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S M Whitcup

Publications and source records attributed to S M Whitcup.

At least 19 recordsLinked to original sources
PubMed2001

Skewed abrogation of tolerance to a neo self-antigen in double-transgenic mice coexpressing the antigen with interleukin-1beta or interferon-gamma.

Transgenic (Tg) mice expressing hen egg lysozyme (HEL) under the control of the alphaA-crystallin promoter exhibit tolerance to HEL by both their T- and B-cell compartments. Here, we show that double-Tg mice, coexpressing HEL with either interleukin-1beta or interferon (IFN)-gamma, demonstrated unresponsiveness to HEL by their T-cell compartment, but most of them developed antibodies against HEL following a challenge with the antigen. The abrogation of humoral tolerance was more pronounced in the HEL/IL-1 double-Tg mice than in the HEL/IFN-gamma mice. Unlike their controls, double-Tg mice exhibited remarkable levels of variability in their antibody levels. The skewed abrogation of tolerance in the double-Tg mice is proposed to be due to the cytokines' capacity to rescue from clonal deletion small numbers of T cells, which provide help to antibody producing B cells. This notion is supported by the finding that adoptive transfer of small numbers of Th1 or Th2 cells into HEL-Tg mice made possible antibody production similar to that seen in the double-Tg mice.

Adoptive Transfer↗
PubMed2001

Visual functioning and general health status in patients with uveitis.

OBJECTIVE: To measure the visual functioning and quality of life in patients with uveitis. METHODS: Consecutive adult patients with noninfectious uveitis were enrolled. The Medical Outcomes Study 36-Item Short Form (SF-36) and the National Eye Institute Visual Functioning Questionnaire (NEI VFQ-25) were administered by a trained interviewer. Sociodemographic and clinical data were also collected. RESULTS: Seventy-six patients were enrolled. The overall NEI VFQ-25 score was significantly lower among patients with uveitis than in a normal reference group (P<.001). The SF-36 physical (PCS) and mental (MCS) component summary scores were also significantly lower among patients with uveitis than in the general US population (P<.007). Among patients with uveitis, visual acuity, binocular involvement, intensity of therapy, employment status, and PCS and MCS scores were all significantly associated with overall NEI VFQ-25 scores in multivariable analysis. Medical comorbidity, ocular comorbidity, and NEI VFQ-25 scores were significantly associated with PCS scores. Medical comorbidity and NEI VFQ-25 scores were significantly associated with MCS scores. Regression models including NEI VFQ-25 scores explained an additional 7% of the variance in PCS scores and 16% of MCS scores. Models including both PCS and MCS scores explained an additional 12% of the variance in NEI VFQ-25 scores. CONCLUSIONS: Patients with uveitis reported markedly poorer visual functioning and general health status than normal subjects. Patients with more severe uveitis have poorer visual functioning and general health status than patients with milder disease. Visual functioning and general health status measurement contribute complementary information and should both be performed in patients with uveitis to measure the effect of disease and its therapy on their quality of life.

Adult↗
PubMed2001

Differential efficacy of tumor necrosis factor inhibition in the management of inflammatory eye disease and associated rheumatic disease.

OBJECTIVE: To evaluate the clinical usefulness of tumor necrosis factor (TNF) inhibitors in patients with inflammatory eye disease that is resistant to conventional immunosuppressive therapies. METHODS: Sixteen patients (4 males and 12 females aged 7 to 78 years) who received etanercept (n = 14) or infliximab (n = 2) for either inflammatory eye disease or associated joint disease were studied retrospectively to determine the effect of these medications on their ocular inflammation. RESULTS: Nine cases of uveitis and 7 cases of scleritis were treated. Systemic diagnoses included rheumatoid arthritis (n = 8), juvenile rheumatoid arthritis (n = 3), ankylosing spondylitis (n = 1), and psoriatic spondylarthropathy (n = 1). Three patients had uveitis without associated systemic disease. Although 12 of 12 patients with active articular inflammation (100%) experienced improvement in joint disease, only 6 of 16 with ocular inflammation (38%) experienced improvement in eye disease. Five patients developed inflammatory eye disease for the first time while taking a TNF inhibitor. No patient discontinued treatment because of adverse drug effects. CONCLUSION: TNF inhibitors are well tolerated immunosuppressive medications that may benefit certain subgroups of patients with inflammatory eye disease, but they appear to be more effective in controlling associated inflammatory arthritis.

Adolescent↗
PubMed2001

High-dose intravitreal ganciclovir and foscarnet for cytomegalovirus retinitis.

