Reduced Self-Reactivity of an Autoreactive T Cell After Activation with Cross-reactive Non–Self-Ligand

Autoreactive CD4+ T lymphocytes are critical to the induction of autoimmune disease, but because of the degenerate nature of T cell receptor (TCR) activation such receptors also respond to other ligands. Interaction of autoreactive T cells with other non–self-ligands has been shown to activate and expand self-reactive cells and induce autoimmunity. To understand the effect on the autoreactivity of naive cross-reactive T cells of activation with a potent nonself ligand, we have generated a TCR transgenic mouse which expresses a TCR with a broad cross-reactivity to a number of ligands including self-antigen. The activation of naive transgenic recombination activating gene (Rag)2−/− T cells with a potent non–self-ligand did not result in a enhancement of reactivity to self, but made these T cells nonresponsive to the self-ligand and anti-CD3, although they retained a degree of responsiveness to the non–self-ligand. These desensitized cells had many characteristics of anergic T cells. Interleukin (IL)-2 production was selectively reduced compared with interferon (IFN)-γ. p21ras activity was reduced and p38 mitogen-activated protein kinase (MAPK) was relatively spared, consistent with known biochemical characteristics of anergy. Surprisingly, calcium fluxes were also affected and the anergic phenotype could not be reversed by exogenous IL-2. Therefore, activation with a hyperstimulating non–self-ligand changes functional specificity of an autoreactive T cell without altering the TCR. This mechanism may preserve the useful reactivity of peripheral T cells to foreign antigen while eliminating responses to self

The RIPI-f (Reporting Integrity of Psychological Interventions delivered face-to-face) checklist was developed to guide reporting of treatment integrity in face-to-face psychological interventions.

Objectives: Intervention integrity is the degree to which the study intervention is delivered as intended. This article presents the RIPI-f checklist (Reporting Integrity of Psychological Interventions delivered face-to-face) and summarizes its development methods. RIPI-f proposes guidance for reporting intervention integrity in evaluative studies of face-to-face psychological interventions. Study Design and Setting: We followed established procedures for developing reporting guidelines. We examined 56 documents (reporting guidelines, bias tools, and methodological guidance) for relevant aspects of face-to-face psychological intervention integrity. Eighty four items were identified and grouped as per the template for intervention description and replication (TIDieR) domains. Twenty nine experts from psychology and medicine and other scholars rated the relevance of each item in a single-round Delphi survey.Amultidisciplinary panel of 11 experts discussed the survey results in three online consensus meetings and drafted the final version of the checklist. Results: We propose RIPI-f, a checklist with 50 items. Our checklist enhances TIDieR with important extensions, such as therapeutic alliance, provider’s allegiance, and the adherence of providers and participants. Conclusion: RIPI-f can improve the reporting of face-to-face psychological interventions. The tool can help authors, researchers, systematic reviewers, and guideline developers. We suggest using RIPI-f alongside other reporting guidelines.post-print504 K

The RIPI-f (Reporting Integrity of Psychological Interventions delivered face-to-face) checklist was developed to guide reporting of treatment integrity in face-to-face psychological interventions

Objective: Intervention integrity is the degree to which the study intervention is delivered as intended. This article presents the RIPI-f checklist (Reporting Integrity of Psychological Interventions delivered face-to-face) and summarizes its development methods. RIPI-f proposes guidance for reporting intervention integrity in evaluative studies of face-to-face psychological interventions. Study design and setting: We followed established procedures for developing reporting guidelines. We examined 56 documents (reporting guidelines, bias tools, and methodological guidance) for relevant aspects of face-to-face psychological intervention integrity. Eighty-four items were identified and grouped according to the template for intervention description and replication (TIDieR) domains. Twenty-nine experts from psychology and medicine and other scholars rated the relevance of each item in a single-round Delphi survey. A multidisciplinary panel of 11 experts discussed the survey results in three online consensus meetings and drafted the final version of the checklist. Results: We propose RIPI-f, a checklist with 50 items. Our checklist enhances TIDieR with important extensions, such as therapeutic alliance, provider's allegiance, and the adherence of providers and participants. Conclusion: RIPI-f can improve the reporting of face-to-face psychological interventions. The tool can help authors, researchers, systematic reviewers, and guideline developers. We suggest using RIPI-f alongside other reporting guidelines

