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.

The influence of CTLA-4 gene polymorphism on long-term kidney allograft function in Caucasian recipients.

The aim of the study was to examine whether CTLA-4 (CD152) and CD28 gene polymorphisms affect the outcome of kidney transplantation (KTx). Polymorphisms of the CTLA-4 gene (-318 C>T, +49 A>G, and the microsatellite polymorphism in the 3'UTR of exon 4 (AT)(n)) and a CD28 gene (IVS3 +17T>C) were investigated in 314 allograft recipients with a mean age of 41.9+/-12 years. The median time since KTx was 97.5 months. The genotypes of the SNPs were determined by SSP-PCR and (AT)(n) genotype by PCR and capillary electrophoresis (ABI Prism 310). In general, no relationship was found between the allele variants and acute rejection or graft function. Univariate and multivariate analyses showed no influence of CTLA-4 or CD28 polymorphism on graft/patient survival. In the individuals bearing the combination of the homozygous variant of low AT repeat number (82 bp) and the homozygous variant A (adenine) in CTLA-4 +49 A>G, higher eGFR was observed at one year after KTx, which was also maintained at 10 years. In summary, 24.2% of the studied patients carrying the "favorable" CTLA-4 genotype exhibited significantly higher allograft function than the 16.9% recipients with the "unfavorable" genotype up to 10 years post transplantation.

CD28 downregulation on CD4+ T cells is associated with age of kidney transplant recipient.

There is a growing body of evidence showing that the intensity of rejection is weaker in older kidney allograft recipients while chronic complications, but not rejection, are the main causes of graft loss. To investigate whether the age of the recipient is a factor affecting the expressions of the CD28, CTLA-4, and CD40L costimulatory molecules on CD4+ T cells. Their expression levels were determined in 78 kidney transplant recipients aged 17-68 years. The expression was assessed on unstimulated and anti-CD3 antibody + IL-2-stimulated CD4+ T cells. Median time after transplantation was 20 months and median serum creatinine was 1.5 mg/dl. Significant correlations between age and CD28 expression (r = -0.4, P = 0.0004) on CD4+ T cells and between age and CTLA-4 expression after stimulation (r = 0.34, P = 0.008) were found. CD40L expression on CD4+ T cells was not affected by recipient age. The decreased expression of CD28 and enhanced expression of CTLA-4 (after stimulation) associated with age may be helpful in transplant acceptance.

[Variable expression of CD28 costimulatory molecule and CTLA4 inhibitory molecule on peripheral blood CD4+ cells in kidney allograft recipients with and without acute graft rejection]. / Zróznicowana ekspresja kostymulujacej czqsteczki CD 28 i hamujacej CTLA4 na limfocytach krwi obwodowej CD4+ biorców przeszczepu nerki z ostrym i bez ostrego odrzucania.

UNLABELLED: Alloimune activation is one of the most significant post transplant events, which results in increased expression of costimulatory molecules. These molecules have been suggested to play a role in determining the outcome of immune response including graft rejection. MATERIAL AND METHODS: We examined the CD28 and both surface and intracellular CTLA-4 expression on freshly drawn and anti-CD3+rlL-2 stimulated peripheral blood CD4+ T cells in kidney transplant recipients with acute graft rejection and with non-complicated post transplant course. Dual immunofluorescence and flow cytometry methods were used. The proportion of freshly isolated CD4+/ CTLA4 was higher in both groups of graft recipients in comparison to healthy controls reflecting in vivo allostimulation. RESULTS: We found the increased percentage of CD4+ cells expressing surface CTLA4 after stimulation, unstimulated intracellular CTLA4 and lower percentage of CD4+ cells expressing CD28 after stimulation in kidney recipients without rejection. CONCLUSIONS: Our results indicate the possible relationship between the expression pattern of CTLA4 inhibitory molecule on CD4+ cells and clinical course after renal transplantation.

CD40L, CD28, and CTLA-4 expression on CD4+ T cells in kidney graft recipients: a relationship with post-transplantation clinical course.

BACKGROUND: Experimental studies have demonstrated that the intensity of alloreactivity against a transplanted organ results from an interaction of positive (CD40/CD40L and B.7/CD28) and inhibitory (B.7/CTLA-4) signals between antigen-presenting cells (APCs) and T lymphocytes. METHODS: We examined the CD40L, CD28, and both surface (s) and intracellular (i) CTLA-4 expressions on freshly drawn and anti-CD3+rIL-2-stimulated peripheral blood CD4+ T cells in groups of kidney transplant recipients in relation to distinct clinical course using the tri-color immunofluorescence method. RESULTS: The median proportions of freshly isolated CD3+/CD4+/CTLA-4+ and CD3+/CD4+/CD40L+ cells in all groups of graft recipients were higher than in control subjects. In patients with stable graft function (SGF), non-significantly higher sCTLA-4, significantly higher iCTLA-4 expression, and significantly lower CD40L expression on freshly drawn CD4+ T cells compared with recipients with chronic allograft nephropathy (CAN) were found. Moreover, CD4+ T cells from SGF patients showed a higher potential to express sCTLA-4 and CD40L molecules and to down-regulate the CD28 molecule in response to ex vivo stimulation than those from patients with CAN. In patients without acute graft rejection (NAGR), a markedly higher proportion of freshly drawn CD3+/CD4+/iCTLA-4+ cells compared with patients with acute graft rejection (AGR) and an up-regulation of the median percentage of CD3+/CD4+/CD40L+ cells after ex vivo stimulation was found. CONCLUSIONS: In patients with SGF, peripheral blood CD4+ T cells exhibited a higher potential to express surface CTLA-4 and CD40L and to down-regulate CD28 costimulatory molecules in response to ex vivo stimulation, indicating a relationship between the expression patterns of both costimulatory and inhibitory molecules in CD4+ T cells and clinical course after renal transplantation.

