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PubMed1994

Acute febrile neutrophilic dermatosis (Sweet's syndrome) associated with extreme infiltration of eosinophils.

A remarkable infiltration of eosinophils was observed in skin biopsy specimens in two cases of Sweet's syndrome. One patient was a 29-year-old woman, whose clinical and histological features included associated asthma, a prior respiratory tract infection, red plaques, blood eosinophilia, and a dense dermal infiltrate of neutrophils and eosinophils, without evidence of vasculitis. The other patient was a 61-year-old man characterized by a fever, red plaques, erythema nodosum-like lesions, hepatic dysfunction, a dermal infiltrate of neutrophils accompanied by eosinophils, and a subcutaneous prominent infiltrate of eosinophils. Clinical and histological evidence supported the diagnosis of Sweet's syndrome in both of these patients. While the literature describes eosinophil infiltration in this disease, extreme eosinophil infiltration could be misleading in the diagnosis.

Adult↗

PubMed1997

The inhibitory effect of anti-adhesion molecule antibodies on eosinophil infiltration in cutaneous late phase response in Balb/c mice sensitized with ovalbumin (OVA).

In this study, we investigated the involvement of the adhesion molecules intercellular adhesion molecule-1 (ICAM-1), vascular cell adhesion molecule-1 (VCAM-1), very late activation antigen-4 (VLA-4), lymphocyte function-associated antigen 1 (LFA-1) and macrophage antigen-1 (Mac-1) on eosinophil infiltration in the cutaneous late phase response (LPR) in OVA-sensitized Balb/c mice by two approaches, immunostaining and inhibition assays with each monoclonal antibody. The eosinophil infiltration into the skin reached a peak at 12 hr after an intradermal challenge with OVA. Infiltrated eosinophils and mononuclear cells in the skin expressed Mac-1 (eosinophils: 38.9 +/- 1.55%, mononuclear cells: 51.2 +/- 2.15%), LFA-1 (eosinophils: 33.3 +/- 0.95%, mononuclear cells: 23.1 +/- 1.07%) and VLA-4 (eosinophils: 14.3 +/- 1.6%, mononuclear cells: 17.2 +/- 1.38%) at 12 h. Intraperitoneal administration of anti-mouse ICAM-1, VCAM-1, and VLA-4 monoclonal antibodies (mAb) before the challenge decreased the eosinophil infiltration by 66.2%, 61.0%, and 54.0%, respectively. On the other hand, pretreatment with anti-mouse LFA-1 mAb or Mac-1 mAb did not significantly decrease the infiltration. These results suggest that VCAM-1/VLA-4 interaction and ICAM-1 play important roles in eosinophil infiltration in cutaneous LPR.

Animals↗

PubMed1999

Characterization of infiltrating T cells in human scalp explants from alopecia areata to SCID nude mice: possible role of the disappearance of CD8+ T lymphocytes in the process of hair regrowth.

T cells may play a role in the pathogenesis of alopecia areata (AA). We attempted to elucidate the linkage between infiltrating T cells and hair regrowth processes by grafting scalp skin from the affected region of patients with AA onto severe combined immune deficiency (SCID) nude mice. When the AA scalp was grafted into the mice, the grafts were accepted, and normal hair regrowth was observed. Before grafting, CD4+ and CD8+ T cells had infiltrated into the peribulb area. After grafting, the telogen hair shifted to anagen hair, and the CD4+ and CD8+ T cell infiltrates in the bulb area decreased in all cases. CD8+ T cells had almost disappeared from all portions of the follicles. It has been suggested that CD8+ T cells play a crucial role in the pathogenesis of AA. The absence of CD8+ T lymphocytes that responded to follicular autoantigens may induce hair regrowth in the grafted skin. In addition, the CD4+ human T cells that had infiltrated or still remained in the upper-middle portions including the bulge area accompanied the HLA-DR expression after grafting. Infiltrating or surviving T cell phenotypes and locations changed during the hair cycle in the grafts. These results indicate that the location of infiltrated T cells and their phenotypes may participate not only in hair loss but also in regrowth of hair in AA.

Adult↗

PubMed2002

Initial recruitment of interferon-gamma-producing CD8+ effector cells, followed by infiltration of CD4+ cells in 2,4,6-trinitro-1-chlorobenzene (TNCB)-induced murine contact hypersensitivity reactions.

