3-hydroxykynurenine suppresses CD4+ T-cell proliferation, induces T-regulatory-cell development, and prolongs corneal allograft survival

Copyright © 2011 Association for Research in Vision and Ophthalmology. This article is available open access through the publisher’s website at the link below.Purpose. IDO (indoleamine 2,3-dioxygenase) modulates the immune response by depletion of the essential amino acid tryptophan, and IDO overexpression has been shown to prolong corneal allograft survival. This study was conducted to examine the effect of kynurenines, the products of tryptophan breakdown and known to act directly on T lymphocytes, on corneal graft survival. Methods. The effects of kynurenines on T-cell proliferation and death, T-regulatory-cell development, and dendritic cell function, phenotype, and viability were analyzed in vitro. The effect of topical and systemic administration of 3-hydroxykynurenine (3HK) on orthotopic murine corneal allograft survival was examined. Results. T-lymphocyte proliferation was inhibited by two of the four different kynurenines: 3HK and 3-hydroxyanthranilic acid (3HAA). This effect was accompanied by significant T-cell death. Neither 3HK nor 3HAA altered dendritic cell function, nor did they induce apoptosis or pathogenicity to corneal endothelial cells. Administration of systemic and topical 3HK to mice receiving a fully mismatched corneal graft resulted in significant prolongation of graft survival (median survival of control grafts, 12 days; of treated, 19 and 15 days, respectively; P < 0.0003). While systemic administration of 3HK was associated with a significant depletion of CD4+ T, CD8+ T, and B lymphocytes in peripheral blood, no depletion was found after topical administration. Conclusions. The production of kynurenines, in particular 3HK and 3HAA, may be one mechanism (in addition to tryptophan depletion) by which IDO prolongs graft survival. These molecules have potential as specific agents for preventing allograft rejection in patients at high rejection risk.Fight for Sight and the Wellcome Trust

HLA-DP Allele-Specific T Cell Responses to Beryllium Account for DP-Associated Susceptibility to Chronic Beryllium Disease

Abstract Occupational exposure to small molecules, such as metals, is frequently associated with hypersensitivity reactions. Chronic beryllium (Be) disease (CBD) is a multisystem granulomatous disease that primarily affects the lung, and occurs in ∼3% of individuals exposed to this element. Immunogenetic studies have demonstrated a strong association between CBD and possession of alleles of HLA-DP containing glutamic acid (Glu) at position 69 in the HLA-DPβ-chain. T cell clones were raised from three patients with CBD in whom exposure occurred 10 and 30 years previously. Of 25 Be-specific clones that were obtained, all were restricted by HLA-DP alleles with Glu at DPβ69. Furthermore, the proliferative responses of the clones were absolutely dependent upon DPβ Glu69 in that a single amino acid substitution at this position abolished the response. As befits a disease whose pathogenesis involves a delayed type hypersensitivity response, the large majority of Be-specific clones secreted IFN-γ (Th1) and little or no IL-4 (Th2) cytokines. This study provides insights into the molecular basis of DP2-associated susceptibility to CBD

Assessment of rectal toxicities after radiation therapy for localized prostate cancer: experience of the Akanda Cancer Institute in Gabon

Background: The purpose was to evaluate the incidence of acute and late rectal toxicities and their correlation with the clinical and dosimetric parameters of patients who underwent curative radiotherapy for localized prostate cancer at the Akanda Cancer Institute, Gabon. Materials and methods: Between 2013 and 2021, a cohort of 46 patients with clinically localized stage cT1c–T4 prostate cancer was treated with three-dimensional conformal radiation therapy (3D-CRT) at the national cancer institute with doses ranging from 66 to 80 Gy. Post-radiation gastrointestinal (GI) toxicities were classified and graded according to the Common Terminology Criteria for Adverse Events (CTCAE) v4.0. Results: In our study, 17.4% (8/46) developed acute GI. Grades 1 and 3 acute GI complications were seen in 13.0% (6/46) and 4.3% (2/46), respectively. No patient developed acute grade 2 or grade higher than 3 complications. Late GI side effects were limited. The median time to the development of late GI Grade ≥ 1 toxicities was 12 months (range: 9-19 months). 10.9% (5/46) had experience late GI. Among them, grade 1 and 2 were seen in 6.5% (3/46), and 4.3% (2/46), respectively. There was no grade 3 or higher complications. Statistically, we did not find any correlation between the presence of rectal toxicity and clinical factors or the presence of comorbidity. On the dosimetric level, the Mann-Whitney statistical test found a correlation between the presence of late GI toxicity and rectal volume irradiated at the prescribed dose (p = 0.02). Conclusion: Despite the high radiation doses involved, our results showed an acceptable complication rate.