Costimulatory pathways as a basic mechanisms of activating a tolerance signal in T cells.

Immune tolerance is an active response leading to the T cell unresponsiveness in the presence of the graft, which may develop through a couple of mechanisms including costimulation blockade. The CD28/B7 and CD40L/CD40 costimulatory pathways have been described as the critical for T cell activation. When activated T cell upregulate CTLA4, which importance as a negative regulatory costimulatory molecule is highlighted by the recent evidence suggesting that CTLA4 may function as a master switch for peripheral T cell tolerance. The effects of CTLA4 engagement are directed at the inhibition of CD28 signaling. Modulation of proximal TCR signals and down-stream effector pathways of T cell activation result in altered T cell differentiation and downregulation of immune responses. CTLA4 may regulate signal transduction in a rare subset of CD4+CD25 + T cells which leads to differentiation into regulatory cells. CD40L/CD40 interaction provides a bi-directional signal for T and B cell activation. A possible mechanisms of tolerance induction by CD40L/CD40 blockade involve reduction in expression of B7 molecules, effects on bcl-xL gene and APC function modification. The role of the new discovered pathways: ICOS/B7RP-I and PD-I/PD-LI in regulation of T cell response in transplantation is becoming apparent.

New possibilities of therapeutic interventions in transplantation.

Immune tolerance of the graft would allow for long-term graft survival without immunosuppressive drugs. Experimental studies showed that both CD28/B7 and CD40L/CD40 costimulations are critical for allograft rejection and their blockade during transplantation induced a decrease of proliferation of alloreactive T cells and an increase of their death by apoptosis. Blocking B7 costimulation increased rodent allograft survival of kidney, liver and pancreatic islets but this is insufficient weapon in the induction of graft tolerance. The combination of the two treatments has synergistic effects. Additional CD40/CD40L blockade represents a adjunct strategy to prevent graft rejection and it has been reported to induce donor specific peripheral tolerance. This therapy prevented acute cardiac allograft rejection and it markedly prolonged allograft survival of kidney and islets in nonhuman primates. A loss of donor-specific alloreactivity has been demonstrated in these experimental models. Calcineurin inhibitors may antagonize the therapeutic effects of costimulatory blockade which may suggest that T cell receptor signaling may be required for tolerance induction.

[Evaluation of health-related quality of life in dialysis patients. Personal experience using questionnaire SF-36]. / Ocena zaleznej od zdrowia jakosci zycia u chorych przewlekle dializowanych. Doswiadczenia wlasne z uzyciem kwestionariusza SF-36.

INTRODUCTION: Patients' perception of health is an important outcome measure in the assessment of influence of chronic disease and received treatment. The purpose of this study was: 1) to investigate the relation between selected demographic and clinical characteristics and Health-related Quality of Life (HRQoL) scores in patients with end-stage renal disease (ESRD) who receive dialysis, 2) to compare HRQoL in dialysis patients with their peers from the control group, 3) to evaluate the usefulness of SF-36 questionnaire. MATERIAL AND METHODS: We evaluated Health-Realated Quality of Life (HRQoL) of dialysis patients by the Polish version of the Short Form 36 Items Health Survey (SF-36). The SF-36 consists of eight scales: physical functioning (PF), social functioning (SF), role limitation attributable to physical problems (RP), role limitation attributable to emotional problems (RE), mental health (MH), vitality (VT), bodily pain (BP) and general health perception (GH). This study included 97 patients (44 men and 53 women), aged 28-86 years (mean age: 57.2) treated with HD (n = 77) and CAPD (n = 20) for 3-245 months (mean: 61 months). We compared the results with the data obtained from 217 healthy control subjects (105 men and 112 women), aged 20-92 years (mean age 51.1). The patients were divided into four age-groups and compared with the appropriate groups of controls. RESULTS: The perception of health of dialysis patients was worse than that of controls. We have found, that in the group aged over 65 years patients' scores were quite close to those of the control population. Our results show the following patient-connected factors to be independently associated with quality of life (QoL): age, sex, occupation, level of education, family situation and comorbidities. On average, females reported lower scores; the impact of ageing was more evident in physical scales. CONCLUSIONS: 1) age, sex, occupation, level of education, family situation as well as comorbidities are independent factors of HRQoL, 2) subjective QoL of elderly patients seems acceptable in comparison with healthier peers, 3) the SF-36 questionnaire is applicable in dialysis patients and SF-36 scores are related to important clinical aspects.