Liver HLA-G expression is associated with multiple clinical and histopathological forms of chronic hepatitis B virus infection.

As the mechanisms leading to the persistence of hepatitis B virus (HBV) infection are poorly understood and as the histocompatibility leucocyte antigen (HLA)-G is well described as a tolerogenic molecule, we evaluated HLA-G expression in 74 specimens of HBV liver biopsies and in 10 specimens obtained from previously healthy cadaver liver donors. HBV specimens were reviewed and classified by the METAVIR score, and HLA-G expression was assessed by immunohistochemistry. No HLA-G expression was observed in control hepatocytes. In contrast, 57 (77%) of 74 HBV specimens showed soluble and membrane-bound HLA-G expression in hepatocytes, biliary epithelial cells or both. No associations between the intensity of HLA-G expression and patient age or gender, HBeAg status, severity of liver fibrosis, and grade of histological findings were observed. Although significance was not reached (P = 0.180), patients exhibiting HLA-G expression presented a higher median HBV DNA viral load (105 copies/mL) than those who did not express HLA-G (10(3.7) copies/mL). These results indicate that HLA-G is expressed in most cases of chronic HBV infection in all stages and may play a role in the persistency of HBV infection.

Interferon-γ +874 polymorphism in the first intron of the human interferon-γ gene and kidney allograft outcome.

BACKGROUND: Despite advances in immunosuppressive therapy in the past decade, allograft rejection remains an important cause of kidney graft failure. Cytokines play a major role in the inflammatory and immune responses that mediate allograft outcomes. Several studies have shown that the production of cytokines varies among individuals. These variations are determined by genetic polymorphisms, most commonly within the regulatory region of cytokine genes. The aim of the present study was to assess the effect of allelic variation on acute rejection episodes (ARE) or chronic allograft nephropathy (CAN) after kidney transplantation. METHODS: To determine a possible correlation between the interferon (INF)-γ +874 polymorphism and kidney allograft outcome, we isolated genomic DNA from 74 patients who underwent isolated kidney allografts and were classified into 2 groups--a rejection and a nonrejection group--for comparison with a control group of 163 healthy subjects. RESULTS: We genotyped INF-γ +874 polymorphisms in all groups. The transplant group showed a significantly increased homozygous genotype T/T (P = .0118) compared with healthy controls. Similarly, considering only patients with CAN, the homozygous genotype T/T (P = .0067) was significantly increased compared with the healthy controls. The rejection group indicated a significant increased homozygous genotype T/T compared with the control group (P = .0061). CONCLUSION: Homozygous genotype T/T was associated with increased levels of INF-γ and greater numbers among the rejection and CAN cohorts.

Interleukin-17 and kidney allograft outcome.

UNLABELLED: Acute rejection episodes (ARE) are important complications that involve the interplay between mechanisms that maintain graft tolerance and promote rejection. The proinflammatory cytokine interleukin-17 (IL-17) has been implicated in many conditions in humans and mice. In kidney transplant patients, the evaluation IL-17 levels has been performed in only a few patients. We performed a cross-sectional study correlating quantitative IL-17 levels and clinical outcomes. PATIENTS AND METHODS: We studied 19 specimens from biopsies performed in patients (n = 19) who received isolated kidney grafts. ARE signs were present in 9 (47%) patients who provide specimens; whereas, 10 (53%) others showed no signs of rejection. Eighteen healthy control sample IL-17 underwent measurement, all of which were performed by an enzyme-linked immunosorbent assay method. We assessed other factors, such as the recipients demographic data, cold ischemia time, HLA mismatches, time elapsed from transplantation to the biopsy, posttransplantation status, antibody panel, donor type, and immunosuppressive treatment. RESULTS: IL-17 levels were clearly increased among samples derived from patients with ongoing rejection (125.7 +/- 27.06 pg/mL) in contrast, to the nonrejection group, (30 +/- 13.32 pg/mL) (P < .05). Healthy controls showed no detectable IL-17 levels. CONCLUSIONS: These findings suggested that IL-17 was important in the pathophysiology of acute kidney rejection.

