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Biomedical subjects

G Wildner

Publications and source records attributed to G Wildner.

At least 19 recordsLinked to original sources
PubMed2007

Beneficial effects of CCR1 blockade on the progression of chronic renal allograft damage.

The biology of chemokines and their receptors have been linked to the development of chronic allograft damage. Effects of CCR1 antagonist BX 471 were studied in a Fischer to Lewis renal transplantation model at days 10, 21 and 42 after transplantation. BX 471 treatment did not effectively reduce signs of acute rejection at day 10 but significantly improved allograft function and morphology at day 21 posttransplantation. When therapy was initiated on day 21 after transplantation, glomerulosclerosis and tubulointerstitial fibrosis were significantly inhibited by day 42 posttransplantation. Parallel decrease in infiltrating and proliferating mononuclear cells (ED1, CD8 and Ki67) was observed in treated allografts. Expression of acute phase reactive and proinflammatory genes (HO-1, osteopontin) and molecules associated with fibrosis (PAI-1, TGF-beta1, biglycan) was downregulated at day 21; reduced collagen deposition was observed, parallel to a significant lower number of alpha-SMA+ interstitial myofibroblasts. In situ hybridization demonstrated that biglycan expression was reduced following CCR1 blockade in interstitium of treated allografts. CCR1 antagonism was found to inhibit CCL5-induced secretion of biglycan by macrophages in vitro. CCR1 blockade significantly inhibited development and progression of chronic allograft damage. CCR1 antagonists may represent a therapeutic option for chronic inflammation and fibrosis in renal grafts.

Animals↗
PubMed2005

The acute coronary syndrome--pre-hospital diagnostic quality.

BACKGROUND AND OBJECTIVE: In the Austrian emergency medical service (EMS), emergency medical technician-staffed and physician-staffed vehicles are in operation. Patients with suspected acute coronary syndromes (ACS) are treated in the pre-hospital phase and transported to the hospital by an emergency physician (EP). This study evaluates the diagnostic performance of EPs in ACS and the impact of this emergency system on the outcome of ACS in an urban area. DESIGN: Retrospective case control study. METHODS: All protocol sheets from the emergency physicians were searched for the diagnosis of ACS. The database of the emergency department (ED) was searched for patients with ACS as an admission diagnosis or ACS as discharge diagnosis. For patients admitted to an intensive care unit (ICU), the medical history from the ICU was reviewed. According to the diagnosis and the aggressiveness of therapy, patients were divided in five categories of severity at each stage of care (pre-hospital category, ED category, ICU category). RESULTS: A total of 3585 patients was analysed. Only 17.8% of the patients with ACS as the admission diagnosis and 20.3% of the patients with ACS as the discharge diagnosis were transported by an EP. 46.8% of the ACS diagnosis by EPs were confirmed in hospital. Patients transported by EPs showed a higher all-cause mortality in hospital (1.6% vs. 0.6%; p=0.011). There was no significant correlation between the pre-hospital category of patients treated by EPs and the ED category. When a 12-lead-electrocardiogram was recorded, the correlation improved slightly (rho: 0.139; p=0.006). CONCLUSIONS: The percentage of ACS patients transported to hospital by an EP is very low, and EPs seem to be "over-aware" in the diagnosis of ACS.

Acute Disease↗
PubMed2002

Immunopathology of recurrent uveitis in spontaneously diseased horses.

Equine recurrent uveitis (ERU) is the most serious eye disease in horses worldwide. Despite the fact that ERU is generally considered to be immune mediated, a detailed description of the histopathology of the posterior part of ERU eyes is lacking. Here, we examined sections of paraffin-embedded eyes using histological and immunhistological methods. Twenty seven eyes of 20 horses with ERU and 30 eyes of 15 healthy control horses were included in this study. We could consistently demonstrate an involvement of the retina and the choroid in all examined eyes of horses with spontaneous ERU. In eyes with minimal histopathological changes, the infiltrates consisted almost exclusively of T-cells. Histopathological changes start with the destruction of the photoreceptor outer segments, which often leads to focal retinal detachment. In more severely affected eyes, there is additional disintegration of the ganglion cell layer and the inner nuclear layer. In almost all examined eyes, lymphoid follicle formation could be demonstrated. Typical localizations of these follicles were the iris stroma and the choroid underneath the transition zone of the retina without photoreceptor cells to the region containing photoreceptor cells. These follicles consist of a T-cell rich periphery with a small center of CD3-negative lymphocytes. In cases with extreme histopathological changes, the retinal architecture is widely disintegrated with massive infiltration of the retina, the choroid, and the ciliary body by several types of inflammatory cells. Necrotic remnants of the retina are end-stage findings and there is only a minor inflammatory infiltration left. This study provides clear evidence that the retina is involved in all stages of ERU. Inflammation is mainly driven by T-cells as T-cells were demonstrated in mild stages of the disease and are also the predominating cell type in all other stages of ERU.

