Differences in Chronic Intragraft Inflammation Between Positive Crossmatch and ABO-Incompatible Kidney Transplantation

Bentall, Andrew; Herrera, Laura Viviana; Cornell, Lynn D.; Gonzales, Manuel A. Moreno; Dean, Patrick G.; Park, Walter D.; Gandhi, Manish J.; Winters, Jeffrey L.; Stegall, Mark D.

doi:10.1097/tp.0000000000000188

Cited by 20 publications

(34 citation statements)

References 27 publications

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“…A humanized antibody that inhibits C5 cleavage to C5a and C5b has been introduced in renal transplantation. Although this treatment has been successful in many instances, cases of AMR resistant to eculizumab after renal transplantation have been reported . A recent study monitored transplant glomerulopathy over a 2‐year period and reported that eculizumab did not protect in patients with high anti‐HLA class II DSAs and a high B lymphocyte flow cross‐match .…”

Section: Discussionmentioning

confidence: 99%

HLA Class II Antibody Activation of Endothelial Cells Promotes Th17 and Disrupts Regulatory T Lymphocyte Expansion

Lion

Taflin

Cross

et al. 2016

American Journal of Transplantation

109

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Kidney transplantation is the most successful treatment option for patients with end-stage renal disease, and chronic antibody-mediated rejection is the principal cause of allograft loss. Predictive factors for chronic rejection include high levels of HLA alloantibodies (particularly HLA class II) and activation of graft endothelial cells (ECs). The mechanistic basis for this association is unresolved. We used an experimental model of HLA-DR antibody stimulation of microvascular ECs to examine the mechanisms underlying the association between HLA class II antibodies, EC activation and allograft damage. Activation of ECs with the F(Ab 0 ) 2 fragment of HLA-DR antibody led to phosphorylation of Akt, ERK and MEK and increased IL-6 production by ECs cocultured with allogeneic peripheral blood mononuclear cells (PBMCs) in an Akt-dependent manner. We previously showed that HLA-DR-expressing ECs induce polarization of Th17 and FoxP3 bright regulatory T cell (Treg) subsets. Preactivation of ECs with anti-HLA-DR antibody redirected EC allogenicity toward a proinflammatory response by decreasing amplification of functional Treg and by further increasing IL-6-dependent Th17 expansion. Alloimmunized patient serum containing relevant HLA-DR alloantibodies selectively bound and increased EC secretion of IL-6 in cocultures with PBMCs. These data contribute to understanding of potential mechanisms of antibody-mediated endothelial damage independent of complement activation and FcR-expressing effector cells.

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Section: Discussionmentioning

confidence: 99%

HLA Class II Antibody Activation of Endothelial Cells Promotes Th17 and Disrupts Regulatory T Lymphocyte Expansion

Lion

Taflin

Cross

et al. 2016

American Journal of Transplantation

109

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“…There are also reports of a higher incidence of IFTA lesions and TG at 1 year in PKB of ABOi transplants in comparison with ABOc transplants, whereas another group did not show more IFTA nor TG lesions in ABOi transplants …”

Section: Discussionmentioning

confidence: 95%

“…Blood group O was present in 53.3% of the recipients. A median of 6 IA per patient or a median of 7 PE was required. On the day of surgery, the patients had a median IgG anti‐A/B titer of 2 (0–4).…”

Section: Resultsmentioning

confidence: 99%

“…Despite the good intermediate‐ to long‐term outcome of ABOi KT, little is known about the impact of histologic changes and their influence on long‐term allograft function and survival. There are only a few studies with systematic follow‐up biopsies in ABOi KTs compared with living‐donor ABOc transplantation . Although it is well known that transplant biopsies from ABOi recipients can show C4d positivity even years after transplantation in the absence of other evidence of antibody‐mediated rejection (ABMR), there is little knowledge about borderline rejections, interstitial fibrosis and tubular atrophy (IFTA) lesions, and transplant glomerulopathy (TG) in ABOi protocol biopsies.…”

Section: Introductionmentioning

confidence: 99%

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Borderline rejection in ABO‐incompatible kidney transplantation

Sánchez-Escuredo

Oppenheimer

Solé

et al. 2016

Clinical Transplantation

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“…Many transplant centres worldwide have gathered experience in handling presensitized patients on the wait list, and several different desensitization strategies have now been published, both in the context of live and deceased donor transplantation . Over the years, however, it has turned out that, despite improved overall patient survival , many desensitized high‐risk recipients develop clinical and subclinical ABMR culminating in adverse average long‐term allograft survival .…”

Section: General Remarksmentioning

confidence: 99%

Complement inhibition as potential new therapy for antibody-mediated rejection

et al. 2015

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Antibody-mediated rejection (ABMR) is a leading cause of kidney allograft failure. While the exact mechanisms contributing to donor-specific antibody (DSA)-triggered tissue injury are still incompletely understood, complement activation via the classical pathway is believed to be one of the key players. There is now growing interest in complement blockade as an antirejection treatment. One attractive strategy may be inhibition of terminal complex formation using anti-C5 antibody eculizumab. Anecdotal reports, case series, and a unique cohort of flow crossmatch-positive live donor kidney transplant recipients subjected to eculizumab-based desensitization have demonstrated successful prevention and reversal of acute clinical ABMR. Nevertheless, maybe due to complement activation steps proximal of C5 or even complement-independent mechanisms, subclinical rejection processes that might culminate in chronic injury were found to escape inhibition. Larger studies designed to clarify the actual clinical value of terminal complement inhibition as an antirejection treatment are currently underway. In addition, alternative concepts, such as therapies that target key component C1, are currently under development, and we will see in the near future whether new strategies in the pipeline will have the potential to beneficially impact clinical practice.

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Differences in Chronic Intragraft Inflammation Between Positive Crossmatch and ABO-Incompatible Kidney Transplantation

Abstract: These data suggest that +XMKTxs have high rates of chronic inflammation at 1 and 5 years after transplantation, which may explain the higher rates of graft loss and lower renal function compared with other factors such as anti-donor antibody or intragraft complement deposition.

Cited by 20 publications

References 27 publications

HLA Class II Antibody Activation of Endothelial Cells Promotes Th17 and Disrupts Regulatory T Lymphocyte Expansion

HLA Class II Antibody Activation of Endothelial Cells Promotes Th17 and Disrupts Regulatory T Lymphocyte Expansion

Borderline rejection in ABO‐incompatible kidney transplantation

Complement inhibition as potential new therapy for antibody-mediated rejection

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