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J N Leonard

Publications and source records attributed to J N Leonard.

At least 19 recordsLinked to original sources
PubMed2006

Antiviral RNAi therapy: emerging approaches for hitting a moving target.

The field of directed RNA interference (RNAi) has rapidly developed into a highly promising approach for specifically down regulating genes to alleviate disease pathology. This technology is especially well-suited to treating viral infections, and numerous examples now illustrate that a wide range of viruses can be inhibited with RNAi, both in vitro and in vivo. One principle that has arisen from this work is that antiviral RNAi therapies must be tailored to the unique life cycle of each pathogen, including the choice of delivery vehicle, route of administration, gene(s) targeted and regulation and duration of RNAi induction. Although effective strategies will be customized to each virus, all such therapies must overcome similar challenges. Importantly, treatment strategies must compensate for the inevitable fact that viral genome sequences evolve extremely rapidly, and computational and bioinformatics approaches may aid in the development of therapies that resist viral escape. Furthermore, all RNAi strategies involve the delivery of nucleic acids to target cells, and all will therefore benefit from the development of enhanced gene design and delivery technologies. Here, we review the substantial progress that has been made towards identifying effective antiviral RNAi targets and discuss strategies for translating these findings into effective clinical therapies.

Genetic Engineering↗
PubMed1999

Sarcoidosis in a patient with linear IgA disease.

We report a patient with four conditions in association with linear IgA disease (LAD), only three of which have been reported previously; these latter are ulcerative colitis, autoimmune thyroid disease and carcinoma of the colon, although the carcinoma may have been caused by the ulcerative colitis in this case. Recently, our patient also presented with respiratory symptoms and was found to have sarcoidosis as well, a previously unreported association of this autoimmune bullous disorder. The aetiology of this development may be related to the patient's HLA status or possibly to his treatment with the immunosuppressive agent cyclophosphamide; it is also possible that it is coincidental.

Adenocarcinoma↗
PubMed1997

Absence of toxicity of oats in patients with dermatitis herpetiformis.

BACKGROUND: People with gluten sensitivity should avoid foods containing wheat, rye, and barley, but there has been debate about whether they should avoid oats. Although patients with celiac disease have recently been shown to tolerate oats, less is known about the effects of oats on patients with dermatitis herpetiformis. METHODS: We studied seven men and three women (mean age, 58 years) with biopsy-confirmed dermatitis herpetiformis. They had followed a strict gluten-free diet for a mean of 15.8 years, which controlled their rash and enteropathy. The patients added oats that were not contaminated with gluten to their diets for 12 weeks (mean [+/-SD] daily intake, 62.5+/-10.8 g). RESULTS: None of the patients had any adverse effects. Serologic tests for antigliadin, antireticulin, and antiendomysial antibodies were negative before oats were introduced into the diet and after they were discontinued. Villous architecture remained normal: the mean (+/-SE) ratio of the height of villi to the depth of crypts was 3.59+/-0.11 before the diet and 3.71+/-0.09 afterward (normal, 3 to 5), and the mean enterocyte heights were 31.36+/-0.58 microm and 31.75+/-44 microm, respectively (normal range, 29 to 34). Duodenal intraepithelial lymphocyte counts all remained within normal limits (mean, 13.8+/-1.03 per 100 enterocytes before the diet and 14.2+/-1.2 per 100 enterocytes afterward; normal range, 10 to 30). Dermal IgA showed no significant changes. CONCLUSIONS: Patients with dermatitis herpetiformis can include moderate amounts of oats in their gluten-free diets without deleterious effects to the skin or intestine.

Adult↗
PubMed1997

T-cell receptor V beta expression is restricted in dermatitis herpetiformis skin.

An infiltrate of T-cells is found in lesional dermatitis herpetiformis skin, but the role of these cells in the pathogenesis of the skin lesions is unknown. The purpose of this study was to examine T-cell receptor V beta expression in skin biopsies taken from patients with dermatitis herpetiformis. Expression of eleven T-cell receptor V beta families in biopsies obtained from 10 patients was examined by immunoperoxidase staining and compared simultaneously with peripheral blood lymphocytes. Over-representation of V beta 2 (p < 0.02), V beta 5.2/5.3 (p < 0.01) and V beta 5.3 (p < 0.05) was found in lesional dermatitis herpetiformis skin compared with peripheral blood lymphocytes. These results suggest that recognition of an antigen(s) or superantigen is involved in the pathogenesis of dermatitis herpetiformis skin lesions.

