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Biomedical subjects

A D Dick

Publications and source records attributed to A D Dick.

At least 55 records · Page 3Linked to original sources
PubMed1998

Immunosuppressive treatment of choroidal neovascularization associated with endogenous posterior uveitis.

OBJECTIVE: To determine whether resolution of choroidal neovascularization (CNV), a recognized sight-threatening complication of endogenous posterior uveitis, and maintenance of vision could be achieved with immunosuppression. PATIENTS AND METHODS: Fourteen patients (17 eyes) with CNV associated with endogenous posterior uveitis were enrolled in an open study. Ages ranged from 5 to 51 years. Three eyes had extrafoveal CNV, 6 juxtafoveal, and 8 subfoveal. Three patients were treated with a single course of oral corticosteroids, 2 had additional cyclosporine for up to 2 years, and 9 continued to receive a low-dose regimen of a combination of immunosuppressive drugs. RESULTS: After a median follow-up of 15 months (range, 7 months to 6 1/2 years), 9 of 17 eyes had an improvement in visual acuity; 6 remained within 1 Snellen line of initial visual acuity, and 2 had lost 2 Snellen lines. Angiographically, CNV resolved in 13 eyes, resolved then recurred in 3, and improved but persisted in 4. CONCLUSION: These results support a role for immunosuppressive therapy in the treatment of CNV associated with endogenous posterior uveitis.

Adolescent↗
PubMed1998

Neutralizing TNF-alpha activity modulates T-cell phenotype and function in experimental autoimmune uveoretinitis.

Inhibiting TNF-alpha activity prevents tissue destruction without inhibiting retinal T cell infiltration in experimental autoimmune uveoretinitis (EAU) in Lewis rats. To further determine the role of TNF-alpha in autoimmune uveitis we characterized T cells isolated from retinae after treatment with a TNF-alpha antagonist. TNF-alpha activity was neutralized in vivo with a p55 TNF-alpha receptor-Ig fusion protein (sTNFr-Ig), administered 8 and 10 days after induction of EAU with heterologous retinal antigens. Retinal T-cell phenotype expression was examined by flow cytometry with respect to OX22 status (CD45RBlow or CD45RBhigh), activation (OX40 and CD25 expression) and rate of T-cell apoptosis (Annexin V+PI- expression). Lymphocyte reactivity was assessed by proliferation responses and cytokine production to retinal antigens. Despite greater than 40% of CD4+ T cells being activated at the height of disease, the proportion of OX22low expression was reduced and T cells exhibited reduced IFN-gamma and elevated IL-4 production. Retinal T cells maintained antigen-specific proliferation and demonstrated a low apoptotic rate. Although in both animal groups, comparable numbers of T cells were isolated, neutralizing TNF activity suppressed Th1 effector mechanisms protecting against target organ damage.

Animals↗
PubMed1998

Uveitogenic epitopes of retinal S-antigen are generated in vivo via an alternative antigen-presentation pathway.

We have found that different antigen-processing pathways are involved in the induction of experimental autoimmune uveoretinitis (EAU) by the retinal autoantigens S-antigen and interphotoreceptor retinoid-binding protein (IRBP). Although in vitro T-cell proliferative responses to IRBP were completely inhibited in the presence of irreversible cysteine protease inhibitors, no significant reduction of S-antigen proliferative responses was found. Furthermore, acidic proteolysis of S-antigen by the cysteine protease cathepsin B prior to immunization radically reduced pathogenicity (disease severity). In addition, in vitro processing of S-antigen, but not IRBP, was also found to be resistant to the action of cycloheximide and lysosomotropic agents, inhibition of proliferation only occurring after extended exposure of antigen-presenting cells to methyl amine or high concentrations of chloroquine. These data indicate that an alternative pathway of antigen processing exists for S-antigen, which is independent of processing within the normal endolysosomal pathway and that uveitogenic peptides of naturally processed S-antigen bind to major histocompatibility complex class II antigens either at the cell surface or within very early endosomes where cathepsin B is inactive.

Animals↗
PubMed1998

Tacrolimus (FK506) in failed cyclosporin A therapy in endogenous posterior uveitis.