Human leukocyte antigen-G expression after kidney transplantation is associated with a reduced incidence of rejection.

UNLABELLED: HLA-G is a non-classic Human Leukocyte Antigen (HLA-G) Class I of low polymorphism and restricted tissue distribution that displays tolerogenic functions. In heart transplantation and in combined liver/renal allograft transplantation, the expression of HLA-G has been associated with a lower incidence of acute graft rejection episodes and absence of chronic dysfunction. Since the expression of HLA-G in renal biopsies has been investigated only in few patients who received a combined kidney and liver transplant, in this study we performed a cross-sectional study, systematically comparing the expression of HLA-G in post-transplanted renal grafts, stratifying patients according to the presence or absence of rejection. PATIENTS AND METHODS: Seventy-three renal specimens (10 with acute rejection and 13 with chronic allograft nephropathy, and 50 with no signs of rejection) were immunohistochemically evaluated for HLA-G expression. RESULTS: In the group as a whole, HLA-G molecules were detected in 40 cases (54.8%). Among specimens that presented HLA-G expression, 2 out of 40 (5%) exhibited acute rejection, 2 (5%) exhibited chronic allograft nephropathy, and the remaining 36 (90%) exhibited no signs of rejection. The comparison between patients with rejection and those without rejection showed that the expression of HLA-G was significantly increased in specimens exhibiting no signs of rejection (p<0.0001). Considering only patients with acute rejection, 8 out of 10 patients showed no HLA-G expression in their kidney biopsies when compared to patients exhibiting no signs of rejection and absence of HLA-G was observed in 14 out of 50 (p=0.0032). Similarly, considering only patients with chronic allograft nephropathy, absence of HLA-G expression was observed in 11 out of 13 specimens, whereas in patients without rejection absence of HLA-G was observed in 14 out of 50 (p=0.003). Therapy with tacrolimus was significantly associated with the expression of HLA-G and a better graft prognosis. CONCLUSIONS: Our results suggest that HLA-G expression in the kidney allograft and the use of tacrolimus are associated with a lower frequency of acute renal rejection and chronic allograft nephropathy.

Frequency of insertion/deletion polymorphism in exon 8 of HLA-G and kidney allograft outcome.

Human leukocyte antigen-G (HLA-G) is a non-classical major histocompatibility complex (MHC) class Ib molecule predominantly expressed in cytotrophoblasts, where it acts as a specific immunosuppressor. Literature data have shown that grafts in some settings, such as cardiac and liver/kidney-associated transplantations, express HLA-G and this expression is associated with less severe rejection and also reduces the incidence of rejection. Fourteen-base pair deletion/insertion polymorphism has been reported in exon 8 of the 3'-untranslated region of HLA-G. This polymorphism within exon 8 of the HLA-G gene might influence transcription activity, which in turn may influence the stability of HLA-G transcripts. This influences the stability of the HLA-G protein and therefore is of potential functional relevance. In order to determine a possible correlation between the 14-bp insertion/deletion polymorphism and kidney allograft outcome, we isolated genomic DNA from 83 patients who had received isolated kidney allografts, and we classified the 83 specimens into two groups, grafts presenting Banff features of rejection group and a non-rejection group, and compared them with a control group of 97 healthy subjects. The 14-bp polymorphism at exon 8 was genotyped in all groups. There was no significant difference in allelic frequencies of 14-bp insertion/deletion polymorphism between normal controls and kidney transplant patients. In the RG, the homozygous genotype +14/+14 bp (P = 0.0238) was significantly increased in the group with acute rejection compared with the healthy control group. Analysis of other HLA-G polymorphisms and functional studies on immune regulation are essential to elucidate the role of HLA-G in kidney allografts.