Local Suppression of T Cell Responses by Arginase-Induced L-Arginine Depletion in Nonhealing Leishmaniasis

The balance between T helper (Th) 1 and Th2 cell responses is a major determinant of the outcome of experimental leishmaniasis, but polarized Th1 or Th2 responses are not sufficient to account for healing or nonhealing. Here we show that high arginase activity, a hallmark of nonhealing disease, is primarily expressed locally at the site of pathology. The high arginase activity causes local depletion of L-arginine, which impairs the capacity of T cells in the lesion to proliferate and to produce interferon-γ, while T cells in the local draining lymph nodes respond normally. Healing, induced by chemotherapy, resulted in control of arginase activity and reversal of local immunosuppression. Moreover, competitive inhibition of arginase as well as supplementation with L-arginine restored T cell effector functions and reduced pathology and parasite growth at the site of lesions. These results demonstrate that in nonhealing leishmaniasis, arginase-induced L-arginine depletion results in impaired T cell responses. Our results identify a novel mechanism in leishmaniasis that contributes to the failure to heal persistent lesions and suggest new approaches to therapy

Local Increase of Arginase Activity in Lesions of Patients with Cutaneous Leishmaniasis in Ethiopia

The leishmaniases are a complex of diseases caused by Leishmania parasites. Currently, the diseases affect an estimated 12 million people in 88 countries, and approximately 350 million more people are at risk. The leishmaniases belong to the most neglected tropical diseases, affecting the poorest populations, for whom access to diagnosis and effective treatment are often not available. Leishmania parasites infect cells of the immune system called macrophages, which have the capacity to eliminate the intracellular parasites when they receive the appropriate signals from other cells of the immune system. In nonhealing persistent leishmaniasis, lymphocytes are unable to transmit the signals to macrophages required to kill the intracellular parasites. The local upregulation of the enzyme arginase has been shown to impair lymphocyte effector functions at the site of pathology. In this study, we tested the activity of this enzyme in skin lesions of patients presenting with localized cutaneous leishmaniasis. Our results show that arginase is highly upregulated in these lesions. This increase in arginase activity coincides with lower expression of a signalling molecule in lymphocytes, which is essential for efficient activation of these cells. These results suggest that increased arginase expression in the localized cutaneous lesions might contribute to persistent disease in patients presenting with cutaneous leishmaniasis

Age-Related Alteration of Arginase Activity Impacts on Severity of Leishmaniasis

It is well documented that ageing alters many aspects of immune responses; however, a causal relation between impaired immune functions in ageing individuals and the response to infection has not been established. Experimental leishmaniasis is an excellent model to analyse protective and pathological immune responses. Leishmania parasites are obligate intracellular pathogens and invade mainly macrophages, which have dual function: they can kill the parasites or promote their growth. We have recently shown that arginase, an enzyme induced in infected macrophages, is a key factor for parasite survival. Here, we show that ageing reduces the expression levels of arginase in macrophages, resulting in more efficient control of parasite growth. Our results suggest that age-related differences in the metabolism of arginase in macrophages might contribute to the higher susceptibility of children to leishmaniasis

Quiescent and activated mouse granulocytes do not express granzyme A and B or perforin: similarities or differences with human polymorphonuclear leukocytes?

Polymorphonuclear leukocytes have been shown to use a multitude of effector functions to combat pathogens and tumors, including enzymes, defensins, and toxic products such as oxygen radicals and nitrogen oxides. Recent studies provided evidence for the expression of granzymes (gzms) and perforin (perf) within the cytotoxic arsenal of human neutrophils, the validity of which was questioned by 2 subsequent studies. We have now used cytology, intracellular flow cytometry, enzymatic assays, immunoelectron microscopy, and quantitative reverse transcriptase-polymerase chain reaction to obtain evidence of the presence of gzms and/or perf in mouse Gr-1+ granulocyte populations. The data obtained clearly demonstrate that neither in vitro-nor in vivo-derived mouse granulocytes synthesize gzmA and gzmB or perf, even following infection/immunization with pathogens or pathogen-derived material. A parallel comparable analysis on the expression of gzmB in human neutrophils from 3 healthy control subjects and 4 patients with diverse diseases failed to detect gzmB expression. The data indicate that polymorphonuclear leukocytes from mice and humans lack the 3 cytotoxic effector molecules, gzmA, gzmB, and perf, generally associated with natural killer and cytotoxic T lymphocytes