Tacrolimus (FK506) is effective in Japanese endogenous posterior uveitis (EPU), but there is limited data on its role in refractory EPU where cyclosporin A (CsA) toxicity/resistance develops. This open prospective clinical study aimed to assess the efficacy and adverse effects of low-dose FK506 therapy in western patients with refractory EPU where CsA resistance or toxicity has developed. Patients with CsA resistant/toxic EPU were started on low-dose (< 0.10 mg/kg/day) FK506 therapy. Immunosuppressive efficacy was assessed by visual acuity, binocular indirect ophthalmoscopy (BIO) scores, and change in clinical features. Adverse effects were assessed by routine biochemical tests (including serum creatinine) and symptoms. Seven patients (13 eyes), aged (mean +/- SD) 37.5 +/- 14.8 years, were recruited with previous CsA nephrotoxicity as the main indication and prior duration of EPU of (mean +/- SD) 13.1 +/- 7.3 years. Behçet's disease was the commonest diagnosis. FK506 therapy was maintained at 0.06 +/- 0.02 mg/kg/day, trough level of 8.7 +/- 1.8 ng/ml, in combination with low-dose prednisolone (0.11 +/- 0.04 mg/kg/day) in all patients for a mean duration of 8.7 months (range 1.0-17.7). From baseline (for 11 eyes with meaningful follow-up), visual acuity was maintained in nine eyes and BIO score improved in nine eyes. No major adverse effects developed, with only a 7.5 +/- 6.5% maximum increase in serum creatinine in patients with previous CsA-induced nephrotoxicity. Minor adverse effects (especially mild hyperglycaemia and neurological symptoms) were common and usually well tolerated, except for two patients in whom drug withdrawal was necessary, thus producing therapeutic failure. Low-dose FK506 is effective in refractory EPU as CsA-rescue therapy, and should be considered earlier in the evolution of refractory EPU.

Adult↗
PubMed1998

Cyclosporin A therapy in refractory non-infectious childhood uveitis.

AIMS: To assess the immunosuppressive efficacy, steroid sparing effect and adverse effects of cyclosporin A (CsA) therapy in refractory non-infectious childhood uveitis. METHODS: A retrospective case series review of the medical records of children on CsA therapy attending a tertiary referral centre for refractory endogenous uveitis was performed. Low dose (< or = 5.0 mg/kg/day) CsA therapy was started either as monotherapy or in combination with other agents. The CsA immunosuppressive efficacy was assessed by visual acuity and binocular indirect ophthalmoscopy (BIO) score outcomes and steroid sparing effect by growth charts and ability to withdraw or maintain a low steroid dose. Possible CsA adverse effects were monitored by routine biochemistry (including serum creatinine) and haematological tests, blood pressure recordings, and symptoms. RESULTS: 14 patients (25 eyes, 10 males, four females) were recruited with steroid failure as the most common CsA indication. Age (mean (SD)) at start of CsA therapy was 8.7 (4.1) years with a duration of CsA therapy of 20.9 (range 3.5-88.3) months at a maintenance CsA dose of 4.0 (1.0) mg/kg/day. From baseline, visual acuity improved or was maintained in 23 (92%) eyes and BIO score improved in 19 (76%) eyes. Height centiles were preserved and the maintenance prednisolone dose was 6.3 (3.3) mg/day, where required, in 10 (71%) patients. Nephrotoxicity was not observed, with transient systemic hypertension developing in one patient. Minor adverse effects were more common but were well tolerated. CONCLUSIONS: Cyclosporin A therapy is effective and safe in the medium term, if closely monitored, in refractory non-infectious childhood uveitis.

Adolescent↗
PubMed1998

Effects of mycophenolate mofetil on nasal mucosal tolerance induction.