Constraints on the Galactic Halo Dark Matter from Fermi-LAT Diffuse Measurements

We have performed an analysis of the diffuse gamma-ray emission with the Fermi Large Area Telescope (LAT) in the Milky Way halo region, searching for a signal from dark matter annihilation or decay. In the absence of a robust dark matter signal, constraints are presented. We consider both gamma rays produced directly in the dark matter annihilation/decay and produced by inverse Compton scattering of the e+/e produced in the annihilation/decay. Conservative limits are derived requiring that the dark matter signal does not exceed the observed diffuse gamma-ray emission. A second set of more stringent limits is derived based on modeling the foreground astrophysical diffuse emission using the GALPROP code. Uncertainties in the height of the diffusive cosmic-ray halo, the distribution of the cosmic-ray sources in the Galaxy, the index of the injection cosmic-ray electron spectrum, and the column density of the interstellar gas are taken into account using a profile likelihood formalism, while the parameters governing the cosmic-ray propagation have been derived from fits to local cosmic-ray data. The resulting limits impact the range of particle masses over which dark matter thermal production in the early universe is possible, and challenge the interpretation of the PAMELA/Fermi-LAT cosmic ray anomalies as the annihilation of dark matter

Immunology and genetics of type 1 diabetes

Type 1 diabetes is one of the most well-characterized autoimmune diseases. Type 1 diabetes compromises an individual's insulin production through the autoimmune destruction of pancreatic Β-cells. Although much is understood about the mechanisms of this disease, multiple potential contributing factors are thought to play distinct parts in triggering type 1 diabetes. The immunological diagnosis of type 1 diabetes relies primarily on the detection of autoantibodies against islet antigens in the serum of type 1 diabetes mellitus patients. Genetic analyses of type 1 diabetes have linked human leukocyte antigen, specifically class II alleles, to susceptibility to disease onset. Environmental catalysts include various possible factors, such as viral infections, although the evidence linking infections with type 1 diabetes remains inconclusive. Imbalances within the immune system's system of checks and balances may promote immune activation, while undermining immune regulation. A lack of proper regulation and overactive pathogenic responses provide a framework for the development of autoimmune abnormalities. Type 1 diabetes is a predictable and potentially treatable disease that still requires much research to fully understand and pinpoint the exact triggering events leading to autoimmune activation. In silico research can aid the comprehension of the etiology of complex disease pathways, including Type I diabetes, in order to and help predict the outcome of therapeutic strategies aimed at preserving Β-cell function. Mt Sinai J Med 75:314–327, 2008. © 2008 Mount Sinai School of MedicinePeer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/60987/1/20052_ftp.pd

The politics of ageing: health consumers, markets and hegemonic challenge

In recent years ageing has travelled from the placid backwaters of politics into the mainstream of economic, social and cultural debate. What are the forces that have politicised ageing, creating a sustained opposition to the supply side hegemony of pharmaceuticals, medicine and state which has historically constructed, propagated and legitimised the understanding of ageing as decline in social worth? In addressing this question, the paper develops Gramsci's theory of hegemony to include the potentially disruptive demand side power of consumers and markets. It shows how in the case of ageing individuals acting in concert through the mechanisms of the market, and not institutionalised modes of opposition, may become the agents of hegemonic challenge through a combination of lifecourse choice and electoral leverage. In response, the hegemony is adapting through the promotion of professionally defined interpretations of ‘active ageing’ designed to retain hegemonic control. With the forces of hegemony and counter‐hegemony nicely balanced and fresh issues such as intergenerational justice constantly emerging, the political tensions of ageing are set to continue

Vasodilator factors in the systemic and local adaptations to pregnancy

We postulate that an orchestrated network composed of various vasodilatory systems participates in the systemic and local hemodynamic adaptations in pregnancy. The temporal patterns of increase in the circulating and urinary levels of five vasodilator factors/systems, prostacyclin, nitric oxide, kallikrein, angiotensin-(1–7) and VEGF, in normal pregnant women and animals, as well as the changes observed in preeclamptic pregnancies support their functional role in maintaining normotension by opposing the vasoconstrictor systems. In addition, the expression of these vasodilators in the different trophoblastic subtypes in various species supports their role in the transformation of the uterine arteries. Moreover, their expression in the fetal endothelium and in the syncytiotrophoblast in humans, rats and guinea-pigs, favour their participation in maintaining the uteroplacental circulation. The findings that sustain the functional associations of the various vasodilators, and their participation by endocrine, paracrine and autocrine regulation of the systemic and local vasoactive changes of pregnancy are abundant and compelling. However, further elucidation of the role of the various players is hampered by methodological problems. Among these difficulties is the complexity of the interactions between the different factors, the likelihood that experimental alterations induced in one system may be compensated by the other players of the network, and the possibility that data obtained by manipulating single factors in vitro or in animal studies may be difficult to translate to the human. In addition, the impossibility of sampling the uteroplacental interface along normal pregnancy precludes obtaining longitudinal profiles of the various players. Nevertheless, the possibility of improving maternal blood pressure regulation, trophoblast invasion and uteroplacental flow by enhancing vasodilation (e.g. L-arginine, NO donors, VEGF transfection) deserves unravelling the intricate association of vasoactive factors and the systemic and local adaptations to pregnancy

Monocytes and macrophages in pregnancy and pre-eclampsia

Preeclampsia is an important complication in pregnancy, characterized byhypertension and proteinuria in the second half of pregnancy. Generalizedactivation of the inflammatory response is thought to play a role in thepathogenesis of preeclampsia. Monocytes may play a central role in thisinflammatory response. Monocytes are short lived cells, that mature in thecirculation and invade into tissues upon an inflammatory stimulus anddevelop into macrophages. Macrophages are abundantly present in theendometrium and play a role in implantation and placentation in normalpregnancy. In preeclampsia, these macrophages appear to be present in largernumbers and are also activated. In the present review we focused on the roleof monocytes and macrophages in the pathophysiology of preeclampsia