Animals↗
PubMed2001

Comparison of lactate or BE during out-of-hospital cardiac arrest to determine metabolic acidosis.

During cardiopulmonary resuscitation, pH and base excess (BE) decrease to a variable degree due to metabolic acidosis. The main cause has been shown to be lactate, which cannot be eliminated sufficiently because of low perfusion during cardiac massage. Both BE and lactate can be measured in the prehospital phase. The aim of the study was to determine if BE and lactate are comparable variables during cardiopulmonary resuscitation (CPR) and if the measurement of lactate level alone would be sufficient to determine the patient's metabolic status and sufficiently reliable to determine the administration of buffer solutions. During the observation period, we registered 31 patients (21 males, ten females) who were resuscitated according to European Resuscitation Council recommendations, who had blood gas analysis and lactate levels measured in blood taken by arterial puncture or arterial line. The first measurement from each patient was taken after primary resuscitation (within 5-20 min). The mean lactate level was 9.85+/-2.98 (range, 4.1-18.7) mmol/l, and the mean BE was -15.0+/-5.98 (range, 5.5 to -24.3). There were statistically significant correlations between the lactate level and BE and pH (linear correlation, r=-0.673, P<0,001 and r=-0,683, P<0,001, respectively), but not with pO2 and pCO2. The receiver-operated curve analysis showed that a cut-off point of 7.0 mmol/l lactate indicates a BE below -10 with a sensitivity of 96% and a specificity of 67%. Lactate measurement is a valuable tool to determine metabolic acidosis during CPR and may be able to replace blood gas analysis in this situation.

Acidosis↗
PubMed2001

Immune responses to retinal autoantigens and peptides in equine recurrent uveitis.

PURPOSE: To test the hypothesis that autoimmune mechanisms are involved in horses in which equine recurrent uveitis (ERU) develops spontaneously. METHODS: Material obtained from horses treated for spontaneous disease by therapeutic routine vitrectomy was analyzed for total IgG content and IgG specific for S-Antigen (S-Ag) and interphotoreceptor retinoid-binding protein (IRBP). The cellular infiltrate of the vitreous was analyzed by differential counts of cytospin preparations and flow cytometry using equine lymphocyte-specific antibodies. Antigen-specific proliferation assays were performed comparing peripheral blood lymphocytes (PBLs) with vitreal lymphocytes by stimulation with S-Ag and several S-Ag- and IRBP-derived peptides. RESULTS: The total IgG content of specimens from horses with ERU was very high with great variability among the investigated samples (11.5 +/- 8.0 mg). Autoantibodies to S-Ag or IRBP or both were found in 72% of vitreous specimens from horses with uveitis. The leukocyte infiltrates (up to 2 x 10(8) cells per sample) were dominated by lymphocytes (>90%) in most cases (22/32). Flow cytometry showed that more than 50% of these cells were CD4(+) T cells. In vitro stimulation of vitreal lymphocytes, but not of PBL, showed a strong proliferative response to peptides derived from S-Ag or IRBP in 9 of 12 patients. CONCLUSIONS: In the eyes of horses with ERU, IgG antibodies and autoreactive T cells specific for retinal antigens were detected. These results strongly support the hypothesis that ERU is an autoimmune-mediated disease and is highly similar to recurrent uveitis in humans in both clinical and immunologic parameters.

Animals↗
PubMed2000

Anti-MHC autoimmunity in Behçet's disease: T cell responses to an HLA-B-derived peptide cross-reactive with retinal-S antigen in patients with uveitis.