PURPOSE: The authors investigated mucosal tolerance therapy as a treatment for autoimmune conditions, including uveitis. Although nasal antigen administration was unable to suppress the disease when given to primed animals, previous studies of experimental autoimmune uveoretinitis (EAU) have shown that nasal antigen administration can maintain disease suppression when combined with oral cyclosporin A. This study aimed to determine whether mucosal tolerance can be induced when EAU is suppressed with mycophenolate Mofetil (MM) and whether tolerance can be maintained when immunosuppression with MM is stopped. METHODS: Lewis rats were immunized with retinal extract, and then they received either oral MM 7 to 20 days after immunization or retinal extract intranasally in combination with oral MM on days 7 to 20. Thereafter, weekly nasal administration of the antigen was given until the termination of the experiment at day 38. One group of control animals received the drug vehicle orally and phosphate-buffered saline intranasally. Clinical and histologic changes were assessed along with changes in immune status including delayed-type hypersensitivity, antibody responses to retinal antigens, and flow cytometric phenotyping of infiltrating ocular leukocytes. RESULTS: EAU was delayed, but not prevented, by a short-term course of MM (7-20 days after immunization). Tolerance to the retinal extract could not be induced during MM treatment by nasal retinal extract administration. Despite the delay in onset of EAU in MM and in MM- and nasal antigen-treated animals, profound target organ damage occurred as seen in untreated controls with EAU. However, fluoroscein-activated cell sorter analysis of retinal leukocytic infiltrate indicated that there was a reduced macrophage recruitment at all time points, whereas lymphocyte infiltration was reduced in proportion to the overall reduction in leukocyte infiltration during therapy. CONCLUSIONS: Nasal retinal antigen administration does not induce tolerance or maintain disease suppression when combined with MM therapy during the effector stage of the (auto)immune response. MM therapy delays disease onset, but target organ damage occurs when therapy is stopped, despite a marked inhibition of macrophagemonocyte infiltration into the chorioretina.

Animals↗
PubMed1997

Direct ex vivo flow cytometric analysis of human microglial cell CD4 expression: examination of central nervous system biopsy specimens from HIV-seropositive patients and patients with other neurological disease.

OBJECTIVE: To define a clear ex vivo flow cytometric phenotype for adult human microglia that would distinguish it from all other macrophage lineage cells in the central nervous system (CNS) or blood, and to utilize this phenotype to examine the activation state and CD4 expression of microglia freshly derived from CNS tissue of HIV-positive patients and those with other neurological diseases. DESIGN: Fresh human CNS tissue from both HIV-uninfected and HIV-infected individuals was obtained by biopsy or resection, and cells isolated immediately, labelled for flow cytometry and analysed. METHODS: A Percoll density gradient isolation technique and phenotypic characteristics used for rodent microglia were applied and modified. RESULTS: Resident microglia could clearly be defined by the flow cytometric phenotype CD45low CD4- CD11b+ CD11chigh major histocompatibility complex (MHC) class II+ CD26- CD14-. Assuming normally low-level MHC class II expression in the healthy CNS, it was likely that MHC class II positivity reflected underlying pathology necessitating biopsy or resection and appeared to be a 'leaky' activation marker. Microglia activation was observed in specimens from only six (35%) out of 17 HIV-uninfected but all four (100%) HIV-infected patients, defined strictly as any level of upregulation of CD4 expression, to produce the phenotype CD45low/medium CD4low CD11b+ CD1.1Chigh MHC class II+/+2 CD26- CD14-. Where examined by immunohistology, CD68 was also upregulated in these cases. CONCLUSIONS: When activated in situ, microglia express low levels of CD4 and this is always seen in tissue from HIV-infected patients. Using the flow cytometric phenotype established here, microglia from HIV-infected tissue can now be isolated in pure form and studied directly ex vivo.

Adult↗
PubMed1997

Nasal administration of retinal antigens maintains immunosuppression of uveoretinitis in cyclosporin-A-treated Lewis rats: future treatment of endogenous posterior uveoretinitis?

PURPOSE: Current treatment of autoimmune endogenous posterior uveoretinitis (EPU) is limited by drug toxicity, unpredictable relapses on dose reduction and resistance to therapy. Administration of autoantigens via gastrointestinal or respiratory mucosa prior to antigen exposure induces immune hyporesponsiveness (mucosal tolerance) to further antigen sensitisation. In this study we assessed whether mucosal tolerance induction was possible after immunisation with retinal antigens in experimental autoimmune uveoretinitis (EAU) in animals that were short-term immunosuppressed with cyclosporin A (CsA) to determine whether mucosal administration of retinal antigens can maintain immunosuppression in sensitised and immunosuppressed individuals. METHODS: Female Lewis rats were immunised with retinal extract (RE) and then treated as follows. Group 1 received no specific therapy and served as control; group 2 were fed CsA from day 7 to day 20 post-immunisation; group 3 received inhalational tolerance therapy with RE in addition to CsA; tolerance therapy was continued after day 20 when CsA was stopped. Experiments varying the timing and dosage of both tolerising and immunising antigen were also performed, the details of which are described. Incidence, day of onset and clinical activity were recorded and histopathological assessment of intraocular inflammation, in particular the extent of autoimmune target-organ damage, was graded semiquantitatively. RESULTS: Compared with controls and group 2, group 3 showed both a marked delay in disease onset and a reduction in disease severity. This effect was both dose and dose-timing dependent. Tissue damage assessed in terms of preservation of rod outer segments was significantly less in group 3. CONCLUSIONS: The success of combination therapy, clinically, remains unknown at present but these results support continuing present clinical trials of mucosal tolerance therapy and in particular have future implications for either maintaining or inducing immunosuppression in autoimmune diseases in combination with present immunosuppressive therapies.