Contact hypersensitivity (CHS) is an antigen-specific, T-cell-mediated skin reaction in sensitized individuals. Recent studies have demonstrated that the murine CHS reaction to 2,4-dinitrofluorobenzene (DNCB) is mediated by CD8+ T cells and down-regulated by CD4+ T cells. We studied cellular events and functions of infiltrating cells in CHS reactions to 2,4,6-trinitro-1-chlorobenzene (TNCB) in the skin and draining lymph nodes (LN) of BALB/c mice and compared them with the CHS reaction to a house dust mite antigen, Dermatophagoides farinae (Df). Mice were sensitized with TNCB or Df antigens, and CHS reactions elicited with the corresponding antigens were examined immunohistologically. Cytokines produced by individual cells isolated from the CHS reactions were analyzed by flow cytometry, and the expression of cytokine mRNA was assayed by reverse transcription-polymerase chain reaction (RT-PCR). Results demonstrated that the intensity of TNCB-elicited CHS skin reactions reached its peak at 24 hr after elicitation and decreased gradually. Flow cytometric analysis of isolated cells from the TNCB-elicited CHS reactions demonstrated that the infiltrating cells were composed of approximately 25% CD4+ and CD8+ cells at 12, 24, and 36 hr after challenge, although infiltrating cells became dense at 36 hr by histological observation. The percentage of IFN-gamma-producing CD8+ cells (Tc1) in the cell fractions reached its peak at 12 hr and decreased gradually. The peak infiltration of IFN-gamma-producing CD4+ cells (Th 1) was observed at 24 hr. IL-4-producing cells, however, were always below 5% in the cell fractions. The RT-PCR method demonstrated that IFN-gamma mRNA was detected in the TNCB-elicited skin reactions at 12, 18 and 24 hr after elicitation, became weak at 48 hr, and disappeared at 72 hr. No IL-4 mRNA was detected from 12 to 72 hr. In the draining LN cells, however, the percentages of both IFN-gamma-producing CD8+ (Tc1) and CD4+ cells (Th1) decreased 12 to 36 hr after TNCB elicitation. CHS reactions of Df antigens were predominantly composed of infiltrations of CD4+ cells in to the skin, associated with the expression of IL-4 mRNA from 12 to 48 hr after elicitaion. The expression of IFN-gamma mRNA was detected at 48 hr or later. Our findings indicate that the CHS skin reaction to TNCB is induced by early recruitment of IFN-gamma-producing CD8+ effector cells (Tcl), followed by infiltration of IFN-gamma-producing CD4+ cells (Th1), whereas IL-4-producing T cells (Th2) induce the early CHS response to Df antigens.

Animals↗

PubMed2004

Evaluation of inflammatory infiltrate and fibrogenic cytokines in pseudopelade of Brocq suggests the involvement of T-helper 2 and 3 cytokines.

BACKGROUND: Pseudopelade of Brocq (PB) is an acquired progressive cicatricial alopecia which is characterized by some distinctive clinical features. It may represent either a distinct entity, i.e. an idiopathic primary scarring alopecia, or the end stage of various forms of scarring alopecia such as discoid lupus erythematosus (DLE) or lichen planopilaris (LPP). OBJECTIVES: The aim of the study was to evaluate a set of patients with a clinically defined PB, to ascertain whether their PB was idiopathic or secondary, and then to study the phenotype of the inflammatory infiltrate and the presence of any fibrogenic and antifibrogenic cytokines to identify idiopathic or secondary forms in more detail. METHODS: Twelve female patients with PB were studied by means of histology, direct immunofluorescence (DIF) and immunohistochemistry, by using monoclonal antibodies to cell markers (lymphocyte subtypes, Langerhans cells, macrophages, fibroblasts, mastocytes and activation markers) and fibrogenic and antifibrogenic cytokines. RESULTS: Using histology and DIF, we diagnosed two cases as DLE and three cases as LPP. Seven cases had nonspecific histology or DIF appearances and were classified as noncharacterized pseudopelade (NCPB). Two major phenotypic patterns of dermal infiltrate were identified by immunohistochemistry. These were: (i) a conspicuous infiltrate of CD3+ cells with a high CD4+/CD8+ ratio, variable numbers of macrophages, mast cells and fibroblasts always fewer than lymphocytes; (ii) an infiltrate of CD3+ cells with variable CD4+/CD8+ ratio and conspicuous amounts of macrophages, mast cells and fibroblasts, more numerous than infiltrating lymphocytes. The first pattern was typical of DLE and LPP, the second one was typical of NCPB. Fibrogenic cytokines were observed in all cases, but basic fibroblastic growth factor (bFGF) and transforming growth factor (TGF)-beta were more strongly expressed in NCPB. Interferon (IFN)-gamma was found in LPP. CONCLUSIONS: In our PB patients we identified five of 12 secondary PB and seven of 12 idiopathic PB by means of histology and DIF. The phenotypic pattern of infiltration allowed us to further differentiate secondary (richer in lymphocytes) from idiopathic PB (richer in resident cells). The pattern of cytokine expression showed the presence of fibrogenic molecules (interleukins 4 and 6, bFGF and TGF-beta) in all cases, suggesting the involvement of mechanisms mediated by T-helper 2 and 3 cytokines in PB.