Immune response to retinal autoantigens plays a central role in the pathogenesis of uveitis. A synthetic peptide (B27PD) from a common sequence of various HLA-B molecules associated with uveitis, such as HLA-B27 and 51, which shares amino acid homologies with a retinal-S antigen (S-Ag)-derived peptide (PDSAg), was shown to be immunogenic in human and experimental uveitis in the rat. In this study we investigated T cell responses to B27PD and PDSAg in patients with Behçet's disease and posterior uveitis (BD-posterior uveitis; n = 33) in comparison with non-Behçet anterior uveitis (AU, n = 14), Behçet's patients without uveitis (BD, n = 15) and healthy controls (HC, n = 32) in a 6-day proliferation assay. Patients with BD and posterior uveitis had significantly higher responses (stimulation index (SI) 2.8 +/- 1.3) than those with AU (SI 1.5 +/- 0.4), BD without uveitis (SI 1.1 +/- 0.4) and HC (SI 1.1 +/- 0.6) for B27PD (P < 0.0001). Responses to PDSAg were also higher in BD with posterior uveitis patients (SI 3.3 +/- 1.6) than AU (SI 1.5 +/- 0.4), BD without uveitis (SI 1.2 +/- 0.3) and HC (SI 1.1 +/- 0.6) (P < 0. 0001). A significant correlation between the responses to PDSAg and B27PD (r = 0.56, P < 0.001) was observed. Elevated levels of IL-2 and tumour necrosis factor-alpha were also observed in culture supernatants obtained from peripheral blood mononuclear cells after stimulation with the peptides, but no correlation was found between the proliferative responses and cytokine levels. These results suggest that cellular immunity to cross-reactive HLA-B and S-Ag-derived peptides might play a role in the pathogenesis of posterior uveitis in BD.

Adult↗
PubMed1999

Oral tolerance with an HLA-peptide mimicking retinal autoantigen as a treatment of autoimmune uveitis.

Endogenous uveitis is a T cell mediated autoimmune disease leading to impairment of visual acuity. The association of different uveitis entities with HLA-class I antigens and the discovery of antigenic mimicry between a peptide of uveitis-associated HLA-class I antigens and a peptide of retinal autoantigen led to a new hypothesis for the pathogenesis of uveitis. On the basis of this mechanism an open trial of oral tolerance induction with the HLA-peptide B27PD was initiated for nine patients with long lasting, therapy-refractive uveitis. Within 6 weeks of oral peptide treatment all patients responded with a marked decrease of intraocular inflammation, which allowed a reduction of systemic corticosteroids in seven patients. One patient, who suffered from an acute relapse, responded within 2 weeks, followed by an increase of visual acuity. In addition, two patients discontinued azathioprine immediately prior to oral tolerance induction without the occurrence of relapses. Visual acuity remained unchanged or increased in 14 of 16 eyes. One patient did not finish oral peptide treatment. None of these patients experienced any adverse events. It was concluded that the oral application of highly tolerogenic peptides might be a potent approach for the treatment of autoimmune diseases.

Administration, Oral↗
PubMed1997

Molecular mimicry as a therapeutic approach for an autoimmune disease: oral treatment of uveitis-patients with an MHC-peptide crossreactive with autoantigen--first results.

In the rat model of experimental autoimmune uveitis (EAU) we have demonstrated that a peptide from the sequence of human disease-associated MHC-class I antigens can induce uveitis upon immunization. Moreover, oral administration of this MHC-peptide tolerized Lewis rats to the disease induced with two different retinal autoantigens, retinal S-antigen (S-Ag) and IRBP. In uveitis patients T cells responding to S-Ag peptide also respond to the MHC-peptide, which shows crossreactivity with the major epitope from S-Ag due to some shared discontinuous amino acid homologies. The 14-mer peptide B27PD is derived from the sequence of all HLA-B antigens that are statistically associated with uveitis (including HLA-B27). Patients with long-lasting endogenous uveitis, suffering from side effects of conventional immuno-suppressive therapy or being therapy-refractive, were orally tolerized with peptide B27PD in this first open therapeutic trial. Patients received peptide three times a week over a 12 weeks period, while only low dose steroids were allowed as concomitant medication. The aims were (1) to investigate whether immunosuppressive therapy could be discontinued and steroids reduced while relapses of ocular inflammation reside and (2) to search for side effects. The Helsinki Declaration was strictly observed and the study design approved by the local ethical committee. The first patients orally tolerized with the HLA-peptide (two had stopped azathioprine immediately prior to onset of oral peptide treatment) could discontinue their steroids because of reduced intraocular inflammation. No side effects of therapy were observed. Oral tolerance induction with a peptide derived from the patients' own HLA-antigens and crossreactive with the organ-specific autoantigen seems to be a potent therapeutic approach.

Administration, Oral↗
PubMed1997

HLA-B27-derived peptides as autoantigens for T lymphocytes in ankylosing spondylitis.