PURPOSE: To describe the chronic use of high doses of intravitreal ganciclovir, in combination with foscarnet, for the treatment of cytomegalovirus retinitis. METHODS: A 31-year-old man with human immunodeficiency virus (HIV) infection and unilateral active cytomegalovirus retinitis was treated with escalating intravitreal injections of ganciclovir (up to 3.0 mg twice a week) in combination with foscarnet (up to 2.4 mg twice a week) over the course of approximately 1 year. RESULTS: Complete regression of the retinitis was obtained with high doses of intravitreal ganciclovir and foscarnet. Visual acuity in the affected eye remained 20/20 throughout the course of therapy. No ganciclovir retinal toxicity was identified. CONCLUSION: High doses of intravitreal ganciclovir in combination with foscarnet can be well tolerated and may be required to successfully control cytomegalovirus retinitis in some patients.

AIDS-Related Opportunistic Infections↗
PubMed2001

Comparison of once- or twice-daily bimatoprost with twice-daily timolol in patients with elevated IOP : a 3-month clinical trial.

OBJECTIVE: To compare the safety, tolerability, and efficacy of bimatoprost 0.03% instilled once daily or twice daily with timolol 0.5% twice daily. DESIGN: Multicenter, 3-month, randomized, double-masked, interventional comparison trial. PARTICIPANTS: Patients diagnosed with ocular hypertension or glaucoma (n = 596). INTERVENTION: Patients received bimatoprost 0.03% ophthalmic solution once daily (8 PM, with vehicle control at 8 AM), bimatoprost 0.03% twice daily (8 AM; 8 PM), or timolol 0.5% twice daily (8 AM; 8 PM) in an uneven 2:2:1 randomization. Scheduled visits were at prestudy, baseline (day 0), weeks 2 and 6, and month 3. Intraocular pressure (IOP) was measured at 8 AM (predose), 10 AM, and 4 PM. MAIN OUTCOME MEASURES: The primary outcome measure was reduction in IOP in the eye with higher IOP at baseline. Secondary outcome measures included safety variables (adverse events, ophthalmoscopy, biomicroscopy, iris pigmentation, laser-flare meter, visual acuity, visual fields, heart rate, blood pressure, blood chemistry, hematology, and urinalysis). RESULTS: At month 3, the mean reduction in IOP from baseline at 8 AM was 9.16 mmHg (35.2%) with bimatoprost once daily, 7.78 mmHg (30.4%) with bimatoprost twice daily, and 6.74 mmHg (26.2%) with timolol twice daily. At all follow-up visits, mean IOP reductions were significantly greater in the bimatoprost once daily group than in the timolol group at each time point (8 AM, 10 AM, and 4 PM; P < 0.001). Twice-daily dosing of bimatoprost also provided significantly greater mean reductions in IOP than timolol at most time points but was not as effective as once-daily dosing. Bimatoprost was associated with significantly more hyperemia and eyelash growth than timolol, whereas timolol was associated with significantly more burning and stinging sensation in eyes. Overall, bimatoprost was well tolerated with few discontinuations because of adverse events. CONCLUSIONS: Bimatoprost 0.03% once daily was safe and statistically superior to timolol 0.5% twice daily in lowering IOP in patients with ocular hypertension or glaucoma. Bimatoprost given once daily consistently provided IOP reductions approximately 2 to 3 mmHg greater than those provided by timolol. Once-daily dosing of bimatoprost, 0.03%, demonstrated greater IOP-lowering effect and better ocular tolerability than twice-daily dosing.

Adult↗
PubMed2001

Immune response to retinal antigens in patients with gyrate atrophy and other hereditary retinal dystrophies.

PURPOSE: Gyrate atrophy (GA) is a rare hereditary disease that causes retinal destruction. Retinal damage in GA and other heredodegenerative diseases such as retinitis pigmentosa (RP) releases sequestered antigens and may trigger immune response to these molecules. Here, we studied the immune response to retinal antigens in patients with GA and RP and compared it with that of patients with inactive posterior uveitis and normal volunteers. PATIENTS AND METHODS: Peripheral blood was collected from 24 patients with RP, 10 patients with GA, 10 patients with inactive posterior uveitis, and 16 normal volunteers. Cell-mediated immune responses to human S-antigen (HS-Ag), bovine S-antigen (BS-Ag), and interphotoreceptor retinoid-binding protein (IRBP) were investigated by lymphocyte proliferation assay. In addition, serum levels of soluble intercellular adhesion molecule-1 (sICAM-1) and soluble vascular cell adhesion molecule-1 (sVCAM-1) were studied by ELISA. Immunologic data were correlated with clinical and electrophysiological findings. RESULTS: Patients with GA or RP responded to HS-Ag and BS-Ag more vigorously than patients with uveitis or healthy controls, as shown by higher mean stimulation indices and larger proportions of responders. Unlike S-Ag, IRBP stimulated low lymphocyte responses in only a small proportion of RP patients. The mean sVCAM-1 levels were significantly higher in the sera from patients with GA than in that from normal controls. CONCLUSION: An elevated cellular immune response to S-Ag is common in patients with GA and RP. This elevated cellular immune response to S-Ag may exacerbate retinal destruction in patients with GA and RP.