Adult↗

PubMed1992

Immunohistochemical characterization of infiltrating mononuclear cells in the rat heart with experimental autoimmune giant cell myocarditis.

The pathogenesis of giant cell myocarditis remains unclear. Subsets of inflammatory infiltrating cells may reflect the pathogenesis and etiology of the disease. Therefore, we examined subsets of infiltrating mononuclear cells in the heart of the rat with experimental giant cell myocarditis. Lewis rats were immunized with cardiac myosin in Freund's complete adjuvant (FCA). Severe myocarditis characterized by congestive heart failure and multinucleated giant cells were elicited. The lesions were composed of predominant mononuclear cells, polymorphonuclear neutrophils and fragments of degenerated myocardial fibres. The subsets of infiltrating mononuclear cells were investigated using MoAbs against rat CD4+ T cell (W3/25), CD8+ T cell (CX8), B cell (OX33) and macrophage (OX42). By serial examination, bound immunoglobulin could only be found on degenerated myocardial fibres. In this model, most infiltrating mononuclear cells were composed of macrophages and CD4+ T cells. The frequencies of macrophages and CD4+ T cells were 73.7% and 13.8%, respectively. CD8+ T cells were scarce and B cells were rare in the lesions. The frequencies of CD8+ T cells and B cells were 4.5% and 0.4%, respectively. The dominance of macrophages and CD4+ T cells was the constant finding among the sites of the lesions and throughout the course of the disease. These characteristic subsets of infiltrating cells were in contrast to those of murine viral myocarditis which were mainly composed of natural killer (NK) cells and CD8+ T cells. Clarifying the subsets of infiltrating cells in myocarditis may contribute to differential diagnosis of myocarditis between viral and autoimmune types. From this study, the pathogenesis of experimental autoimmune giant cell myocarditis seemed to be closely related to CD4+ T cells and macrophages.

Animals↗

PubMed2005

IL-6, its receptors and its relationship with bcl-2 and bax proteins in infiltrating and in situ human breast carcinoma.

AIMS: To characterize the expression pattern of IL-6 and its receptors (IL-6R(alpha) and gp130), to relate this pattern to bcl-2 and bax expression and to elucidate the effects on the proliferation/apoptosis equilibrium in benign conditions and in situ and infiltrating breast cancer. METHODS AND RESULTS: The immunoexpression of IL-6 and its receptors (IL-6R(alpha) and gp130), and their relationship with bcl-2 and bax proteins, were studied in in situ and infiltrating tumours and in benign breast lesions by means of Western blotting and immunohistochemistry. The percentages of samples positive for IL-6, bcl-2 and bax and their immunoreaction densities were higher in in situ carcinomas and infiltrating tumours than in benign lesions; although in in situ lesions were not so high as in infiltrating tumours, except for bax, whose immunoexpression was as weak as in benign conditions, resulting in a bcl-2/bax ratio higher than in infiltrating tumours. CONCLUSIONS: The high expression of IL-6 and its receptors in tumours might be related to the enhanced cell proliferation occurring in breast cancer. IL-6 could act by increasing bcl-2 expression and thus altering the proliferation/apoptosis balance toward neoplastic cell proliferation. The increased bax immunoreactivity observed only in infiltrating tumours, which was not so high as the increase in bcl-2 immunoreactivity, might be interpreted as an attempt to hinder cell proliferation.

Adolescent↗

PubMed1996

Effect of pre- vs postoperative tonsillar infiltration with local anesthetics on postoperative pain after tonsillectomy.

