HLA-G14bp ins/del polymorphism and post-transplant weight gain in kidney transplantation. Potential implications beyond tolerance

Background: Human leukocyte antigen (HLA)-G is a non-classical HLA molecule with immunomodulant and immunosuppressive functions, involved in transplantation tolerance. HLA-G14bp ins/del polymorphism in exon 8 has been associated with allograft rejection and kidney transplant outcome, with controversial results. We investigated associations of HLA-G14bp ins/del polymorphism on onset of some of the main post-transplant risk factors, like excess body weight, lipid abnormalities, increased fasting plasma glucose. Polymorphisms of cytokines with both immunosuppressive and metabolic effects were also assessed for comparisons and associated analysis. Methods: The present study involved kidney transplant recipients (n = 173) in which body mass index, cholesterol, triglycerides, fasting plasma glucose were registered in the first years after transplantation and analyzed in association with genotypes. Presence of hypertension and smoking habits, demographic, transplant-related and therapeutic data of patients were also recorded. Polymerase chain reaction, sequence-specific primer amplification and Taqman allelic discrimination techniques were used for genotyping of HLA-G14bp ins/del, interleukin (IL)-10(-1082G > A,-819 T > C,-592A > C), transforming growth factor-β(+ 869 T > C,+915C > G), IL-6(-174G > C), tumor necrosis factor-α(-308G > A) and IL-18(-137G > C,-607C > A). Effects of genotypes on clinical markers at each time point (pre-transplant and 1 to 5 years after transplant) were analyzed using a repeated-measures general linear model analysis; adjustment for potential confounders was performed. Results: Results showed that HLA-G14bp ins/ins was significantly associated with obesity, in particular after transplantation (3 years, p = 0.002, OR = 4.48, 95% CI:1.76-11.41). Post-transplant body mass index was significantly increased in HLA-G14bp ins/ins carriers (3 and 4 years, p = 0.033 and p = 0.044); effects of HLA-G14bp genotypes on post-transplant BMI were confirmed by using repeated-measures analysis and after controlling for confounding variables. Cytokine genotypes did not associate with the examined factors. Conclusions: The study of transplanted patients allowed to evidence a potential relationship between post-transplant weight gain and HLA-G14bp ins/del polymorphism, previously involved in rejection for its immunosuppressive/tolerogenic activity. This novel association could widen the knowledge of the role and functions of HLA-G molecules in diseases and transplantation

Reduced number and function of peripheral dendritic cells in coeliac disease.

Dendritic cells (DC) play a pivotal role in shaping the immune response in both physiological and pathological conditions. In peripheral blood at least two subsets, the myeloid and plasmacytoid, have been described as having different T stimulatory functions and a variable degree of maturation. Certainly, antigen presentation plays a crucial role in the pathogenesis of coeliac disease and circulating immune cells are thought to reflect the state of immune response within the gut. Therefore,we aimed to investigate the quantitative and phenotypical modifications of peripheral bloodDC, together with their functional properties, in this pathological condition. Blood samples from 11 untreated patients before and after a course of gluten-free diet, 27 treated patients and 14 controls underwent flow-cytometric analysis, while immunomagnetically sorted DC from the CD patients and eight human leucocyte antigen (HLA)-DQ2/8+ bone marrow donors were used to evaluate maturation status through the CD83 expression, cytokine profile for interleukin (IL)-6, IL-10, IL-12 and interferon (IFN)-a by enzyme-linked immunosorbent assay (ELISA), and functional properties by mixed leucocyte reaction before and after pulsing with digested gliadin. We found that in both untreated and treated patients, a significant reduction of the entire DC population, mainly the plasmacytoid subset, in comparison to healthy controls was observed. In active disease, an impaired allogenic lymphocyte reaction and a significant reduction of IFN-a production, paralleled by the presence of a more immature status, were also demonstrated. All the latter modifications have been reverted by pulsing DC with digested gliadin