Adolescent↗
PubMed2001

Inhibition of leukocyte sticking and infiltration, but not rolling, by antibodies to ICAM-1 and LFA-1 in murine endotoxin-induced uveitis.

PURPOSE: Cell-adhesion molecules are critical elements in intravascular rolling and sticking of leukocytes during acute inflammation. In this process, selectins are thought to be involved in initial adhesion and rolling, and integrin-Ig superfamily interactions are believed primarily to mediate stronger adhesion and transendothelial migration. This study clarifies the role of two adhesion molecules, intercellular adhesion molecule (ICAM)-1 and leukocyte functional antigen (LFA)-1, in endotoxin-induced uveitis (EIU). METHODS: Intravital microscopy was used to record the movement and location of leukocytes in the irises of mice with uveitis induced by intravitreal injection of 250 ng Escherichia coli endotoxin. Each mouse concurrently received an intraperitoneal injection of monoclonal neutralizing antibodies for ICAM-1, LFA-1, or both or control irrelevant antibodies. RESULTS: Mice treated with endotoxin and control antibodies had an inflammatory response that was clearly present at the 6- and 24-hour time points and was mostly resolved by 48 hours. Mice that received anti-ICAM-1 or anti-LFA-1 had significantly fewer cells infiltrating their irises at 6 and 24 hours. Detailed analysis of the 6-hour time point recordings revealed that neither anti-ICAM-1 nor anti-LFA-1 significantly reduced the number of leukocytes rolling on venule endothelial surfaces, but the treatments reduced the number of firmly adherent cells. CONCLUSIONS: These data confirm previous reports that ICAM-1 and LFA-1 are important mediators of EIU. The dynamic in vivo images clearly support the hypothesis that integrin-mediated cell adhesion is more critical for the firm adhesion of sticking cells than for leukocyte rolling.

Acute Disease↗
PubMed2000

Breakdown of tolerance to a neo-self antigen in double transgenic mice in which B cells present the antigen.

Transgenic (Tg) mice expressing a foreign Ag, hen egg lysozyme (HEL), under control of the alphaA-crystallin promoter ("HEL-Tg" mice) develop immunotolerance to HEL attributed to the expression of HEL in their thymus. In this paper we analyzed the immune response in double (Dbl)-Tg mice generated by mating the HEL-Tg mice with Tg mice that express HEL Abs on their B cells ("Ig-Tg" mice). The B cell compartment of the Dbl-Tg mice was unaffected by the HEL presence and was essentially identical to that of the Ig-Tg mice. A partial breakdown of tolerance was seen in the T cell response to HEL of the Dbl-Tg mice, i.e., their lymphocyte proliferative response against HEL was remarkably higher than that of the HEL-Tg mice. T-lymphocytes of both Dbl-Tg and Ig-Tg mice responded to HEL at concentrations drastically lower than those found stimulatory to lymphocytes of the wild-type controls. Cell mixing experiments demonstrated that 1) the lymphocyte response against low concentrations of HEL is due to the exceedingly efficient Ag presenting capacity of the Ab expressing B cells and 2) breakdown of tolerance in Dbl-Tg mice can also be attributed to the APC capacity of B cells, that sensitize in vivo and stimulate in vitro populations of T cells with low affinity toward HEL, assumed to be escapees of thymic deletion. These results thus indicate that T cell tolerance can be partially overcome by the highly potent Ag presenting capacity of Ab expressing B cells.

Animals↗
PubMed2000

Cytomegalovirus retinitis in the era of highly active antiretroviral therapy.