BACKGROUND: Since pre-incisional peritonsillar infiltrations of local anesthetic solutions have been suggested to reduce postoperative pain after tonsillectomy, we compared the efficacy of either pre- or postoperative local anesthetic infiltration upon post-tonsillectomy pain. METHODS: After the induction of general anesthesia, 68 consecutive healthy patients, ranging in age from 8 to 65 years, were randomly allocated to either receive peritonsillar infiltration with 0.25% bupivacaine (group 1) or normal saline (group 2) before incision. A third group (group 3) had their peritonsillar region infiltrated with 0.25% bupivacaine after the completion of surgery but before the patients were awakened from anesthesia. All the patients were treated in the same way in the postoperative period: NSAIDs were given intravenously to adults and rectally to children. Acetaminophen was given intravenously or rectally (children aged < 15 yr) if additional analgesic support was requested by the patient. Additional acetaminophen consumption was recorded daily. Pain scores were assessed on every patient with the use of a visual analogue scale (VAS) at rest, 1, 5, 9, 13, 17, 21 and 36 h after surgery, and also on swallowing during the first postoperative day. RESULTS: Global VAS pain scores were lower in the groups treated with bupivacaine infiltration during the first 24 h after surgery (P < 0.05). Supplementary analgesic consumption was lower in group 3 than in group 2 during the 0-9 h interval immediately following surgery (P < 0.05). There were no statistically significant differences for any other parameters between the 3 groups. CONCLUSION: These results suggest that the timing of peritonsillar infiltration with bupivacaine is not of clinical importance and does not affect the quality of postoperative analgesia in patients undergoing tonsillectomy.

Adolescent↗

PubMed1988

Mononuclear cells infiltrating kidney allografts in the absence of rejection. Effect of conversion from cyclosporin to azathioprine therapy.

Focal small mononuclear cell infiltrates were found in renal allograft biopsies of 13/14 transplant recipients with a stable function after long-term cyclosporin A (CsA) therapy. Phenotypical analysis of the infiltrating cells using monoclonal antibodies showed a slight preponderance of T cells (56% +/- 8%), with only small percentages of B cells (5% +/- 2%), NK cells (2% +/- 1%), and monocytes (2% +/- 1%). Within the T-cell population the median calculated CD4/CD8 ratio was 1:3. Thirty-five percent of the infiltrating mononuclear cells remained unidentified with the monoclonal antibody panel used (silent cells). Three months after immunosuppressive therapy had been changed from CsA to azathioprine (AZA), the size of the infiltrates was significantly increased and there was a marked invasion of mononuclear cells between tubular epithelium despite a significant improvement in creatinine clearance (P less than 0.01). the phenotypical composition of these infiltrates was dominated by T cells (84% +/- 3%), with a median CD4/CD8 ratio of 2:7 due to an increase in CD4+ cells and a decrease in CD8+ after conversion (P less than 0.05). The percentages of B cells, NK cells, and monocytes showed no significant changes after conversion. During AZA therapy nearly all infiltrating mononuclear cells were stained with the monoclonals used, leaving no silent cells postconversion.

Azathioprine↗

PubMed2005

Local infiltration of high- and low-molecular-weight RNA from silenced sunflower (Helianthus annuus L.) plants triggers post-transcriptional gene silencing in non-silenced plants.

Using grafting procedures, we have characterized post-transcriptional gene silencing (PTGS) in transgenic sunflower expressing beta-glucuronidase (GUS) activity. Silencing was observed as early as 2 weeks after grafting of non-silenced scions on to silenced rootstock. Transmission of the systemic signal occurs solely from stock to scion, is independent of the physiological age of the rootstock and is not heritable. Furthermore, we report, for the first time in plants, an easy and low-cost method of activating RNA silencing by infiltration of purified RNA from silenced plants. Local application of total RNA derived from silenced sunflower plants to leaves of non-silenced plants induces PTGS in newly developed leaves above the point of infiltration, as shown by reduced GUS activity and mRNA levels. Silenced plants contain 21-23-nucleotide RNAs hybridizing to transgene target sequences, in contrast with leaves of non-silenced plants. However, de novo production of GUS-specific short RNA in non-silenced plants can be activated by leaf infiltration of low-molecular-weight RNAs isolated from leaves of silenced plants. Significant levels were detected as early as 2 weeks after infiltration, peaked at 3 weeks and declined 5 weeks after infiltration. Our results provide evidence that RNA infiltration in sunflower induces transient silencing and is not transmitted to offspring. This approach could be of major use in dissecting the mechanisms involved in PTGS.

