Allorecognition and the spectrum of kidney transplant rejection

Callemeyn, Jasper; Lamarthée, Baptiste; Koenig, Alice; Koshy, Priyanka; Thaunat, Olivier; Naesens, Maarten

doi:10.1016/j.kint.2021.11.029

Cited by 104 publications

(91 citation statements)

References 207 publications

(279 reference statements)

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“…Currently, studies on macrophage polarization in the field of transplantation mainly focus on ischemia-reperfusion injury, and research on rejection, especially ABMR, is still lacking ( Zhang et al, 2018 ; Ye et al, 2020 ). More importantly, recent studies have pointed out that monocytes and macrophages could be considered as secondary effectors and capable of direct allorecognition, indicating the potential therapeutic target for ABMR treatment ( Callemeyn et al, 2022 ; Lebraud et al, 2022 ). The concrete molecular mechanism needs to be studied further.…”

Section: Discussionmentioning

confidence: 99%

Iguratimod Attenuates Macrophage Polarization and Antibody-Mediated Rejection After Renal Transplant by Regulating KLF4

et al. 2022

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Background: This study aimed to explore the effect and mechanism of iguratimod (IGT) on M1 macrophage polarization and antibody-mediated rejection (ABMR) after renal transplant.Methods: Bioinformatics analysis was performed using three public databases derived from the GEO database. Sprague–Dawley (SD) rats were pre-sensitized with donors of Wistar rats in skin transplantation and a rat renal transplant ABMR model was established from the donors to skin pre-sensitized recipients. Subsequently, IGT was treated on the ABMR model. Routine staining and immunofluorescence (IF) staining were performed to observe the pathological changes in each group and flow cytometry was performed to detect the changes of DSA titers in peripheral blood. In addition, bone-marrow-derived macrophage (BMDM) was extracted and interfered with IGT to explore the effect of IGT in vivo. PCR, IF staining, and Western blot were used to detect the expression of related genes and proteins.Results: Bioinformatics analysis revealed that several immune cells were significantly infiltrated in the ABMR allograft, while M1 macrophage was noticed with the most significance. Results of IF staining and PCR proved the findings of the bioinformatics analysis. Based on this, IGT was observed to significantly attenuate the degree of peritubular capillary vasculitis and arteriolitis in the rat renal transplant ABMR model, whereas it decreases the expression of C4d and reduces the titer of DSA. Results in vitro suggested that M1 macrophage-related transcripts and proteins were significantly reduced by the treatment of IGT in a dose- and time-dependent manner. Furthermore, IGT intervention could remarkably decrease the expression of KLF4.Conclusion: Polarization of M1 macrophages may aggravate ABMR after renal transplant by promoting DSA-mediated endothelial cell injury, and IGT may attenuate the pathogenesis of ABMR by targeting KLF4.

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Section: Discussionmentioning

confidence: 99%

Iguratimod Attenuates Macrophage Polarization and Antibody-Mediated Rejection After Renal Transplant by Regulating KLF4

et al. 2022

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“…However, several teams have recently reported evidence of a direct role for innate cells in allograft rejection. NK cells and monocytes/macrophages are able to distinguish between self and non-self and trigger an alloimmune response ( 153 ). Recruitment of these cells in response to nonspecific “danger” signals from various causes (for example, ischemia–reperfusion after organ transplantation) could elicit inflammation associated with tissue injury.…”

Section: Antibody-independent MVImentioning

confidence: 99%

Microvascular Inflammation of the Renal Allograft: A Reappraisal of the Underlying Mechanisms