Administration, Intranasal↗
PubMed1997

Interphotoreceptor retinoid binding protein is a potent tolerogen in Lewis rat: suppression of experimental autoimmune uveoretinitis is retinal antigen specific.

AIMS: Administration of unfractionated retinal antigen(s) (retinal extract, RE) suppresses RE induced experimental autoimmune uveoretinitis (EAU) and offers a potential therapeutic alternative to non-specific immunosuppressive therapies for posterior uveitis and autoimmune diseases. S-Ag and interphotoreceptor retinoid binding protein (IRBP) are two major autoantigens within soluble RE. It was aimed to assess, firstly, as has previously been shown with S-Ag, if IRBP can induce intranasal tolerance and, secondly, the contribution of both these major autoantigens to tolerance induction by whole RE. METHODS: Animals were tolerised by intranasal administration with S-Ag or IRBP, either alone or in combination, or RE before immunisation with either IRBP or RE. Control animals were administered nasally either PBS or MBP. Daily clinical responses were recorded biomicroscopically and histological grades were obtained using a semiquantitative scoring system. Weekly serum antibody levels to retinal antigens were measured by ELISA and delayed hypersensitivity responses (DTH) were assessed by skin reactivity to intradermal inoculation with retinal or non-specific antigens. RESULTS: Microgram doses of IRBP successfully suppressed both clinically and histologically IRBP induced EAU. This suppression was accompanied by reduced antigen specific DTH reactivity but maintained T cell dependent (IgG2a) antibody responses. Furthermore, combined S-Ag and IRBP administration afforded equal suppression of RE induced EAU when compared with RE therapy alone. Suppression of RE induced EAU was not achieved with administration of a non-retinal specific autoantigen, MBP. Although individually, both S-Ag and IRBP suppressed RE induced EAU, whole RE was unable to protect against IRBP induced disease. CONCLUSIONS: Intranasal administration of IRBP suppressed IRBP induced EAU in the Lewis rat. S-Ag and IRBP are the major contributors to the tolerogenicity within RE, despite the known uveogenicity of other retinal antigens within RE and induction of tolerance was retinal antigen specific. Furthermore, suppression induced by single antigen administration is antigen specific although concomitant bystander suppression may also play a role. RE was unable to protect against IRBP induced disease despite tolerogenic levels of antigen within RE. Although this may be due in part to a dose effect of either tolerising or immunising antigen, further investigation into the possible antigen dominance of IRBP or mucosal processing of combinations of antigens is necessary so that the full efficacy of mucosal tolerance therapy can be assessed.

Administration, Intranasal↗
PubMed1997

Phenotypic analysis of retinal leukocyte infiltration during combined cyclosporin A and nasal antigen administration of retinal antigens: delay and inhibition of macrophage and granulocyte infiltration.

Nasal antigen administration successfully suppresses a model of organ-specific autoimmune disease, experimental autoimmune uveoretinitis (EAU), when administered prior to immunisation. We have previously shown that nasal antigen therapy for active disease or in primed, sensitised animals does not reliably or consistently suppress histological disease. However, when nasal antigen administration is combined with cyclosporin A (CsA) therapy, rod outer segment destruction (target organ) is reduced despite the presence of clinical and histological leukocytic infiltration of the eye. In this study, two colour flow cytometric phenotypic analysis of retinal and choroidal leukocytic infiltration of animals treated with either CsA alone, combined therapy with CsA and inhalational tolerance therapy with retinal antigens or sham treated controls was performed. There was no clinical difference between the two treated groups. Flow cytometric phenotypic analysis was performed in all groups at both maximal clinical disease and during resolution of clinical signs. Although the cell number within the infiltrate was reduced in combined treated group, CD4+ IL-2R+ T cells were still present in large numbers, in contrast to the markedly reduced numbers of ED7+ (macrophages/granulocytes) cells infiltrating during height of disease. In the CsA-nasal antigen treated group, when clinical inflammation had subsided, an increase in both macrophages and granulocyte numbers in the chorioretina was observed. The cell numbers were always less than CsA-only treated animals. Despite the late cellular influx of monocytes/macrophages, rod outer segment (ROS) integrity as determined histologically, was maintained. Nasal antigen administration of retinal antigens in CsA-only treated animals (combined therapy group) protects against target organ damage without inhibiting activated T cell traffic to the eye. These results suggest that recruitment of macrophages to the target tissue is central to autoimmune target organ damage, the mechanisms of which are discussed.