Journal Article↗

PubMed1986

In situ characterisation of the (peri)portal inflammatory infiltrate in acute hepatitis A.

The portal and acinar zone 1 (periportal) inflammatory infiltrate in acute hepatitis A (HA) strongly resembles piecemeal necrosis (PMN) in chronic hepatitis B (HB). The latter infiltrate has been characterized in detail previously, and a predominance of suppressor/cytotoxic T cells has been demonstrated. For comparison we analyzed the infiltrate in acute HA in three liver biopsies, applying a broad panel of monospecific and monoclonal antibodies. In two cases, helper/inducer T cells surrounded by B lymphoid cells represented the main lymphoid subset in all portal areas. In the third liver biopsy, a case of acute HA superimposed on a pre-existing chronic HB, the cellular composition of the inflammatory infiltrate varied from one portal tract to another. Despite the morphological resemblance between the inflammatory infiltrate in acute HA and PMN in chronic HB, a clear-cut difference in the composition of both infiltrates is obvious from our results. By virtue of the presence of numerous suppressor/cytotoxic T cells, PMN in chronic HB represents the morphological expression of a cellular immune response, whereas the predominance of helper/inducer T cells, admixed with B cells and plasma cells in acute HA represents the morphological expression of a humoral immune response.

Acute Disease↗

PubMed1986

Focal lymphocytic infiltration in the human labial salivary glands: a postmortem study.

Focal lymphocytic infiltration in the human labial salivary glands was examined in a series of 190 postmortem subjects after suitable exclusion had been made. Focal lymphocytic infiltration, with or without a slight degree of parenchymal atrophic change, was found in 22.4% of the males and in 35.7% of the females. Of these, 9.0% (12 subjects) of the males and 10.7% (6 subjects) of the females with focal lymphocytic infiltration did not show any atrophic changes of the parenchyma. In the series reported here, the prevalence of focal lymphocytic infiltration apparently differs from the results of earlier investigators who had reported that none of the postmortem subjects without autoimmune diseases or connective tissue diseases showed focal lymphocytic infiltration in minor salivary glands. Although the pathological significance of focal lymphocytic infiltration in the minor salivary glands remains obscure, its diagnostic value for Sjögren's syndrome is discussed.

Adult↗

PubMed1995

Anamnestic development of lymphocytic infiltration in murine experimental autoimmune oophoritis is primarily localized in the stroma and theca.

PROBLEM: Neonatal thymectomy performed on day 3 of life (NTX3) induces autoimmune oophoritis and ovarian failure in B6A mice. These mice develop high-titer autoantibodies specific to oocytes, and ultimately the ovaries become fibrotic and devoid of primordial follicles. These findings implicate the oocyte as a primary target of the autoimmune process. However, in previous work we demonstrated that in developing disease the lymphocytic infiltration was confined to the stroma and theca, and not found involving oocytes. Here, we investigate the possibility that lymphocytic infiltration involving oocytes develops as part of end-stage disease. METHOD: We transplanted normal syngeneic ovaries to B6A mice with confirmed autoimmune ovarian failure, and, as a control, to normal oophorectomized mice. We then defined the time course and histologic distribution of lymphocytic infiltration in the transplanted ovaries. Lymphocytes were identified by morphology with the aid of an immunohistochemical leukocyte marker (CD45). RESULTS: Autoimmune oophoritis developed by 7 days after transplantation to the NTX3 mice. Compared to control mice, in these mice we found significantly increased stromal and thecal lymphocytic infiltration. In no case did we observe lymphocytic infiltration involving oocytes. CONCLUSIONS: Our findings agree with our previous report and suggest that the ovarian failure in this model is not mediated by a direct lymphocytic attack against intact oocytes. Other immune-mediated mechanisms are responsible. The paradoxical development of high-titer oocyte-specific antibodies despite the stromal and thecal location of the lymphocytic infiltration remains to be explained.

Animals↗

PubMedDate not supplied

A rapid screening-level method to optimize location of infiltration ponds.