et al. 2022

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Antibody-mediated rejection (ABMR) is associated with poor transplant outcomes and was identified as a leading cause of graft failure after kidney transplantation. Although the hallmark histological features of ABMR (ABMRh), i.e., microvascular inflammation (MVI), usually correlate with the presence of anti-human leukocyte antigen donor-specific antibodies (HLA-DSAs), it is increasingly recognized that kidney transplant recipients can develop ABMRh in the absence of HLA-DSAs. In fact, 40-60% of patients with overt MVI have no circulating HLA-DSAs, suggesting that other mechanisms could be involved. In this review, we provide an update on the current understanding of the different pathogenic processes underpinning MVI. These processes include both antibody-independent and antibody-dependent mechanisms of endothelial injury and ensuing MVI. Specific emphasis is placed on non-HLA antibodies, for which we discuss the ontogeny, putative targets, and mechanisms underlying endothelial toxicity in connection with their clinical impact. A better understanding of these emerging mechanisms of allograft injury and all the effector cells involved in these processes may provide important insights that pave the way for innovative diagnostic tools and highly tailored therapeutic strategies.

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“…Notably, a key feature of the adaptive immune system compared with the innate immune system is that the former generates antigen-specific memory effectors (i.e., memory T and B cells), which respond rapidly when the same antigen is re-encountered. Importantly, although this vision of rejection as being largely dependent on the ability of the adaptive immune system to discriminate between alloantigens (i.e., a process named allorecognition) largely remains dominant, independent reports from basic-research and early clinical studies suggest that some innate effectors (including monocytes and natural killer cells) are also capable of allorecognition, leading to previously overlooked types of “innate” rejection episodes ( 7 – 9 ) and interfering with the adaptive immune mechanisms at stakes in “classical” rejection episodes ( 10 ).…”

Section: Strategies To Evaluate Alloimmune Riskmentioning

confidence: 99%

“…Finally, as well as participating in graft damage on recruitment by adaptive effectors, innate immune effectors might be able to recognize allogeneic non-self ( 7 – 9 ). While we wait for experimental studies to translate into robust clinical findings, and reliable assays are developed to guide decisions, we do not recommend that innate immune alloreactivity is evaluated in routine clinical practice.…”

Section: Considerations To Improve Stratification Of Alloimmune Risk ...mentioning

confidence: 99%

Alloimmune Risk Stratification for Kidney Transplant Rejection

Bestard

Thaunat²,

Bellini³

et al. 2022

Transpl Int

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Different types of kidney transplantations are performed worldwide, including biologically diverse donor/recipient combinations, which entail distinct patient/graft outcomes. Thus, proper immunological and non-immunological risk stratification should be considered, especially for patients included in interventional randomized clinical trials. This paper was prepared by a working group within the European Society for Organ Transplantation, which submitted a Broad Scientific Advice request to the European Medicines Agency (EMA) relating to clinical trial endpoints in kidney transplantation. After collaborative interactions, the EMA sent its final response in December 2020, highlighting the following: 1) transplantations performed between human leukocyte antigen (HLA)-identical donors and recipients carry significantly lower immunological risk than those from HLA-mismatched donors; 2) for the same allogeneic molecular HLA mismatch load, kidney grafts from living donors carry significantly lower immunological risk because they are better preserved and therefore less immunogenic than grafts from deceased donors; 3) single-antigen bead testing is the gold standard to establish the repertoire of serological sensitization and is used to define the presence of a recipient’s circulating donor-specific antibodies (HLA-DSA); 4) molecular HLA mismatch analysis should help to further improve organ allocation compatibility and stratify immunological risk for primary alloimmune activation, but without consensus regarding which algorithm and cut-off to use it is difficult to integrate information into clinical practice/study design; 5) further clinical validation of other immune assays, such as those measuring anti-donor cellular memory (T/B cell ELISpot assays) and non–HLA-DSA, is needed; 6) routine clinical tests that reliably measure innate immune alloreactivity are lacking.

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Allorecognition and the spectrum of kidney transplant rejection

Cited by 104 publications

References 207 publications

Iguratimod Attenuates Macrophage Polarization and Antibody-Mediated Rejection After Renal Transplant by Regulating KLF4

Iguratimod Attenuates Macrophage Polarization and Antibody-Mediated Rejection After Renal Transplant by Regulating KLF4

Microvascular Inflammation of the Renal Allograft: A Reappraisal of the Underlying Mechanisms

Alloimmune Risk Stratification for Kidney Transplant Rejection

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