Distribution of killer cell immunoglobulin-like receptors genes in the Italian Caucasian population

BACKGROUND: Killer cell immunoglobulin-like receptors (KIRs) are a family of inhibitory and activatory receptors that are expressed by most natural killer (NK) cells. The KIR gene family is polymorphic: genomic diversity is achieved through differences in gene content and allelic polymorphism. The number of KIR loci has been reported to vary among individuals, resulting in different KIR haplotypes. In this study we report the genotypic structure of KIRs in 217 unrelated healthy Italian individuals from 22 immunogenetics laboratories, located in the northern, central and southern regions of Italy. METHODS: Two hundred and seventeen DNA samples were studied by a low resolution PCR-SSP kit designed to identify all KIR genes. RESULTS: All 17 KIR genes were observed in the population with different frequencies than other Caucasian and non-Caucasian populations; framework genes KIR3DL3, KIR3DP1, KIR2DL4 and KIR3DL2 were present in all individuals. Sixty-five different profiles were found in this Italian population study. Haplotype A remains the most prevalent and genotype 1, with a frequency of 28.5%, is the most commonly observed in the Italian population. CONCLUSION: The Italian Caucasian population shows polymorphism of the KIR gene family like other Caucasian and non-Caucasian populations. Although 64 genotypes have been observed, genotype 1 remains the most frequent as already observed in other populations. Such knowledge of the KIR gene distribution in populations is very useful in the study of associations with diseases and in selection of donors for haploidentical bone marrow transplantation

Local and distant recurrences in rectal cancer patients are predicted by the nonspecific immune response; specific immune response has only a systemic effect - a histopathological and immunohistochemical study

BACKGROUND: Invasion and metastasis is a complex process governed by the interaction of genetically altered tumor cells and the immunological and inflammatory host reponse. Specific T-cells directed against tumor cells and the nonspecific inflammatory reaction due to tissue damage, cooperate against invasive tumor cells in order to prevent recurrences. Data concerning involvement of individual cell types are readily available but little is known about the coordinate interactions between both forms of immune response. PATIENTS AND METHODS: The presence of inflammatory infiltrate and eosinophils was determined in 1530 patients with rectal adenocarcinoma from a multicenter trial. We selected 160 patients to analyze this inflammatory infiltrate in more detail using immunohistochemistry. The association with the development of local and distant relapses was determined using univariate and multivariate log rank testing. RESULTS: Patients with an extensive inflammatory infiltrate around the tumor had lower recurrence rates (3.4% versus 6.9%, p = 0.03), showing the importance of host response against tumor cells. In particular, peritumoral mast cells prevent local and distant recurrence (44% versus 15%, p = 0.007 and 86% versus 21%, p < 0.0001, respectively), with improved survival as a consequence. The presence of intratumoral T-cells had independent prognostic value for the occurrence of distant metastases (32% versus 76%, p < 0.0001). CONCLUSIONS: We showed that next to properties of tumor cells, the amount and type of inflammation is also relevant in the control of rectal cancer. Knowledge of the factors involved may lead to new approaches in the management of rectal cancer

Implications of the polymorphism of HLA-G on its function, regulation, evolution and disease association

The HLA-G gene displays several peculiarities that are distinct from those of classical HLA class I genes. The unique structure of the HLA-G molecule permits a restricted peptide presentation and allows the modulation of the cells of the immune system. Although polymorphic sites may potentially influence all biological functions of HLA-G, those present at the promoter and 3′ untranslated regions have been particularly studied in experimental and pathological conditions. The relatively low polymorphism observed in the MHC-G coding region both in humans and apes may represent a strong selective pressure for invariance, whereas, in regulatory regions several lines of evidence support the role of balancing selection. Since HLA-G has immunomodulatory properties, the understanding of gene regulation and the role of polymorphic sites on gene function may permit an individualized approach for the future use of HLA-G for therapeutic purposes

