Pretransplant IgG Subclasses of Donor-Specific Human Leukocyte Antigen Antibodies and Development of Antibody-Mediated Rejection

Hönger, Gideon; Hopfer, Helmut; Arnold, Marie-Luise; Spriewald, Bernd M.; Schaub, Stefan; Amico, Patrizia

doi:10.1097/tp.0b013e31821cdf0d

Cited by 89 publications

(99 citation statements)

References 21 publications

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“…Our data confirm previous studies showing that IgG1 represents the predominant anti-HLA DSA subclass reported in the solid organ transplantation literature, which is variably associated with the other IgG subclasses (IgG2, 3, and 4). 12,[22][23][24][25][26][27][28] The initial appearance of strong complementfixing IgG1 and IgG3 antibodies may expand to weak or noncomplement-binding IgG2 and IgG4 antibodies; therefore, various profiles of IgG subclasses are seen in transplant recipients. 29 Previous studies have failed to firmly identify a predictive subclass pattern due to the heterogeneous IgG subclass response and to several technical [30][31][32] and methodological limitations, mainly related to the small number of recipients included 26,33,34 or the lack of precise clinical and histologic phenotyping of the ABMR injury.…”

Section: Discussionmentioning

confidence: 99%

“…29 Previous studies have failed to firmly identify a predictive subclass pattern due to the heterogeneous IgG subclass response and to several technical [30][31][32] and methodological limitations, mainly related to the small number of recipients included 26,33,34 or the lack of precise clinical and histologic phenotyping of the ABMR injury. 23,24 The integration of different properties of circulating anti-HLA DSA, including HLA class specificity, strength, complementbinding capacity and IgG subclasses, allowed us to identify three distinct clinical and histologic patterns of antibody-mediated injury, as recognized by the latest Banff classification: aABMR, sABMR, and ABMR-free. 35 The unsupervised PCA allowed us to hierarchically rank the variables that characterize these different patterns of antibody-mediated injury.…”

Section: Discussionmentioning

confidence: 99%

“…Post-transplant IgG3 DSA have been associated with poor allograft survival and chronic ABMR in liver recipients, 22 whereas no correlation was observed between the IgG subclass profile of pretransplant or post-transplant DSA and kidney transplant recipient outcome. 23,24 Moreover, there is no demonstration in the field of solid organ transplantation of the association of IgG1-4 profiles of circulating anti-HLA DSA with specific clinical and histologic phenotypes in the setting of antibody-mediated damage in allografts.…”

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confidence: 99%

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IgG Donor-Specific Anti-Human HLA Antibody Subclasses and Kidney Allograft Antibody-Mediated Injury

Lefaucheur

Viglietti

Bentlejewski

et al. 2016

Journal of the American Society of Nephrology

253

234

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Antibodies may have different pathogenicities according to IgG subclass. We investigated the association between IgG subclasses of circulating anti-human HLA antibodies and antibody-mediated kidney allograft injury. Among 635 consecutive kidney transplantations performed between 2008 and 2010, we enrolled 125 patients with donorspecific anti-human HLA antibodies (DSA) detected in the first year post-transplant. We assessed DSA characteristics, including specificity, HLA class specificity, mean fluorescence intensity (MFI), C1q-binding, and IgG subclass, and graft injury phenotype at the time of sera evaluation. Overall, 51 (40.8%) patients had acute antibody-mediated rejection (aABMR), 36 (28.8%) patients had subclinical ABMR (sABMR), and 38 (30.4%) patients were ABMR-free. The MFI of the immunodominant DSA (iDSA, the DSA with the highest MFI level) was 67246464, and 41.6% of patients had iDSA showing C1q positivity. The distribution of iDSA IgG1-4 subclasses among the population was 75.2%, 44.0%, 28.0%, and 26.4%, respectively. An unsupervised principal component analysis integrating iDSA IgG subclasses revealed aABMR was mainly driven by IgG3 iDSA, whereas sABMR was driven by IgG4 iDSA. IgG3 iDSA was associated with a shorter time to rejection (P,0.001), increased microcirculation injury (P=0.002), and C4d capillary deposition (P,0.001). IgG4 iDSA was associated with later allograft injury with increased allograft glomerulopathy and interstitial fibrosis/tubular atrophy lesions (P,0.001 for all comparisons). Integrating iDSA HLA class specificity, MFI level, C1q-binding status, and IgG subclasses in a Cox survival model revealed IgG3 iDSA and C1q-binding iDSA were strongly and independently associated with allograft failure. These results suggest IgG iDSA subclasses identify distinct phenotypes of kidney allograft antibody-mediated injury.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

mentioning

confidence: 99%

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IgG Donor-Specific Anti-Human HLA Antibody Subclasses and Kidney Allograft Antibody-Mediated Injury