A number of striking changes have occurred recently in the presentation and course of cytomegalovirus (CMV) retinitis in patients with acquired immunodeficiency syndrome (AIDS) who are receiving highly active antiretroviral therapy (HAART). Before the use of HAART, CMV retinitis was the most common intraocular infection in patients with AIDS, occurring in up to 40% of patients, typically when CD4+ cell counts have decreased to less than 0.10 x 10(9)/L. By studying CMV retinitis, clinicians can investigate whether the rejuvenated immune system that results from HAART can effectively control opportunistic infections in patients with AIDS. In some patients, retinitis has not progressed when specific anti-CMV therapy was discontinued, but a number of patients have developed substantial intraocular inflammation, which has resulted in decreased visual acuity. Anterior uveitis, cataract, vitritis, cystoid macular edema, epiretinal membrane, and disc edema may occur in patients with CMV retinitis who have experienced HAART-associated elevation in CD4+ cell counts. Since immune recovery uveitis does not occur in eyes without CMV retinitis, the ocular inflammation appears to be related to the CMV infection. Anti-CMV maintenance therapy likely can be safely discontinued in some patients with CMV retinitis if CD4+ cell counts are stable or increasing and have been higher than 0.10 x 10(9)/L for at least 3 months. Immune recovery in patients receiving HAART has been effective in controlling opportunistic infections, but it may also result in intraocular inflammation, which can have adverse effects on the eye.

AIDS-Related Opportunistic Infections↗
PubMed2000

Systemic or mucosal administration of immunostimulatory DNA inhibits early and late phases of murine allergic conjunctivitis.

Seasonal allergic conjunctivitis is one of the most common manifestations of allergic disease, affecting 15 % population in the United States annually. Short ragweed (RW) is a major cause of seasonal allergies. Immunostimulatory DNA sequences (ISS or CpG motifs) can inhibit an on-going Th2/allergic response and induce a de novo Th1 response. In this study, we investigated the ability of these ISS to modulate allergic responses in a RW-induced mouse model of seasonal allergic conjunctivitis. Systemic or mucosal administration of ISS oligonucleotide (ISS-ODN) after RW sensitization inhibited both the immediate hypersensitivity response and the late-phase cellular infiltration and induced a RW-specific Th1 response. ISS-ODN administration suppressed the rise of RW-specific IgE titers after repeated allergen challenge. Furthermore, ISS administration was more effective than dexamethasone in inhibiting the allergic response. Mechanistically, the ISS-induced immunomodulatory effects were abolished when mice were treated with anti-IL-12 neutralizing antibodies, suggesting a pivotal role for type 1 cytokines in the inhibition of both the immediate hypersensitivity and the late-phase cellular infiltration. Thus, ISS-ODN is a novel anti-inflammatory and immunomodulatory agent that significantly inhibits the allergic response and may provide an alternative to the current standard care of ocular allergy.

Administration, Topical↗
PubMed2000

Experimental immune-mediated blepharoconjunctivitis in rats induced by immunization with ragweed pollen.

BACKGROUND: A study was performed to compare the effects of immunization with ragweed pollen (RW) in two different adjuvants on the characteristics of a previously described model of experimental immune-mediated blepharoconjunctivitis (EC) in rats. METHODS: Lewis or Brown Norway (BN) rats were immunized with 100 microg of RW in emulsion with aluminum hydroxide [Al(OH)3] or complete Freund's adjuvant (CFA). Three weeks later, the animals were challenged with eye drops containing RW in PBS. Twenty-four hours after topical challenge, eyes, blood, and lymph nodes were obtained for histology, measurement of antigen-specific antibodies, and proliferation or cytokine assays, respectively. In addition to active immunization, recipients of RW-primed lymph node cells were challenged and evaluated as above. RESULTS: RW in both adjuvants induced infiltration with predominantly mononuclear cells in Lewis rats and eosinophils in BN rats. As well as active immunization, eosinophils were detected only in BN rats by adoptive transfer of cells. Lymphocyte proliferative responses to RW were high in immunized Lewis rats when CFA was used as an adjuvant. In contrast, proliferative responses in BN rats were higher when Al(OH)3 was used. RW-specific IgE was detected only in BN rats. There were no significant differences in RW-specific IgG1/IgG2a ratio among the four groups. Lewis rats had higher level of RW-specific interferon-gamma in the culture supernatant. CONCLUSIONS: The characteristics of EC are different in Lewis and BN rats, dependent on the genetic background of the rat strains. The response to RW was similar to other previously used antigens, such as ovalbumin.

Allergens↗
PubMed2000

Immune-recovery uveitis in patients with cytomegalovirus retinitis taking highly active antiretroviral therapy.