OBJECTIVE: To study whether peptides derived from the HLA-B27 molecule sequence can stimulate peripheral blood T lymphocytes (PBL) from patients with HLA-B27-associated spondylarthropathies. METHODS: PBL from 55 HLA-B27+ patients with ankylosing spondylitis (AS), 28 HLA-B27+ patients with other spondylarthropathies, 7 rheumatoid arthritis patients, and 30 HLA-B27+ and 22 HLA-B27- healthy controls were tested in lymphocyte proliferation assays with 4 synthetic peptides derived from the HLA-B*2705 molecule. RESULTS: A 13-mer peptide (B27PA) induced significant proliferative responses in 17 of the 55 AS patients (stimulation index [SI] 2.5-17.5), as well as in 3 of the HLA-B27+ healthy controls (SI 2.5-9.8). Another 13-mer peptide (B27PC) induced PBL proliferation (SI 2.7-5.5) in 10 AS patients and in some donors of the control groups. In B27PA-specific T cell lines, an expansion of cells positive for the gamma/delta T cell receptor could be demonstrated. CONCLUSION: These results indicate that HLA-B27-derived peptides can be recognized as autoantigens by PBL of HLA-B27+ AS patients and B27+ healthy controls. Recent infections preceding the manifestation of AS may be involved in this process of anti-self major histocompatibility complex reactivity.

Adolescent↗
PubMed1996

Orally induced, peptide-specific gamma/delta TCR+ cells suppress experimental autoimmune uveitis.

We investigated the role of gamma/delta TCR+ T cells in induction and suppression of the T cell-mediated disease experimental autoimmune uveitis. Disease induction was studied in Lewis rats perinatally depleted of alpha/beta or gamma/delta TCR+ subpopulations. Depletion of alpha/beta TCR+ cells completely abrogated disease, whereas treatment with anti-gamma/delta antibodies had no influence on onset or intensity of uveitis. However, adoptively transferred gamma/delta+ cells from orally tolerized rats could mediate suppression of uveitis in an antigen-specific fashion. Uveitis induced by a peptide derived from the uveitogenic retinal soluble antigen (S-Ag) was suppressed by gamma/delta+ cells from rats orally tolerized with the same peptide as well as HLA peptide B27PD. This disease ameliorating effect could also be observed when rats were fed with the HLA peptide before immunization with S-Ag peptide. Transfer of alpha/beta+ T cells from the same donors as well as gamma/delta+ or alpha/beta+ cells from animals fed with control peptide had no ameliorating effect.

Administration, Oral↗
PubMed1995

Orally induced bystander suppression in experimental autoimmune uveoretinitis occurs only in the periphery and not in the eye.

Oral administration of retinal soluble antigen (S-Ag) suppresses the induction of S-Ag-mediated experimental autoimmune uveitis (EAU) in Lewis rats. EAU induced with interphotoreceptor retinoid-binding protein (IRBP), another retinal autoantigen, can also be suppressed by oral administration of IRBP. It has been speculated that feeding with one retinal autoantigen could suppress induction of uveitis with the other retinal protein by means of bystander suppression. Both uveitogenic effector and suppressor cells should find their antigens within the retina, where the suppressor cells would be expected to act on the effector cells. However, reciprocal combinations of antigens used for induction and suppression of uveitis failed to prevent onset of disease, demonstrating that bystander suppression obviously does not occur in the eye. To investigate further the localization of suppressor mechanisms, we fed Lewis rats either with retinal S-Ag or with ovalbumin (OVA) and then immunized the animals either with a mixture of S-Ag and OVA or with each antigen separately, injected into contralateral hind legs. Feeding of S-Ag prior to immunization led to suppression of uveitis, whereas feeding of OVA had no tolerizing effect when S-Ag and OVA were injected into different legs. Nevertheless, immunizing rats with a mixture of S-Ag and OVA after OVA feeding suppressed uveitis to a high degree. These findings suggest that orally induced bystander suppression might not occur in the target organ, but rather peripherally at the site of induction of the autoimmune T cells.

Administration, Oral↗
PubMed1994

Cross-reactivity between an HLA-B27-derived peptide and a retinal autoantigen peptide: a clue to major histocompatibility complex association with autoimmune disease.

Statistical correlations between the expression of various HLA antigens and certain autoimmune diseases have been observed for both HLA class I and II antigens. Autoimmune diseases like spondyloarthropathies and anterior uveitis are associated with HLA-B27, but uveitis in Behçet's disease with HLA-B51. We describe a peptide from disease-associated HLA class I antigens sharing sequence homologies with a highly uveitogenic epitope from the retinal autoantigen S-antigen. S-antigen induces autoimmune uveitis in the animal model and is a major autoantigen in human disease. The HLA peptide induced uveitis in the Lewis rat and, moreover, suppressed S-antigen-induced disease when administered orally. Patients' PBL cross-reacted with the HLA- and corresponding retinal peptide, explaining the organ specificity of the disease.