Administration, Intranasal↗
PubMed1996

Inhibition of tumor necrosis factor activity minimizes target organ damage in experimental autoimmune uveoretinitis despite quantitatively normal activated T cell traffic to the retina.

Recent studies demonstrated that administration of a p55-tumor necrosis factor (TNF) receptor IgG-fusion protein (TNFR-IgG) prevented the clinical onset of experimental autoimmune encephalomyelitis but did not alter the number or tissue distribution of autoantigen-specific CD4+ effector T cells which trafficked into the central nervous system. To determine whether specific target tissues of autoimmune damage remain intact after TNFR-IgG treatment despite the presence of inflammatory cells within the tissues, we examined rats with experimental autoimmune uveoretinitis (EAU), as in this model, the main target of autoreactive CD4+ T cells, the retinal rod outer segments (ROS), can be examined readily by light microscopy. As judged by direct ophthalmoscopy, the onset of inflammation in the anterior chamber of the eye in EAU following administration of TNFR-IgG was delayed by 6 days compared to untreated controls, but the magnitude of the response was only slightly less than controls. Histological examination of the retinae and direct assessment of retinal inflammation revealed a disproportionate sparing of ROS in the TNFR-IgG-treated animals despite a level of retinal inflammation not substantially less than controls in which ROS damage was marked. Analysis of retinal leukocytes by immunofluorescence microscopy and flow cytometry indicated that approximately equal numbers of CD4+ alpha beta TCR+ lymphocytes were present in treated and control retinae, more than 30% of CD4+ cells in both experimental groups expressed the CD25 or MRC OX40 activation markers and most cells, which would include the CD4+ T lymphocytes, were activated as evidenced by MHC class II expression. Fewer activated macrophages and granulocytes were present in the treated retinae, possibly reflecting the lower level of tissue damage and subsequent accumulation of these inflammatory cells. The results demonstrate directly that a tissue specifically targeted for autoimmune destruction can be protected despite the influx of fully activated CD4+ T cells.

Animals↗
PubMed1996

Venous stasis orbitopathy: a clinical and echographic study.

AIMS: A variety of acute and chronic orbitopathies may be distinguished by standardised echography. Venous stasis orbitopathy (VSO) often presents with orbital signs when secondary to cavernous sinus and middle cranial fossa disorders. In this study, the aim was to assess whether differentiation between vascular and nonvascular causes of VSO could be made on the basis of clinical and echographic features at the time of presentation. METHODS: This study comprised 37 patients with echographic features of VSO (17 patients with arteriovenous fistulae, confirmed by computed tomography imaging or angiography, and 20 patients with non-vascular diseases). Excluded were patients with orbital mass lesions detected by echography and muscle enlargement due to other causes (for example, orbital myositis). Patients with a suspected mass involving the orbital apex and echographic features of VSO were included. After full neuro-ophthalmic and ocular examination, both orbits were examined to document maximal thickness and reflectivity of four recti muscles and compared with the normal contralateral orbit with standardised A-scan (Kretz-technik 7200MA or Ophthascan) and contact B-scan (Ultrascan or Ophthascan S). RESULTS: Cumulative ocular recti muscle thickness was significantly greater in patients with arteriovenous fistulae compared with the non-fistula group (23.3 (SD 3.7) and 17.8 (2) mm, p = 0.001). Clinically, the presence of a bruit and a uniocular rise in intraocular pressure were significantly greater in the fistula group of patients. CONCLUSIONS: Standardised echography is a safe and non-invasive method of diagnosing VSO in patients presenting with signs of proptosis, ophthalmoplegia, and inflammation of the conjunctiva. Furthermore, using these standard techniques the two major causes of VSO (arteriovenous fistulae and compressive mass lesions) could be differentiated.

Aged↗