KIR and their HLA Class I ligands: Two more pieces towards completing the puzzle of chronic rejection and graft loss in kidney transplantation

Abstract

BackgroundKidney transplantation is a life-saving treatment for patients with end-stage renal disease. However, despite progress in surgical techniques and patient management, immunological rejection continues to have a negative impact on graft function and overall survival. Incompatibility between donors and recipients for human leukocyte antigens (HLA) of the major histocompatibility complex (MHC) generates a series of complex cellular and humoral immune response mechanisms that are largely responsible for rejection and loss of graft function. Within this context, a growing amount of evidence shows that alloreactive natural killer (NK) cells play a critical role in the immune response mechanisms elicited by the allograft. Killer immunoglobulin-like receptors (KIRs) are prominent mediators of NK cell alloreactivity.Methods and findingsA cohort of 174 first cadaveric kidney allograft recipients and their donors were selected from a total cohort of 657 transplanted patients for retrospective immunogenetic analyses. Patients with HLA Class II mismatches were excluded. HLA Class I allele frequencies were compared among patients with chronic rejection, patients with stable graft function and a group of 2388 healthy controls. Activating and inhibitory KIR gene frequencies, KIR haplotypes, KIR-HLA ligand matches/mismatches and combinations of recipient KIRs and donor HLA Class I ligands were compared among patients with and without chronic rejection and a group of 221 healthy controls.Patients transplanted from donors homozygous for HLA-C1 antigens had a significantly higher risk for chronic rejection than patients transplanted from donors homozygous or heterozygous for HLA-C2 antigens or with epitopes belonging to the HLA-Bw4 ligand group.The Kaplan-Meier curves obtained by dividing the patients into 3 groups according to the presence or absence of one or both of the combinations of recipient KIRs and donor HLA ligands (rKIR2DL1/dHLA-C2 and rKIR3DL1/dHLA-Bw4) showed a significantly higher cumulative incidence of chronic rejection in the group of patients completely lacking these functional units. These patients showed a progressively stronger decline in modification of diet in renal disease-estimated glomerular filtration rate.ConclusionsKIR genotyping should be performed at the time of enrolment of patients on the waiting list for organ transplantation. In our study, a significantly higher risk of chronic rejection after kidney transplantation was observed when recipient (r) and donor (d) pairs completely lacked the two functional rKIR-dHLA ligand combinations rKIR2DL1/dHLA-C2 and rKIR3DL1/dHLA-Bw4. This immunogenetic profile corresponds to low levels of NK cell inhibition. Therefore, patients with this high risk profile could benefit from immunosuppressive therapy aimed at reducing NK-cell cytotoxicity.

KIR specificity and avidity of standard and unusual C1, C2, Bw4, Bw6 and A3/11 amino acid motifs at entire HLA:KIR interface between NK and target cells, the functional and evolutionary classification of HLA class I molecules

“…Of importance, in HLA molecular interfaces, atypical amino acid combinations and exceptions are possible (De Santis et al, ), leading to cognate HLA:KIR pair misassignments and potential blurry clinical results. The clinical studies are inhibited or blurred by incomplete functional data on KIR binding for majority of HLA class I molecules or lack of pairing analyses (Littera et al, ; Tran et al, ).…”

Increased natural killer cell subsets with inhibitory cytokines and inhibitory surface receptors in patients with recurrent miscarriage and decreased or normal subsets in kidney transplant recipients late post-transplant

“…An up-regulation of inhibiting and stimulating NKG2 receptors was observed after allogeneic or autologous haematopoietic stem cell transplantation and in patients with rheumatoid arthritis, whereby a gene polymorphism of NKG2 was found to be associated with susceptibility and severity of rheumatoid arthritis [13][14][15]. Certain CD158 determinants summarized as killer cell immunoglobulin-like receptors (KIR) were found to be associated with RM [16][17][18][19] as well as control of viral infection, chronic rejection and graft loss in renal transplantation [20,21].…”

Applying genomics in heart transplantation

“…KIRs play essential roles in educating and regulating the ability of NK cells to sense and respond to HLA Class I surface expression and have been shown to have critical roles in human health and are implicated in multiple immune‐related diseases , and clinical studies show associations of combinatorial diversity of KIR and HLA alleles with multiple diseases, including infections and autoimmune disorders . KIR/HLA Class I incompatibility exemplifies how interactions may negatively impact histocompatibility and while the impact of KIR‐HLA mismatch in transplantation is controversial , recent studies do show evidence of KIR genotype associations with kidney and HCT transplant‐related outcomes , although no well‐powered studies to date have been performed in heart transplantation. There is some recent intriguing data that indicate that surveillance of CD28 and KIR2D receptor expression on T lymphocytes correlate with immune status of both heart and liver recipients .…”