Adult↗
PubMed1997

Linear IgA disease and ulcerative colitis.

Seventy adult patients with linear IgA disease were studied. Five (7.1%) also suffered from ulcerative colitis (the prevalence of ulcerative colitis in the U.K. is 0.05%). A further three patients with this association, from other British centres were also reviewed. In all cases, ulcerative colitis preceded the onset of skin disease, by a median of 6.5 years. The reason for this association remains unclear but the abnormalities in colonic mucosal B cells and mucosal IgA1 production reported in patients with ulcerative colitis may be important in the subsequent development of IgA1 mediated linear IgA disease.

Adult↗
PubMed1996

Autoimmune haemolytic anaemia associated with dermatomyositis.

We report the case of a female patient who at presentation fulfilled the diagnostic criteria of dermatomyositis and also had an autoimmune haemolytic anaemia. Although autoimmune haemolysis is a well recognized feature of a number of autoimmune disorders, it has not previously been described in association with dermatomyositis.

Adult↗
PubMed1996

Protective effect of gluten-free diet against development of lymphoma in dermatitis herpetiformis.

A retrospective study of 487 patients with dermatitis herpetiformis showed that lymphoma developed in eight patients, the expected incidence being 0.21 (standardized registration ratio 3810). All lymphomas occurred in patients whose dermatitis herpetiformis had been controlled without a gluten-free diet (GFD) or in those who had been treated with a GFD for less than 5 years. The results are suggestive of a protective role for a GFD against lymphoma in dermatitis herpetiformis and give further support for advising patients to adhere to a strict GFD for life.

Adult↗
PubMed1995

Lack of proliferative response by gluten-specific T cells in the blood and gut of patients with dermatitis herpetiformis.

The majority of patients with Dermatitis Herpetiformis (DH) have a gluten-sensitive enteropathy which may be triggered by a T cell-mediated immune response to gluten. Using a proliferative assay, the responses to gluten fraction III, recall antigens and mitogens of peripheral blood mononuclear cells (PBMC) and gut T cell lines (TCL) isolated from patients with Dermatitis Herpetiformis (DH) and normal controls were studied. In most cases, neither PBMC nor gut T cell lines (which were predominantly CD3+, CD4+, TCR alpha beta +) from either controls or patients proliferated in response to gluten fraction III alone. However, the addition of 10 U/ml IL-2 to PBMC cultures containing gluten fraction III resulted in a marked increase in proliferation in 9/19 DH patients and 7/11 controls compared to IL-2 alone. Furthermore, gluten-induced upregulation of IL-2 receptor (CD25) expression was demonstrated on PBMC from 4/4 patients with DH and 2/3 controls after 7 days' culture with antigen. A similar effect by exogenous IL-2, or the same concentration of IL-4, was observed in 8/11 (P = 0.02) and 5/6 respectively DH, and 3/4 normal gut T cell lines. No difference was observed in the response of DH and control PBMC to Tetanus toxin, Candida albicans and PPD; both normal and DH gut T cell lines were unresponsive to these antigens. However, the addition of IL-2 increased the response to Candida albicans by DH gut T cell lines. Moreover, the response of DH gut T cell lines to PHA (P < 0.001), Concanavalin A and anti-CD3 were markedly reduced compared to PBMC from the same patients. These findings suggest that gluten-specific T cells present in the blood and gut of normal and DH individuals are activated by but do not proliferate in response to specific antigen.

Candida albicans↗
PubMed1995

Failure of intradermal skin testing with gluten to produce delayed hypersensitivity reactions in patients with dermatitis herpetiformis.

Dermatitis herpetiformis (DH) is characterized by a rash and a gluten-sensitive enteropathy (GSE) indistinguishable from that of coeliac disease. T-cell-mediated mechanisms have been implicated in the pathogenesis of GSE. It seems feasible that intradermal injection of gluten, in patients known to have GSE, could lead to an influx of T cells sensitized to gluten, with subsequent development of a delayed hypersensitivity-type reaction. Six patients with DH and three normal subjects had intradermal injections of 'Frazer's fraction III' (FFIII; the partial peptic tryptic digest of gluten which is known to be antigenic) and phosphate-buffered saline (PBS) as a control. Skin biopsies were taken at PBS and FFIII injection sites at 48 h. In addition, two of the patients with DH had biopsies taken of FFIII injection sites at 6 h. Monoclonal antibodies and the avidin-biotin-peroxidase technique were used to stain for T cells in the skin biopsies. A monoclonal antibody to a neoepitope exposed in the terminal complement complex and an immunofluorescent method were used to detect the presence of terminal complement component in biopsies taken from two of the control subjects and two of the patients. Both patients and control subjects developed a weal and flare within a few minutes of injecting the FFIII, and this persisted for up to 6 h. No skin reaction was present in either the patients or the control subjects at 48 h. No skin reaction was visible at any time following injection of PBS.(ABSTRACT TRUNCATED AT 250 WORDS)

Antibodies↗
PubMed1994

The value of biopsies in the evaluation of chronic progressive conjunctival cicatrisation.

