Novel insights into non‐HLA alloimmunity in kidney transplantation

Reindl‐Schwaighofer, Roman; Heinzel, Andreas; Gualdoni, Guido A.; Laurent, Michel; Claas, Frans H.J.; Oberbauer, Rainer

doi:10.1111/tri.13546

Cited by 32 publications

(30 citation statements)

References 84 publications

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“…In more recent years, preformed and de novo non-HLA specific DSA targeting G-protein coupled receptors expressed on graft glomerular endothelium have been the focus of intense research, as they may account for a significant proportion of HLA-DSA negative acute and chronic ABMR [ 115 , 116 , 117 ]. They include a wide range of autoantibodies against different antigens, all of which represent potential biomarkers for ABMR [ 118 ] ( Table 5 ).…”

Section: Armentioning

confidence: 99%

Recent Advances on Biomarkers of Early and Late Kidney Graft Dysfunction

Quaglia

Merlotti

Guglielmetti

et al. 2020

IJMS

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New biomarkers of early and late graft dysfunction are needed in renal transplant to improve management of complications and prolong graft survival. A wide range of potential diagnostic and prognostic biomarkers, measured in different biological fluids (serum, plasma, urine) and in renal tissues, have been proposed for post-transplant delayed graft function (DGF), acute rejection (AR), and chronic allograft dysfunction (CAD). This review investigates old and new potential biomarkers for each of these clinical domains, seeking to underline their limits and strengths. OMICs technology has allowed identifying many candidate biomarkers, providing diagnostic and prognostic information at very early stages of pathological processes, such as AR. Donor-derived cell-free DNA (ddcfDNA) and extracellular vesicles (EVs) are further promising tools. Although most of these biomarkers still need to be validated in multiple independent cohorts and standardized, they are paving the way for substantial advances, such as the possibility of accurately predicting risk of DGF before graft is implanted, of making a “molecular” diagnosis of subclinical rejection even before histological lesions develop, or of dissecting etiology of CAD. Identification of “immunoquiescent” or even tolerant patients to guide minimization of immunosuppressive therapy is another area of active research. The parallel progress in imaging techniques, bioinformatics, and artificial intelligence (AI) is helping to fully exploit the wealth of information provided by biomarkers, leading to improved disease nosology of old entities such as transplant glomerulopathy. Prospective studies are needed to assess whether introduction of these new sets of biomarkers into clinical practice could actually reduce the need for renal biopsy, integrate traditional tools, and ultimately improve graft survival compared to current management.

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Section: Armentioning

confidence: 99%

Recent Advances on Biomarkers of Early and Late Kidney Graft Dysfunction

Quaglia

Merlotti

Guglielmetti

et al. 2020

IJMS

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“…As such the Banff 2017 working group now allows C4d positive, or validated gene transcripts/classifiers strongly associated with ABMR in a biopsy to substitute for serum detection of HLA DSAs in the diagnosis of active ABMR 12 . Indeed, there are clear examples of non‐HLA antibodies correlating with vascular graft injury (eg, anti‐angiotensin type 1 receptor, anti‐perlecan antibodies, and so on) (reviewed in reference 115) 109‐114 . Unfortunately, unlike the solid‐phase HLA SAB assays that have been well characterized and approved for HLA DSA testing, the solid‐phase assays that companies are producing for non‐HLA antibody evaluation lack clear cut‐offs for a positive result and have not been rigorously validated.…”

Section: Knowledge Gapsmentioning

confidence: 99%

What have we learned about how to prevent and treat antibody-mediated rejection in kidney transplantation?

Nickerson

2020

American Journal of Transplantation

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Antibody-mediated rejection (ABMR) in kidney transplantation is a major cause of late graft loss, and despite all efforts to date the "standard of care" remains plasmapheresis, IVIg, and steroids, which itself is based on low quality evidence. This review focuses on the risk factors leading to memory and de novo donor-specific antibody (DSA)-associated ABMR, the optimal prevention strategies for ABMR, and advances in adjunctive and emerging therapies for ABMR. Because new agents require regulatory approval via a Phase 3 randomized control trial (RCT), an overview of progress in innovative trial design for ABMR is provided. Finally, based on the insights gained in the biology of ABMR, current knowledge gaps are identified for future research that could significantly affect our understanding of how to optimally treat ABMR. K E Y W O R D S alloantibody, clinical research/practice, immunosuppressive regimens, kidney transplantation/ nephrology, rejection: antibody-mediated (ABMR) | 13 NICKERSON FDA report and the novel strategies being taken by the transplant community to address the unmet needs identified at the FDA workshop, with a specific focus on the prevention and treatment of ABMR in kidney transplantation-desensitization will be covered elsewhere.

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“…However, HLA typing does not consider the impact of non-HLA-related alloantigens (55). Growing evidence suggests that as much as 38% of kidney allograft rejections are due to these non-HLA-related alloantigens in comparison to 18% caused by HLA mismatches (14,56). Thus, there is a need for additional methods to assess immunocompatibility between recipient and donor.…”

Section: Discussionmentioning

confidence: 99%

Humanized Mouse Model as a Novel Approach in the Assessment of Human Allogeneic Responses in Organ Transplantation

et al. 2021

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The outcome of organ transplantation is largely dictated by selection of a well-matched donor, which results in less chance of graft rejection. An allogeneic immune response is the main immunological barrier for successful organ transplantation. Donor and recipient human leukocyte antigen (HLA) mismatching diminishes outcomes after solid organ transplantation. The current evaluation of HLA incompatibility does not provide information on the immunogenicity of individual HLA mismatches and impact of non-HLA-related alloantigens, especially in vivo. Here we demonstrate a new method for analysis of alloimmune responsiveness between donor and recipient in vivo by introducing a humanized mouse model. Using molecular, cellular, and genomic analyses, we demonstrated that a recipient’s personalized humanized mouse provided the most sensitive assessment of allogeneic responsiveness to potential donors. In our study, HLA typing provided a better recipient-donor match for one donor among two related donors. In contrast, assessment of an allogeneic response by mixed lymphocyte reaction (MLR) was indistinguishable between these donors. We determined that, in the recipient’s humanized mouse model, the donor selected by HLA typing induced the strongest allogeneic response with markedly increased allograft rejection markers, including activated cytotoxic Granzyme B-expressing CD8+ T cells. Moreover, the same donor induced stronger upregulation of genes involved in the allograft rejection pathway as determined by transcriptome analysis of isolated human CD45+cells. Thus, the humanized mouse model determined the lowest degree of recipient-donor alloimmune response, allowing for better selection of donor and minimized immunological risk of allograft rejection in organ transplantation. In addition, this approach could be used to evaluate the level of alloresponse in allogeneic cell-based therapies that include cell products derived from pluripotent embryonic stem cells or adult stem cells, both undifferentiated and differentiated, all of which will produce allogeneic immune responses.

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Novel insights into non‐HLA alloimmunity in kidney transplantation

Cited by 32 publications

References 84 publications

Recent Advances on Biomarkers of Early and Late Kidney Graft Dysfunction

Recent Advances on Biomarkers of Early and Late Kidney Graft Dysfunction

What have we learned about how to prevent and treat antibody-mediated rejection in kidney transplantation?

Humanized Mouse Model as a Novel Approach in the Assessment of Human Allogeneic Responses in Organ Transplantation

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