane bound form, a soluble isoform of MICA (sMICA), which has the potential to engage the natural killer cell-activating receptor NKG2D resulting in endocytosis and degradation of receptor-ligand interaction complex leading to suppression of NKG2D-mediated host innate immunity, has been a subject of intense discussion. Most studies on sMICA have been directed toward understanding their influence on tumor growth, with limited literature focusing its role in transplant biology. Furthermore, a unique dimorphism (methionine to valine) at position 129 in the α2 domain categorizes MICA alleles into strong (MICA-129 met) and weak (MICA-129 val) binders of NKG2D receptor depending on whether they have methionine or valine at this position. Although the implications of MICA 129 dimorphism have been highlighted in hematopoietic stem cell transplantation, its role in solid organ transplantation is yet to be explored. This review summarizes the currently available information on MICA antibodies, soluble MICA, and MICA-129 dimorphism in a setting of solid organ transplantation.

Project description:BackgroundThe mouse has more than 30 Major histocompatibility complex (Mhc) class Ib genes, most of which exist in the H2 region of chromosome 17 in distinct gene clusters. Although recent progress in Mhc research has revealed the unique roles of several Mhc class Ib genes in the immune and non-immune systems, the functions of many class Ib genes have still to be elucidated. To better understand the roles of class Ib molecules, we have characterized their gene duplication, organization and expression patterns within the H2 region of the mouse strain C57BL/6.ResultsThe genomic organization of the H2-Q, -T and -M regions was analyzed and 21 transcribed Mhc class Ib genes were identified within these regions. Dot-plot and phylogenetic analyses implied that the genes were generated by monogenic and/or multigenic duplicated events. To investigate the adult tissue, embryonic and placental expressions of these genes, we performed RT-PCR gene expression profiling using gene-specific primers. Both tissue-wide and tissue-specific gene expression patterns were obtained that suggest that the variations in the gene expression may depend on the genomic location of the duplicated genes as well as locus specific mechanisms. The genes located in the H2-T region at the centromeric end of the cluster were expressed more widely than those at the telomeric end, which showed tissue-restricted expression in spite of nucleotide sequence similarities among gene paralogs.ConclusionDuplicated Mhc class Ib genes located in the H2-Q, -T and -M regions are differentially expressed in a variety of developing and adult tissues. Our findings form the basis for further functional validation studies of the Mhc class Ib gene expression profiles in specific tissues, such as the brain. The duplicated gene expression results in combination with the genome analysis suggest the possibility of long-range regulation of H2-T gene expression and/or important, but as yet unidentified nucleotide changes in the promoter or enhancer regions of the genes. Since the Mhc genomic region has diversified among mouse strains, it should be a useful model region for comparative analyses of the relationships between duplicated gene organization, evolution and the regulation of expression patterns.

Project description:Presensitized patients awaiting a kidney transplant have a lower graft survival and a longer waiting time because of the limited number of potential donors and the higher risk of antibody-mediated rejection (AMR), particularly in the early posttransplant period, because of preformed donor-specific antibodies binding major histocompatibility complex (MHC) molecules expressed by the graft endothelium followed by the activation of the complement. Advances in kidney preservation techniques allow the development of ex vivo treatment of transplants. We hypothesized that masking MHC ex vivo before transplantation could help to prevent early AMR in presensitized recipients. We evaluated a strategy of MHC I masking by an antibody during ex vivo organ perfusion in a porcine model of kidney transplantation in alloimmunized recipients.MethodsThrough the in vitro calcein-release assay and flow cytometry, we evaluated the protective effect of a monoclonal anti-swine leukocyte antigen class I antibody (clone JM1E3) against alloreactive IgG complement-dependent cytotoxicity toward donor endothelial cells. Kidneys perfused ex vivo with JM1E3 during hypothermic machine perfusion were transplanted to alloimmunized recipients.ResultsIn vitro incubation of endothelial cells with JM1E3 decreased alloreactive IgG cytotoxicity (mean complement-dependent cytotoxicity index [% of control condition] with 1 µg/mL 74.13% ± 35.26 [calcein assay] and 66.88% ± 33.46 [cytometry]), with high interindividual variability. After transplantation, acute AMR occurred in all recipients on day 1, with signs of complement activation (C5b-9 staining) as soon as 1 h after transplantation, despite effective JM1E3 binding on graft endothelium.ConclusionsDespite a partial protective effect of swine leukocyte antigen I masking with JM1E3 in vitro, ex vivo perfusion of the kidney with JM1E3 before transplantation was not sufficient alone at preventing or delaying AMR in highly sensitized recipients.

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The MHC class I MICA gene is a histocompatibility antigen in kidney transplantation.

Publications

The MHC class I MICA gene is a histocompatibility antigen in kidney transplantation.

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