Photochemical Synthesis of Phenyl-2-thienyl Derivatives

The irradiation (in benzene solution) of 5-bromo-and 5-iodo-thiophene-2-carbaldehyde or the corresponding methyl ketones furnishes the corresponding 5-phenyl derivatives. The same reactivity for other halogenothiop henes is reported: 3,5 -di bromot hiophene-2 -carbalde hyde furnishes the 3-bromo-5 -phenyl-2-thienyl derivative while the corresponding di-iodo compound yields 3,5-diphenylthiophene-2 -carbalde h yde. I n contrast, 5-acetyl-2,3-di -iodot hiophene furnishes only the p hotosu bstitution product at C-5. Generally the iodine-containing compounds are more reactive and more stable under the reaction conditions than ones bearing bromine, in agreement with previous reports on the corresponding furan photochemistry. The photochemical synthesis of arylthiophenes (2) and (4) from the corresponding halogenothiophenes (1) and (1) -(2) probably occurs via the formation of the corresponding thienyl radical by homolytic cleavage of the C-I bond. This transformation has not been widely used in organic synthesis.&apos; For this reaction, we observe lower yields than for alternative methods [i.e. the reaction of phenylmagnesium bromide with iodide (1) in the presence of NiCl,(d~pe)~]. Furthermore, since 2-arylthiophenes (2) undergo a photorearrangement on prolonged irradiation, this method should be used with caution.&apos; Finally, no data are available in the literature about the possible extension of this photochemical procedure to halogenothiophenes different from those reported above. Recently we have reported a new synthetic methodology that furnishes aryl-substituted furancarbaldehydes or ketones (6), (8), or (10) in good yields from the corresponding halogen derivatives. (9, (7), or (9).8-10 In this case our data are in agreement with the formation of a transient exciplex of type (11). l 1 In this paper we report our results on the extension of the conversion of type (5) --+ (6) to thiophene derivatives. In this case, the possible formation of an exciplex of type (11) could not be excluded, since the chemical or photochemical generation of a radical-anion of compounds such as thiophene-2-carbaldehyde is a simple and well known process.12*13 We have prepared some thienyl derivatives (Scheme): these compounds were submitted to irradiation in benzene solution. As expected, the substitution reaction occurs giving high yields of the corresponding aryl derivatives. All the proposed structures of the products were confirmed by their 13C n.m.r. data. From the synthetic point of view, this method constitutes a useful methodology for the preparation of unknown or pharmacologically useful compounds; for example, the antiinflammatory activity of the acid (32) has been de~cribed,&apos;~ and it can be prepared from 5-phenylthiophene-2-carbaldehyde (17) through a known pr~cedure.&apos;~ I O C H

Use of Chitosan and Other Natural Compounds Alone or in Different Strategies with Copper Hydroxide for Control of Grapevine Downy Mildew

Grapevine downy mildew (GDM) is one of the most serious diseases of grapevines. Limitations to the use of copper-based products in organic agriculture according to the European Union (EU) regulation EU/2002/ 473 and the later EU Commission implementing regulation 2018/1981 have promoted a search for alternatives. This 5-year field trial evaluated the effectiveness of several strategies against GDM using different chitosan-based formulations and application rates in comparison with other natural compounds applied individually or with copper hydroxide. Trials were performed in commercial vineyards with different environmental conditions and grapevine cultivars. For the natural compounds applied as individual treatments, a 0.5%/0.8% chitosan formulation provided the best protection against GDM; the other compounds and formulations were less effective. When copper hydroxide use was halved by combining it with the natural compounds according to three different strategies, the GDM incidence, severity, and McKinney index were reduced, particularly for copper hydroxide applied in combination with the 0.5%/0.8% chitosan formulation. The 0.5%/0.8% chitosan formulation alone and with copper hydroxide provided good protection against GDM during both high-pressure and low-pressure disease seasons. Therefore, chitosan represents a good alternative to copper formulations for the control of GDM and both organic and integrated disease management