Missing-Self Triggers Nk-Mediated Microvascular Injuries And Chronic Rejection Of Allogenic Kidney Transplants

Background Natural Killer cells (NK) are effectors of the innate immune system carrying inhibitory KIR, which regulate the killing function of these cells by interacting with MHC class I molecules (MHC-I). The “missing-self” hypothesis proposes that NK can sense the absence of self MHC-I on the surface of allogeneic cells. This unique characteristic suggests that NK could promote innate-driven rejection, a concept that has not been validated in clinical transplantation. Methods and Results 938 kidney transplant recipients had a graft biopsy between 2004 and 2012 in our center. Among them, 130 had microvascular inflammation (mvi, g+ptc Banff score ≥ 2), which is usually attributed to humoral rejection. Nevertheless, only 75 had circulating donor-specific antibodies (DSA) directed against HLA antigens or endothelial cells susceptible to explain their microvascular inflammation. We hypothesize that “missing-self” could be responsible for the lesions of the 55 remaining patients (mvi+DSA-). Finally, DNA samples were available for 44 pairs. A matched control group of 55 patients with no microvascular inflammation and no DSA was constructed (mvi-DSA-). Recipients’ KIR genes and donors’ and recipients’ HLA ligands were genotyped and the licensing of the 5 inhibitory KIR with known MHC-I ligands (KIR2DL1/C2, KIR2DL2/C1, KIR2DL3/C1, KIR3DL1/Bw4, KIR3DL2/A3, A11) was assessed for both groups. The proportion of patients with at least 1 licensed inhibitory KIR-ligand mismatch was higher in mvi+DSA- group (66% vs 38%, p=0.009). In a human in vitro model, we demonstrated that the lack of self MHC-I on endothelial cells can activate NK. This activation triggers mTOR pathway in NK, which can be blocked by rapamycine. Using a murine in vivo cellular model of missing-self mediated killing, we found that rapamycine (but not CNI) can prevent the killing of targets. Finally, we confirmed the existence of missing-self induced rejection in a murine heart transplantation model and its sensitivity to mTOR inhibition. Conclusion “Missing-self” triggers NK-mediated chronic vascular rejection of allogeneic kidneys. MTOR inhibitors might be of interest to prevent this previously unrecognized type of rejection.