A rapid-screening technique was developed to identify lithologies that best disperse artificial recharge via surface infiltration and minimize effects on ground water chemistry. The technique prospectively evaluates basin infiltration rates and water chemistry influences by integrating geotechnical, hydraulic, and water quality data with column test data and numerical modeling. The technique was validated using field data collected from surface infiltration basins designed to recharge ground water pumped from the Pipeline pit gold mine in Nevada. Observed recharge rates at these infiltration sites correlated most significantly with depth to groundwater, with basins in coarse-grained lithologies performing better (0.45 to 0.85 m/day) than those with fine-grained layers (< 0.30 m/day). Observed water quality resulting from leaching of the previously unsaturated vadose zone showed a transitory (< six months) increase in solute concentrations followed by a decrease to baseline conditions, a phenomenon also observed in column tests that leached native soils with local ground water. Leaching of fine-grained soils with evaporites resulted in greater solute concentrations (TDS > 2000 mg/L) than coarse-grained soils (< 1200 mg/L). The results of HYDRUS_2D simulations using the accumulated data as input were in agreement with observed ground water chemistry downgradient of the infiltration basins for a variety of lithologies. Sites for infiltration basins can be rapidly screened to include areas with greatest depth to groundwater and in coarsest alluvial sediments, and impact to ground water chemistry can be reliably predicted using computer modeling and column test results.

Computer Simulation↗

PubMed2006

Multidimensional volumetric imaging of pulmonary infiltrates for measuring therapeutic response to antifungal therapy in experimental invasive pulmonary aspergillosis.

Pulmonary infiltrates in neutropenic hosts with invasive pulmonary aspergillosis are caused by vascular invasion, hemorrhagic infarction, and tissue necrosis. Monitoring the dynamics of pulmonary infiltrates of invasive aspergillosis is an important tool for assessing response to antifungal therapy. We, therefore, introduced a multidimensional volumetric imaging (MDVI) method for analysis of the response of the volume of pulmonary infiltrates over time to antifungal therapy in experimental invasive pulmonary aspergillosis (IPA) in persistently neutropenic rabbits. We developed a semiautomatic method to measure the volume of lung lesions, which was implemented as an extension of the MEDx visualization and analysis software using ultrafast computerized tomography (UFCT). Volumetric infiltrate measures were compared with UFCT reading, histopathological resolution of lesions, microbiological clearance of Aspergillus fumigatus, and galactomannan index (GMI). We also studied the MDVI method for consistency and reproducibility in comparison to UFCT. Treatment groups consisted of deoxycholate amphotericin B (DAMB) at 0.5 or 1 mg/kg of body weight/day and untreated controls (UC). Therapeutic monitoring of pulmonary infiltrates using MDVI demonstrated a significant decrease in the infiltrate volume in DAMB-treated rabbits in comparison to UC (P<or=0.001). Volumetric data by MDVI correlated with conventional CT pulmonary scores (r=0.83, P<or=0.001). These results correlated with validated biological endpoints: pulmonary infarct scores (r=0.85, P<or=0.001), lung weights (r=0.76, P<or=0.01), residual fungal burden (r=0.65, P<or=0.05), and GMI (r=0.78, P<or=0.01). MDVI correlated with key biological markers, improved the objectivity of radiological assessment of therapeutic response to antifungal therapy, and warrants evaluation for monitoring therapeutic response in immunocompromised patients with invasive aspergillosis.

Amphotericin B↗

PubMed1999

Modulating phenotype and cytokine production of leucocytic retinal infiltrate in experimental autoimmune uveoretinitis following intranasal tolerance induction with retinal antigens.

BACKGROUND/AIM: Nasal administration of retinal antigens induces systemic tolerance which results in suppression of experimental autoimmune uveoretinitis (EAU) when subsequently exposed to antigen. The aim was to establish if tolerance induction alters retinal infiltrating leucocyte phenotype and cytokine profile in tolerised animals when there is significantly reduced tissue destruction despite immunisation with retinal antigen. METHODS: Female Lewis rats were tolerised by intranasal administration with retinal extract (RE) before immunisation with RE to induce EAU. Control animals were administered phosphate buffered saline (PBS) intranasally. Post immunisation, daily clinical responses were recorded and at the height of disease, retinas were removed and either infiltrating leucocytes isolated for flow cytometric phenotype assessment and intracellular cytokine production, or chorioretina processed for immunohistochemistry. Fellow eyes were assessed for cytokine mRNA by semiquantitative RT-PCR. RESULTS: Flow cytometric analysis showed that before clinical onset of EAU there is no evidence of macrophage infiltration and no significant difference in circulating T cell populations within the retina. By day 14 a reduced retinal infiltrate in tolerised animals was observed and in particular a reduction in numbers of "activated" (with respect to CD4 and MHC class II expression) macrophages. Immunohistochemistry confirmed these findings and additionally minimal rod outer segment destruction was observed histologically. Cytokine analysis revealed that both IL-10 mRNA and intracellular IL-10 production was increased in tolerised eyes 7 days post immunisation. Although by day 14 post immunisation, IL-10 production was equivalent in both groups, a reduced percentage of IFN-gamma + macrophages and IFN-gamma + CD4+ T cells with increased percentage of IL-4+ CD4+ T cells were observed in tolerised animals. CONCLUSIONS: Leucocytic infiltrate is not only reduced in number but its distinct phenotype compared with controls implies a reduced activation status of infiltrating monocyts to accompany increased IL-10 and reduced IFN-gamma production in tolerised animals. This modulation may in turn contribute towards protection against target organ destruction in EAU.