PURPOSE: To investigate the clinical features associated with immune recovery in human immunodeficiency virus (HIV)-infected patients with cytomegalovirus retinitis who are taking highly active antiretroviral therapy. METHODS: Sixteen patients were evaluated prospectively at the National Eye Institute, Bethesda, Maryland. Evaluation included a medical history and a complete ophthalmologic examination. The examination included best-corrected visual acuity score measured by means of logarithmic charts, slit-lamp biomicroscopy, dilated retinal examination, retinal photography, and fluorescein angiography. Immune-recovery uveitis was defined as the ocular inflammation associated with clinical immune recovery in patients taking potent antiretroviral regimens. The ophthalmic characteristics of immune-recovery uveitis were identified, and their effect on visual acuity was statistically analyzed. RESULTS: The mean CD4+ T-lymphocyte count for the 16 patients taking highly active antiretroviral therapy at the time of evaluation was 393 cells/microl (range, 97-1,338 cells/microl). Immune-recovery uveitis was characterized by vitreitis and optic disk and macular edema. Clinically important complications of immune-recovery uveitis included cataract and epiretinal membrane formation. The visual acuity scores were significantly worse in the 23 eyes with cytomegalovirus retinitis (mean, 67.2 letters, 20/50) than in the nine eyes without cytomegalovirus retinitis (mean, 89.8 letters, 20/16) (P <.001). Regression analysis showed that a lower visual acuity score was associated with the presence of moderate to severe macular edema on fluorescein angiography and vitreous haze (P < or =. 001). CONCLUSIONS: Immune-recovery uveitis is an important cause of visual morbidity in HIV-infected patients with cytomegalovirus retinitis in the era of highly active antiretroviral therapy. Although immune recovery associated with highly active antiretroviral therapy has allowed some patients to discontinue specific anticytomegalovirus therapy, the rejuvenated immune response can be associated with sight-threatening inflammation.

AIDS-Related Opportunistic Infections↗
PubMed2000

Guidelines for the use of immunosuppressive drugs in patients with ocular inflammatory disorders: recommendations of an expert panel.

PURPOSE: To provide recommendations for the use of immunosuppressive drugs in the treatment of patients with ocular inflammatory disorders. PARTICIPANTS: A 12-person panel of physicians with expertise in ophthalmologic, pediatric, and rheumatologic disease, in research, and in the use of immunosuppressive drugs in patient care. EVIDENCE: Published clinical study results. Recommendations were rated according to the quality and strength of available evidence. PROCESS: The panel was convened in September of 1999 and met regularly through May 2000. Subgroups of the panel summarized and presented available information on specific topics to the full panel; recommendations and ratings were determined by group consensus. CONCLUSIONS: Although corticosteroids represent one of the mainstays in the management of patients with ocular inflammation, in many patients, the severity of the disease, the presence of corticosteroid side effects, or the requirement for doses of systemic corticosteroids highly likely to result in corticosteroid complications supports the rationale for immunosuppressive drugs (for example, antimetabolites, T-cell inhibitors, and alkylating agents) being used in the management of these patients. Because of the potential for side effects, treatment must be individualized and regular monitoring performed. With careful use of immunosuppressive drugs for treatment of ocular inflammatory disorders, many patients will benefit from them either with better control of the ocular inflammation or with a decrease in corticosteroid side effects.

Drug Therapy, Combination↗
PubMed2000

The role of IL-12 in the induction of late-phase cellular infiltration in a murine model of allergic conjunctivitis.

BACKGROUND: The applied murine model of allergic conjunctivitis mimics human disease, and an immediate hypersensitivity reaction (IHR) and a late-phase cellular reaction typically develop in sensitized mice after topical challenge with the allergen. OBJECTIVE: We investigated the role of IL-4, IFN-gamma, and IL-12 in the early and late phases of ocular allergy with use of cytokine knockout (KO) mice and neutralizing antibodies. METHODS: Ragweed-sensitized wild-type or IL-4KO, IL-12KO, IFN-gamma KO, anti-IL-12 mAb-treated, recombinant murine IL-12-treated, and anti-IFN-gamma mAb-treated mice were challenged with the allergen 10 days after the immunization. IHR, cellular infiltration, lymphoproliferative response, and cytokine production from draining lymph nodes were recorded and compared among groups. RESULTS: We show that IL-12KO mice and anti-IL-12 antibody-treated wild-type animals failed to have a cellular infiltration into the conjunctiva. Treatment with recombinant murine IL-12 also reduced the number of infiltrating PMNs but increased the percentage of mononuclear cells in the conjunctiva compared with controls. IFN-gamma KO mice had a significantly stronger IHR and prolonged infiltration into the conjunctiva after challenge with ragweed than controls. CONCLUSION: Our data suggest that the presence of IL-12, although better known as a T(H)1-inducing cytokine, is important for the development and the regulation of the late-phase pathologic features in ocular allergy. Furthermore, IFN-gamma is a limiting factor in the late phase of allergy and thus may be important in preventing chronic allergic disease.

Animals↗