Killer immunoglobulin-like receptor (KIR) and HLA genotypes affect the outcome of allogeneic kidney transplantation.

BACKGROUND: Recipient NK cells may detect the lack of recipient's (i.e., self) HLA antigens on donor renal tissue by means of their killer cell immunoglobulin-like receptors (KIRs). KIR genes are differently distributed in individuals, possibly contributing to differences in response to allogeneic graft. METHODOLOGY/PRINCIPAL FINDINGS: We compared frequencies of 10 KIR genes by PCR-SSP in 93 kidney graft recipients rejecting allogeneic renal transplants with those in 190 recipients accepting grafts and 690 healthy control individuals. HLA matching results were drawn from medical records. We observed associations of both a full-length KIR2DS4 gene and its variant with 22-bp deletion with kidney graft rejection. This effect was modulated by the HLA-B,-DR matching, particularly in recipients who did not have glomerulonephritis but had both forms of KIR2DS4 gene. In contrast, in recipients with glomerulonephritis, HLA compatibility seemed to be much less important for graft rejection than the presence of KIR2DS4 gene. Simultaneous presence of both KIR2DS4 variants strongly increased the probability of rejection. Interestingly, KIR2DS5 seemed to protect the graft in the presence of KIR2DS4fl but in the absence of KIR2DS4del. CONCLUSIONS/SIGNIFICANCE: Our results suggest a protective role of KIR2DS5 in graft rejection and an association of KIR2DS4 with kidney rejection, particularly in recipients with glomerulonephritis

Does the KIR2DS5 gene protect from some human diseases?

BACKGROUND: KIR2DS5 gene encodes an activating natural killer cell receptor whose ligand is not known. It was recently reported to affect the outcome of hematopoietic stem cell transplantation. METHODOLOGY/PRINCIPAL FINDINGS: In our studies on KIR2DS5 gene associations with human diseases, we compared the frequencies of this gene in patients and relevant controls. Typing for KIR2DS5 gene was performed by either individual or multiplex polymerase chain reactions which, when compared in the same samples, gave concordant results. We noted an apparently protective effect of KIR2DS5 gene presence in several clinical conditions, but not in others. Namely, this effect was observed in ankylosing spondylitis (p=0.003, odds ratio [OR]=0.47, confidence interval [CI]=0.28-0.79), endometriosis (p=0.03, OR=0.25, CI = 0.07-0.82) and acute rejection of kidney graft (p=0.0056, OR=0.44, CI=0.24-0.80), but not in non-small-cell lung carcinoma, rheumatoid arthritis, spontaneous abortion, or leukemia (all p>0.05). In addition, the simultaneous presence of KIR2DS5 gene and HLA-C C1 allotype exhibited an even stronger protective effect on ankylosing spondylitis (p=0.0003, OR=0.35, CI=0.19-0.65), whereas a lack of KIR2DS5 and the presence of the HLA-C C2 allotype was associated with ankylosing spondylitis (p=0.0017, OR=1.92, CI=1.28-2.89), whereas a lack of KIR2DS5 and presence of C1 allotype was associated with rheumatoid arthritis (p=0.005, OR=1.47, CI=1.13-1.92). The presence of both KIR2DS5 and C1 seemed to protect from acute kidney graft rejection (p=0.017, OR=0.47, CI=0.25-0.89), whereas lack of KIR2DS5 and presence of C2 seemed to favor rejection (p=0.0015, OR=2.13, CI=1.34-3.37). CONCLUSIONS/SIGNIFICANCE: Our results suggest that KIR2DS5 may protect from endometriosis, ankylosing spondylitis, and acute rejection of kidney graft

<i>KIR</i> gene frequencies in controls and patients.

<p>Abbreviations: CI, confidence interval; KIR, killer immunoglobulin-like receptor; <i>KIR2DS4fl</i>, <i>KIR2DS4</i> full length gene; <i>KIR2DS4del</i>, <i>KIR2DS4</i> 22-base pair deletion variant of the <i>KIR2DS4</i> gene; OR, odds ratio.</p

Effect of glomerulonephritis on the dependence of odds ratio for kidney graft rejection on <i>HLA-B,-DR</i> matching, <i>KIR2DS4</i> full length (<i>KIR2DS4fl</i>) and/or <i>KIR2DS4</i> deletion variant (<i>KIR2DS4del</i>) gene presence.

<p>For odds ratio calculations, the non-GN group with complete (n = 4) <i>HLA-B,-DR</i> match and lack of any <i>KIR2DS4</i> variant (<i>KIR2DS4fl</i> and <i>KIR2DS4del</i> negative: fl-/del) was taken as 1.</p

Dependence of odds ratio for kidney graft rejection on <i>HLA-B,-DR</i> matching, <i>KIR2DS4</i> full length (<i>KIR2DS4fl</i>) and/or <i>KIR2DS4</i> deletion variant (<i>KIR2DS4del</i>) gene presence.

<p>For odds ratio calculations, the recipient group with complete (n = 4) <i>HLA-B,-DR</i> match with the donor and a lack of any <i>KIR2DS4</i> variant (<i>KIR2DS4fl</i> and <i>KIR2DS4del</i> negative: fl-/del-) was taken as 1.</p

Effects of full-length <i>KIR2DS4</i> gene (fl) and its deletion variant (del) on the outcome of renal transplantation.

<p>Kaplan Kaplan-Meier estimations of probability that graft is not rejected at a given time, S(t). Left panel: <i>KIR2DS4fl</i> present, <i>KIR2DS4del</i> present or absent; right panel: <i>KIR2DS4fl</i> absent, <i>KIR2DS4del</i> present or absent.</p

Patient disposition according to initial calcineurine inhibitor use.

<p>AGR, acute graft rejection; CsA, cyclosporine A; Tac, Tacrolimus.</p

Linkage disequilibrium between <i>KIR2DS4</i> gene variants and <i>KIR2DS5</i> gene in patients and controls.

<p>Abbreviations: AGR, acute graft rejection; HFs, haplotype frequencies; D_KL, Kullback-Leibler divergence from linkage equilibrium; KIR, killer immunoglobulin-like receptor; <i>KIR2DS4fl</i>, <i>KIR2DS4</i> full length gene; <i>KIR2DS4del</i>, <i>KIR2DS4</i> 22-base pair deletion variant of the <i>KIR2DS4</i> gene; R², global squared correlation coefficient for two loci; r, correlation coefficient for alleles frequencies. <i>Likelihood ratio statistics</i> (LRS): {Pts with AGR} <i>vs</i> {Controls+Pts without AGR}; LRS = 11.01; <i>df</i> = 5; p = 0.0513.</p

Clinical characteristics of patients.

<p>Clinical characteristics of patients.</p