Amino Acid Sequence↗
PubMed1994

Treatment of endogenous uveitis with anti-CD4 monoclonal antibody: first report.

A patient with endogenous uveitis was treated with a chimeric monoclonal anti-CD4 antibody. This patient with long-standing therapy-refractive uveitis did not benefit immediately from antibody infusions, although the frequency of uveitis relapses was sharply reduced after this therapy. After treatment with the monoclonal antibody, this patient's response to conventional immunosuppression improved. The patient had very low CD4+ T-cell counts before the beginning of antibody therapy. In this case, peripheral T-cell counts slowly increased. Antigen-specific T-cell responses to retinal S-antigen in this patient were significantly elevated only just prior to a clinical relapse. The initially high level of spontaneous T-cell proliferation normalized after antibody infusions.

Adult↗
PubMed1993

Minor envelope proteins of duck hepatitis B virus are initiated at internal pre-S AUG codons but are not essential for infectivity.

In infected liver tissue three major and several minor duck hepatitis B virus (DHBV) envelope proteins are detectable by immunoblotting. Translation initiation at the second and the most distal internal ATG codon of the Pre-S/S gene is known to lead to synthesis of two major envelope proteins (P36 and P17) whereas the origin of a further major (P28) and other minor envelope proteins is not clear. Therefore, it was investigated whether translation initiation at pre-S ATGs leads to synthesis of these other envelope proteins and, if yes, whether they are components of viral particles and essential for infectivity. Each of the five ATG codons of the pre-S region of an infectious Chinese DHBV genome (DHBV26) was mutated separated by oligonucleotide-directed mutagenesis (point mutations or deletions) and the function of the corresponding mutant viruses were tested in vitro and in vivo. Immunoblot analysis of liver cell extracts or of extracts from hepatoma cells transfected with the DHBV genomes showed expression of minor pre-S proteins of about 35, 33, and 30 kDa. These proteins were not expressed when ATG codons at nucleotide positions 825, 882, and 957, respectively, were mutated. None of the ATG mutations abolished expression of the major P28 pre-S protein. In cell culture supernatants the minor pre-S proteins P35, P33, and P30 were identified as components of viral particles. With the exception of the DHBV genome containing the mutated ATG codon 801 (translation initiation codon for the major P36 pre-S protein) all forementioned DHBV mutant genomes were infectious. These data demonstrate that minor pre-S proteins are initiated at internal AUGs of the pre-S gene and are components of viral particles but are not essential for infectivity. In contrast to previously published speculations, the results also indicate that the major pre-S protein P28 is not initiated at AUG codon 957 but probably produced by proteolysis from larger pre-S proteins.

Animals↗
PubMed1993

Cells of the immune system and their cytokines in epiretinal membranes and in the vitreous of patients with proliferative diabetic retinopathy.

In the present study, we specifically investigated the presence of the main immune cells, namely T helper/inducer lymphocytes, T suppressor/cytotoxic lymphocytes, B lymphocytes and macrophages, for HLA-DR antigen expression and the cytokines IL-1 alpha and IL-2 in epiretinal membranes of proliferative diabetic retinopathy (PDR) using immunohistochemical staining. The levels of the two cytokines (IL-1 alpha and IL-2) in the vitreous were measured by ELISA. The results show that 18 out of the 32 epiretinal specimens reacted positively with monoclonal anti-CD4 (marker for T helper/inducer cell subset) antibody (56%), 21 reacted with monoclonal anti-CD8 (marker for T suppressor/cytotoxic subset) antibody (66%), 15 reacted with monoclonal anti-CD22 (marker for B lymphocytes) antibody (47%), and 25 (78%) were positive for monoclonal anti-macrophage and anti-HLA-DR antibodies. IL-1 alpha and IL-2 were detected in the epiretinal membranes in 8 out of 13 tested cases (62%). However, in the vitreous, IL-1 alpha was detected in only 3 out of 13 cases (70, 75 and 80 pg/ml, respectively), while IL-2 was not detected in any of the vitreous samples. The results clearly demonstrate that immune cells and their cytokines were found in about half of the epiretinal membrane specimens. The invasion of the immunocompetent cells in the membranes seems to be a secondary event. They would not participate in the pathogenesis of PDR, but probably induce unspecific reactions and thus complicate the disease.

Antigens, CD↗