BACKGROUND: Chronic progressive conjunctival cicatrisation is poorly understood, and therapy of this condition remains difficult. This study assessed the value of immunohistochemical investigations in the evaluation of patients who present with chronic cicatrising conjunctivitis similar to cicatricial pemphigoid (CP). METHODS: Bulbar conjunctival biopsies from 36 patients with acute (n = 5), subacute (n = 13) and chronic (n = 18) ocular disease were studied. The biopsy was retaken in 7 patients to evaluate the present immunological findings in comparison with a biopsy more then 5 years ago. All the specimens were investigated for the presence of immunoglobulins and complement at the epithelial basement membrane, and the phenotype of the inflammatory cellular infiltrate was analysed. Twenty-nine patients were evaluated for the presence of circulating IgG-anti-basement membrane zone antibodies. RESULTS: CP was confirmed by immunoglobulins and/or complement deposition at the epithelial basement membrane in 11 patients (31%). IgA was found to be the most frequent deposit. Eleven CP patients, mainly those with active or "burnt-out" disease, showed absence of immunoglobulins and/or complement at the conjunctival basement membrane. In 14 of 36 patients, conjunctival cicatrisation was subsequently felt to be caused by conditions other than CP. The cellular phenotype in the subepithelial conjunctiva was unspecific, but in CP the disease activity was reflected by the number of neutrophils and macrophages. Circulating IgG antibodies were found in none of the patients' serum. CONCLUSION: Immunoglobulin and/or complement deposition at the epithelial basement membrane confirms the diagnosis of mucous membrane pemphigoid. Their absence, however, does not rule it out and is a frequent feature in very active conjunctival disease or after immunosuppressive treatment. The analysis of the cellular phenotype in mucous membrane pemphigoid may be useful in the assessment of disease activity but does not help in determining the underlying disease process causing the cicatrising conjunctivitis.

Acute Disease↗
PubMed1994

25 years' experience of a gluten-free diet in the treatment of dermatitis herpetiformis.

Gluten-free diets have been used in the treatment of patients with dermatitis herpetiformis in our department since 1967. Of the 212 patients with dermatitis herpetiformis attending between 1967 and 1992, 133 managed to take the diet, and 78 of these achieved complete control of their rash by diet alone. Of the remaining 55 patients taking a gluten-free diet, all but three were taking partial diets; over half of these patients managed to substantially reduce the dose of medication required. Of the 77 patients taking a normal diet, eight entered spontaneous remission, giving a remission rate of 10%; a further two patients who had been taking gluten-free diets were found to have remitted when they resumed normal diets. Loss of IgA from the skin was observed in 10 of 41 (24%) patients taking strict gluten-free diets. These patients had been taking their diets for an average of 13 years (range 5-24 years), and their rash had been controlled by diet alone for an average of 10 years (range 3-16 years). The advantages of a gluten-free diet in the management of patients with dermatitis herpetiformis are: (i) the need for medication is reduced or abolished; (ii) there is resolution of the enteropathy, and (iii) patients experience a feeling of well-being after commencing the diet. Thus, we propose that a gluten-free diet is the most appropriate treatment for patients with dermatitis herpetiformis.

Adolescent↗
PubMed1994

T lymphocytes in lesional skin of patients with dermatitis herpetiformis.

Ten patients with dermatitis herpetiformis had biopsies taken from involved and uninvolved skin. Monoclonal antibodies and the avidin-biotin peroxidase staining technique were used to stain for T cells and Langerhans cells in skin sections. A significant increase in the number of CD3-positive T cells was observed in the upper dermis of involved compared with uninvolved skin (P < 0.0005). Most of the T cells in involved skin were CD45RO-positive memory cells; CD4-positive T cells exceeded the number of CD8-positive T cells by a ratio of 4:1. In addition, CD1a-positive dendritic cells were observed within the clumps of T cells in involved dermis in nine of the 10 patients, but were absent from the dermis of uninvolved skin. Double immunofluorescent staining demonstrated that approximately 20-40% of the CD3-positive T cells were activated, and expressed the HLA-DR antigen. These findings suggest that activated T cells are involved in the pathogenesis of dermatitis herpetiformis skin lesions.

