Missing self triggers NK cell-mediated chronic vascular rejection of solid organ transplants

Alice Koenig,Stéphanie Ducreux,Sébastien Dussurgey,Valérie Dubois,Maud Racapé,Antoine Marçais,Béatrice Charreau,Antonino Nicoletti,Jean-Paul Duong-Van-Huyen,Jasper Callemeyn,Thierry Defrance,Chien-Chia Chen,Vannary Meas-Yedid,Thomas Barba,Helena Païdassi ,R Guillemain ,Jean‐Christophe Olivo‐Marin ,Jean‐Luc Taupin ,A Sicard ,Emmanuel Morélon ,Virginie Mathias,Thierry Walzer,Maarten Naesens,Alexandre Loupy,Patrick Bruneval,Maud Rabeyrin,Olivier Thaunat

doi:10.1038/s41467-019-13113-5

Abstract

Current doctrine is that microvascular inflammation (MVI) triggered by a transplant -recipient antibody response against alloantigens (antibody-mediated rejection) is the main cause of graft failure. Here, we show that histological lesions are not mediated by antibodies in approximately half the participants in a cohort of 129 renal recipients with MVI on graft biopsy. Genetic analysis of these patients shows a higher prevalence of mismatches between donor HLA I and recipient inhibitory killer cell immunoglobulin-like receptors (KIRs). Human in vitro models and transplantation of β2-microglobulin-deficient hearts into wild-type mice demonstrates that the inability of graft endothelial cells to provide HLA I-mediated inhibitory signals to recipient circulating NK cells triggers their activation, which in turn promotes endothelial damage. Missing self-induced NK cell activation is mTORC1-dependent and the mTOR inhibitor rapamycin can prevent the development of this type of chronic vascular rejection.

Highlights

Current doctrine is that microvascular inflammation (MVI) triggered by a transplant -recipient antibody response against alloantigens is the main cause of graft failure
We retrospectively reviewed all kidney graft biopsies performed at our University Hospital between September 2004 and September 2012 (n = 2024 in 938 patients) and identified 129 renal recipients with typical graft MVI (g + ptc ≥ 2)
Screening of patients’ sera for anti-angiotensin II type 1-receptor (AT1R) and anti-MHC class I polypeptide-related sequence (MIC), two types of non-HLA antibodies the pathogenicity of which has been demonstrated[26,27], showed that neither the titre nor the proportion of positive patients were increased in the MVI +anti-HLA donor-specific antibodies (DSAs)− group (Supplementary Fig. 1A)

Summary

Introduction

Current doctrine is that microvascular inflammation (MVI) triggered by a transplant -recipient antibody response against alloantigens (antibody-mediated rejection) is the main cause of graft failure. French National Institute of Health and Medical Research (Inserm) Unit 1160, 1, avenue Claude-Vellefaux, 75010 Paris, France. French National Institute of Health and Medical Research (Inserm) Unit 1148, Laboratory of Vascular Translational Science, 46, rue Henri-Huchard, 75018 Paris, France. Introduction of calcineurin inhibitors in the early 1980s led to a dramatic reduction of the incidence of acute cellular rejection, and doubled the percentage of functional renal grafts at 1year post-transplantation[2]. This progress in the control of T cell alloimmune response barely affected graft half-life[3], leading to the emergence of the “humoral theory” of chronic rejection[4]. First identified in renal transplantation in the 2000s5–8, antibody-mediated rejection (AMR) has since been recognised as the main cause of failure in most organ transplantations[9,10,11,12]

Methods

Results

Conclusion