Animals↗

PubMed2003

Suppressive effects of selectin inhibitor SKK-60060 on the leucocyte infiltration during endotoxin induced uveitis.

BACKGROUND: It is well known that selectin is involved in the development of endotoxin induced uveitis (EIU), and has a major role in leucocyte infiltration. Recently, a novel selectin inhibitor (SKK-60060) that can block P and L selectins in vitro has been developed. This study was designed to investigate the anti-inflammatory effects of SKK-60060 on the inflammatory reaction during EIU in rats by studying leucocyte-endothelium interactions. METHODS: EIU was induced in Lewis rats by footpad injection of lipopolysaccharide (LPS). SKK-60060 was administered 15 minutes before LPS injection, and its suppressive effects on inflammatory leucocyte behaviour were evaluated in vivo with acridine orange digital fluorography; the diameters of retinal arteries and veins were also measured. After these studies, aqueous humour was collected to evaluate leucocyte infiltration and protein leakage. RESULTS: After LPS injection, rolling leucocytes were observed in major retinal veins, followed by leucocyte infiltration into the vitreous cavity. Following treatment with SKK-60060, leucocyte rolling was significantly inhibited in the retinal veins (p <0.01), and subsequent leucocyte infiltration into the vitreous cavity was also significantly suppressed (p <0.01). Retinal vasodilation was also substantially suppressed in SKK-60060 treated rats (p <0.01). Similarly, leucocyte infiltration and protein leakage into the aqueous humour were reduced significantly by SKK-60060 (p <0.01). CONCLUSIONS: SKK-60060 treatment significantly inhibited the inflammatory reaction induced by LPS. Its inhibitory effects on P and L-selectin resulted in suppression of leucocyte infiltration and the subsequent inflammatory reaction caused by accumulated leucocytes. The current findings suggest that SKK-60060 may be useful in the management of uveitis.

Animals↗

PubMed1998

Acute liver failure secondary to hepatic infiltration: a single centre experience of 18 cases.

BACKGROUND: Acute liver failure (ALF) secondary to malignant infiltration of the liver is rare and is diagnosed often only after death. AIMS: To determine diagnostic factors and particular clinical patterns of illness. METHODS: Review of case notes from all patients with ALF secondary to hepatic infiltration admitted to this unit over an 18 year period (1978-1995). RESULTS: From a total of 4020 admissions, 18 patients were identified with ALF attributable to hepatic infiltration. Mean age was 40.7 years. Aetiology was non-Hodgkin's lymphoma in nine patients, Hodgkin's disease in three, infiltrative metastatic carcinoma in four, and haemophagocytosis with no precipitant cause in two cases. Prodromal symptoms were non-specific, but occurred at least two to four weeks before onset of ALF, making the presence of such symptoms of value in differential diagnosis of the cause of ALF. Clinical examination and investigations were unhelpful in distinguishing these cases from more usual causes of ALF. Usually, the clinical course was of rapid deterioration and death from multiorgan failure, and only one patient survived. Diagnosis was made during life in 15 patients. Histology showed evidence of widespread hepatocellular necrosis, with diffuse infiltration by tumour cells rather than focal cellular aggregation. CONCLUSIONS: Only with accurate histological diagnosis from liver biopsy and institution of specific therapy early in the management of such patients will the best chance of recovery be achieved. In every case of ALF with prodromal symptoms or abnormal imaging, hepatic histology should be obtained by liver biopsy as soon as possible to diagnose infiltrative hepatic disease.

Adolescent↗