Reassessment of the clinical impact of preformed donor-specific anti-HLA-Cw antibodies in kidney transplantation

Visentin, Jonathan; Bachelet, Thomas; Aubert, Olivier; Bello, Arnaud Del; Martinez, Charlie; Jambon, Frédéric; Guidicelli, Gwendaline; Ralazamahaleo, Mamy; Bouthemy, Charlène; Cargou, Marine; Congy‐Jolivet, Nicolas; Nong, Thoa; Lee, Jar-How; Sberro-Soussan, Rébecca; Couzi, Lionel; Kamar, Nassim; Legendre, Christophe; Merville, Pierre; Taupin, Jean‐Luc

doi:10.1111/ajt.15766

Cited by 24 publications

(44 citation statements)

References 33 publications

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“…In solid organ transplantation investigations into the contribution of HLA‐C to the induction of an alloimmune response or graft rejection have conflicting results . Aubert and Tran describe an increased risk of antibody mediated rejection in transplant patients sensitised against HLA‐C antigens despite a negative pre‐transplant crossmatch, and Visentin goes on to describe lower graft survival specifically because of HLA‐C sensitisation . However Ling et al were unable to detect increased risk of rejection because of either HLA‐C or ‐DP, suggesting loci with lower antigen expression have less influence on transplant rejection.…”

Section: Discussionmentioning

confidence: 99%

HLA‐C expression level in both unstimulated and stimulated human umbilical vein endothelial cells is defined by allotype

Carey

Poulton

Poles

2020

HLA

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Human leukocyte antigens (HLA) are present on the surface of all nucleated cells, with the level of expression dependent on the particular HLA locus, the cell type and cellular activation state. Human umbilical vein endothelial cells (HUVECs) are easily isolated from umbilical cords and may aid our understanding of HLA expression on the vascular endothelium in the setting of transplantation. Endothelial cells on the donor-recipient interface form the barrier between transplanted organs and the host immune system. Increased knowledge of the variation in levels of individual HLA specificities may inform the assessment of transplant risk. HUVECs from 48 full term babies born consecutively following planned caesarean section were isolated, HLA typed and grown on gelatin coated culture wells. Once confluent, cells were stimulated with optimal concentrations of the cytokines TNF-α and IFN-γ for 24 hours and HLA-C expression on both unstimulated and stimulated cells was quantified by flow cytometry using the fluorescent labelled monoclonal antibody DT-9 PE. Unstimulated HLA-C expression varied by over 60% between allotypes (ANOVA, P = .004). Following stimulation, HLA-C levels increased over 15-fold and showed the same variation of expression between allotypes (P < .001). Cell surface HLA-C expression increases between 500% and 3125%, after stimulation for 24 hours. HLA-C level varies between allotypes and cells expressing more HLA-C at baseline tended to have corresponding higher levels of HLA-C following cytokine stimulation (Pearson's correlation coefficient between unstimulated and stimulated expression, P = .002).

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Section: Discussionmentioning

confidence: 99%

HLA‐C expression level in both unstimulated and stimulated human umbilical vein endothelial cells is defined by allotype

Carey

Poulton

Poles

2020

HLA

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“…51 By performing FCXM with cells targeted by only one DSA, either directed at HLA-A, -B or -C, we observed that FCXM results caused by anti-HLA-A and anti-HLA-B antibodies could be correctly predicted by SAFB MFI. 52 Conversely, anti-HLA-C DSA led to random FCXM results, [53][54][55][56][57][58] yet, they did induce a meaningful number of positive FCXM (Table 1).…”

Section: Pathogenicity Of Dsa Directed At Hla-c In Sotmentioning

confidence: 99%

Clinical relevance of donor‐specific antibodies directed at HLA‐C: A long road to acceptance

Visentin

Couzi

Taupin

2020

HLA

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In solid organ transplantation (SOT), the clinical relevance of donor-specific antibodies (DSA) directed at anti-HLA-A,-B,-DR and-DQ antigens is largely recognized while it is still a matter of debate for DSA directed at HLA-C. In this review, we summarize the peculiarities of HLA-C among class I HLA antigens as well as their immunogenicity, which underlie the clinical relevance of HLA-C locus and anti-HLA-C DSA in SOT. Many factors, both intrinsic and extrinsic to the HLA-C gene and HLA-C protein, explain its lower expression in comparison with HLA-A and-B. This lower expression can explain the apparent lower immunogenicity of HLA-C leading to a lower prevalence and strength of anti-HLA-C antibodies. Nevertheless, HLA-C antigens are truly immunogenic and preformed anti-HLA-C DSA are clinically relevant. Indeed, anti-HLA-C DSA are able to bind donor cells and to activate the complement pathway both ex vivo and in vivo. In line with this, numerous clinical studies now show that preformed DSA directed at native HLA-C molecules induce poorer graft outcomes. We then plead for the inclusion of HLA-C in all transplant allocation systems and we propose a strategy to cope with anti-HLA-C DSA in SOT. Beyond SOT, anti-HLA-C antibodies generate a growing interest in the allo-HCT, transfusion and obstetrics fields, while new concepts such as the role of the "missing-self" in solid organ rejection places HLA-C as an inescapable actor in transplant tolerance.

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“…Indeed, majority of mAbs (11 out of 17) that bound multiple HLA Class I alleles did not share an eplet among all their top-10 hits (Supplementary Figure 5D). For the remaining 6 mAbs, the top-10 hits did share an eplet for bound HLA-C antigens (Supplementary Figure 5E and F) (Tumer et al, 2013;Visentin et al, 2019;Xu et al, 2012). Thus, shared eplets could not explain the broad reactivity for the majority of the mAbs.…”

Section: In Situ Immunoglobulin Repertoire In Renal Allograft Rejectionmentioning

confidence: 99%

Intrarenal B cells integratein situinnate and adaptive immunity in human renal allograft rejection

Asano

Daccache

Jain

et al. 2020

Preprint

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In human allograft rejection, intrarenal B cell infiltrates identify those with a poor prognosis. However, how intrarenal B cells contribute to rejection is not known. Single cell RNA-sequencing of intrarenal class-switched B cells revealed a unique innate cell transcriptional state resembling murine peritoneal B1 cells (Bin cells). Comparison to the transcriptome of whole renal allograft rejecting tissue revealed that Bin cells existed within a complex autocrine and paracrine network of signaling axes. The immunoglobulins expressed by Bin cells did not bind donor specific antigens nor were they enriched for reactivity to ubiquitously expressed self-antigens. Rather, Bin cells frequently expressed antibodies reactive with renal expressed antigens. Furthermore, local antigens could drive Bin cell proliferation and differentiation into plasma cells expressing self-reactive antibodies. By contributing to local innate immune networks, and expressing antibodies reactive with renal expressed antigens, Bin cells are predicted to amplify local inflammation and tissue destruction.

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Reassessment of the clinical impact of preformed donor-specific anti-HLA-Cw antibodies in kidney transplantation

Cited by 24 publications

References 33 publications

HLA‐C expression level in both unstimulated and stimulated human umbilical vein endothelial cells is defined by allotype

HLA‐C expression level in both unstimulated and stimulated human umbilical vein endothelial cells is defined by allotype

Clinical relevance of donor‐specific antibodies directed at HLA‐C: A long road to acceptance

Intrarenal B cells integratein situinnate and adaptive immunity in human renal allograft rejection

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