CD3 Complex↗
PubMed1993

Cytokines in the conjunctiva of acute and chronic mucous membrane pemphigoid: an immunohistochemical analysis.

The aim of this study was to evaluate the potential role of certain soluble factors in conjunctival scar tissue formation of pemphigoid patients. Epibulbar conjunctival biopsy specimens were taken from patients with acute ulcerative (n = 4), subacute (n = 8) and chronic (n = 8) mucous membrane pemphigoid and from twelve age-matched healthy individuals. The tissues were embedded in glycol methacrylate and analysed by immunohistochemical methods. Interleukin-2 (IL-2), interferon-gamma, transforming growth factor-beta (TGF-beta), platelet-derived growth factor (PDGF), basic fibroblast growth factor (bFGF), tumour necrosis factor-alpha and proliferating cells (as identified with the antibody Ki-67) were found in both pemphigoid patients and normal controls. Interleukin-4 was not found with this method in either normal or diseased conjunctiva. Significant differences between normal and diseased conjunctiva were found for TGF-beta and for proliferating cells, which were both increased in the acute disease group. More intense staining was found in the subacute disease group for IL-2, bFGF and PDGF. Our findings showed that a variety of cytokines were present in normal and diseased bulbar conjunctiva. Acute conjunctival disease in mucous membrane pemphigoid may indicate active scar tissue formation, implied by an increase in TGF-beta and the presence of proliferating fibroblasts.

Acute Disease↗
PubMed1993

The conjunctiva in acute and chronic mucous membrane pemphigoid. An immunohistochemical analysis.

BACKGROUND: The mechanism of chronic progressive conjunctival cicatrization in mucous membrane pemphigoid is not well understood, and current therapy is often of limited use. Rapid progression of cicatrization follows exacerbations of clinical inflammation, and the investigation of immune mechanisms related to disease activity may provide a clue for more effective therapeutic strategies. METHODS: The authors undertook an immunohistochemical study, using monoclonal and polyclonal antibodies in glycol methacrylate-embedded tissues, of epibulbar conjunctival biopsy specimens obtained from 20 patients with ocular cicatricial pemphigoid and from 12 matched healthy controls. The study patients were classified according to the ocular disease activity as acute ulcerative (n = 4), subacute (n = 8), and chronic (n = 8). RESULTS: The composition of the subepithelial cellular infiltrate varied with disease activity. Acute disease was characterized by an abundance of macrophages and neutrophils. The number of T lymphocytes was significantly raised in all the disease groups, but were most marked in subacute disease. Of the T-cell subsets, there were more CD8- than CD4-positive cells observed, except in acute disease where there were equal numbers. Only approximately 5% of the T cells in all disease groups were activated as demonstrated by expression of interleukin-2 receptor. There was increased expression of major histocompatibility complex class II (MHC II) molecules on macrophages, fibroblasts, and other cells in all the groups. The number of B cells and natural killer cells was not increased. Staining for the fibrogenic cytokines, transforming growth factor-beta (TGF-beta), platelet-derived growth factor, and basic fibroblast growth factor was found in both pemphigoid patients and control persons, but the intensity of TGF-beta staining was significantly greater in acute disease. CONCLUSIONS: The composition of the cellular infiltrate in the bulbar conjunctiva depends on clinical disease activity. The numbers of neutrophils and macrophages seem to reflect clinical disease activity. Fibrogenic cytokines, especially TGF-beta, may play an important role in the formation of conjunctival scar tissue.

Acute Disease↗
PubMed1993

The role of cytokines in the generation of skin lesions in dermatitis herpetiformis.

The infiltration of polymorphonuclear neutrophils (PMN) into the upper dermis which characterizes the skin lesions of dermatitis herpetiformis (DH) has never been satisfactorily explained. This study has shown that lesional skin of patients with DH has increased expression of endothelial leucocyte adhesion molecules (ELAM) in the deep dermis, combined with a markedly increased staining for interleukin 8 (IL-8) in the basal epidermal layer. Dendritic cells which stained for granulocyte macrophage colony stimulating factor (GM-CSF) were also observed at the dermo-epidermal junction, and this phenomenon was more pronounced in lesional than in uninvolved DH skin. ELAM, IL-8 and GM-CSF are known to promote infiltration and activation of PMN, and it is suggested that these cytokines may play a key role in the generation of DH lesions.

Adult↗