Lefaucheur

Viglietti

Bentlejewski

et al. 2016

Journal of the American Society of Nephrology

253

234

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“…[6][7][8][9] Because a fraction of dnDSA-positive patients escape rejection or graft dysfunction, 9,13 the current challenge is to identify clinically relevant dnDSAs in order to better stratify the individual immunologic risk. Several proposed approaches rely on serum dnDSA SAFB mean fluorescence intensity (MFI) strength, 14,15 IgG subclass analysis, 16 or complement-binding ability. 17,18 DSAs are deleterious via different pathways, but complement C4d deposition in peritubular capillaries reflects the central role of complement in AMR endothelial cell aggression.…”

mentioning

confidence: 99%

Non-Complement–Binding De Novo Donor-Specific Anti-HLA Antibodies and Kidney Allograft Survival

Guidicelli¹,

Guerville²,

Lepreux³

et al. 2016

Journal of the American Society of Nephrology

125

112

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C1q-binding ability may indicate the clinical relevance of de novo donor-specific anti-HLA antibodies (DSA). This study investigated the incidence and risk factors for the appearance of C1q-binding de novo DSA and their long-term impact. Using Luminex Single Antigen Flow Bead assays, 346 pretransplant nonsensitized kidney recipients were screened at 2 and 5 years after transplantation for de novo DSA, which was followed when positive by a C1q Luminex assay. At 2 and 5 years, 12 (3.5%) and eight (2.5%) patients, respectively, had C1q-binding de novo DSA. De novo DSA mean fluorescence intensity .6237 and .10,000 at 2 and 5 years, respectively, predicted C1q binding. HLA mismatches and cyclosporine A were independently associated with increased risk of C1q-binding de novo DSA. When de novo DSA were analyzed at 2 years, the 5-year death-censored graft survival was similar between patients with C1q-nonbinding de novo DSA and those without de novo DSA, but was lower for patients with C1q-binding de novo DSA (P=0.003). When de novo DSA were analyzed at 2 and 5 years, the 10-year death-censored graft survival was lower for patients with C1q-nonbinding de novo DSA detected at both 2 and 5 years (P,0.001) and for patients with C1q-binding de novo DSA (P=0.002) than for patients without de novo DSA. These results were partially confirmed in two validation cohorts. In conclusion, C1q-binding de novo DSA are associated with graft loss occurring quickly after their appearance. However, the long-term persistence of C1q-nonbinding de novo DSA could lead to lower graft survival.

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“…The subclass repertoire is potentially more informative for assessing the pathogenicity of DSAs than complement assays, as subclass predicts complement activation, Fcγ receptor-dependent (FcγR-dependent) functions, and the immunobiology of the alloantibody response. A growing number of reports suggest that characterization of DSA IgG subclass may have utility in identifying patients at risk of rejection or graft loss (5, [55][56][57][58][59][60]. While enlightening, these studies have yet to capture the impact of mixtures of subclasses or multiple concurrent DSA specificities.…”

Section: Neutrophil Marginationmentioning

confidence: 99%

Antibody-mediated rejection across solid organ transplants: manifestations, mechanisms, and therapies

Valenzuela¹,

Reed²

2017

Journal of Clinical Investigation

172

147

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Pretransplant IgG Subclasses of Donor-Specific Human Leukocyte Antigen Antibodies and Development of Antibody-Mediated Rejection

Cited by 89 publications

References 21 publications

IgG Donor-Specific Anti-Human HLA Antibody Subclasses and Kidney Allograft Antibody-Mediated Injury

IgG Donor-Specific Anti-Human HLA Antibody Subclasses and Kidney Allograft Antibody-Mediated Injury

Non-Complement–Binding De Novo Donor-Specific Anti-HLA Antibodies and Kidney Allograft Survival

Antibody-mediated rejection across solid organ transplants: manifestations, mechanisms, and therapies

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