Biomedical subjects
W R Goslings
Publications and source records attributed to W R Goslings.
Corneal transplantation in antibody-deficient hosts.
PURPOSE: To examine the role of donor-specific antibodies, with or without complement, in rejection of orthotopic corneal transplants by using mice as recipients in which the genes for the heavy chain of immunoglobulin or the third complement component have been eliminated by homologous recombination. METHODS: BALB/c corneas were transplanted into eyes of B-cell-deficient (n=17) or wild-type control C57BL/6 (n=30) mice and into eyes of complement (C3)-deficient (n=15) or wild-type control 129-C57BL/6 (n=13) mice. After surgery all grafts were evaluated over 8 weeks in a masked manner by biomicroscopy for signs of rejection. RESULTS: The rates of corneal transplant rejection were similar among B-cell-deficient and C3-deficient mice compared with rejection rates in their respective wild-type control subjects. This similarity applied to the time course of rejection and to cumulative survival rates. CONCLUSIONS: Neither donor-specific antibody nor the third component of complement play essential roles in acute rejection of orthotopic corneal allografts in mice.
A small molecular weight factor in aqueous humor acts on C1q to prevent antibody-dependent complement activation.
PURPOSE: Aqueous humor inhibits activation of the classic complement pathway; however, the mechanism of this inhibition is unknown. We have examined at the molecular level potential factors responsible for the inhibition, and we have tried to determine where in the complement pathway the inhibition takes place. METHODS: Fresh rabbit aqueous humor was size fractionated by centrifuge concentrators and by size exclusion column chromatography, and each fraction was assayed for inhibition of the classic complement pathway in a standard CH50 hemolytic assay. Fractions with inhibitory activity were assayed for protein and the presence of ascorbic acid and were subjected to heat treatment. To identify where in the pathway the inhibitor(s) function, the expression of activated complement components bound to the surface of antibody-coated erythrocytes was analyzed by flow cytometry using fluorescein isothiocyanate-labeled antibodies to specific complement components. In addition, hemolytic assays were performed for the function of individual complement components. RESULTS: The most potent inhibition of the classic pathway was in a fraction of aqueous humor of less than 1.3 kDa. The inhibitory activity in the fraction was unassociated with detectable protein or ascorbic acid, and it remained present after heat treatment. The functional analysis through flow cytometry and hemolytic assays for individual complement components showed that the inhibitor in the less than 1.3-kDa fraction caused a blockade in the complement pathway at the level of C1q. CONCLUSIONS: The aqueous humor contains a unique potent anticomplementary factor that has a molecular weight less than 1.3 kDa. This heat-stable inhibitory factor inhibits the classic pathway at the level of C1q. These results imply that within the eye the complement pathway is inhibited at the earliest steps of its initiation. Such inhibition would prevent production of complement products that mediate inflammation and chemotaxis of inflammatory cells. Therefore, as part of the adaptation of immune privilege, the ocular microenvironment is protected from inflammation induced by antigen-antibody complexes.
Lack of effect of different cytokines on expression of membrane-bound regulators of complement activity on human uveal melanoma cells.
Tumor cells are protected from antibody-dependent complement-mediated lysis by membrane-bound regulators of complement activation (m-RCA). m-RCA are expressed on uveal melanoma cells. We determined whether cytokine treatment affects expression of m-RCA on these cells in vitro. m-RCA expression on uveal melanoma cell lines was studied by flow cytometry, using monoclonal antibodies directed against CD46, CD55, and CD59. Cytokines studied were interferon-alpha (IFN-alpha), IFN-gamma, interleukin-1B (IL-1B), IL-12, and tumor necrosis factor-alpha (TNF-alpha). All three m-RCA were expressed on the uveal melanoma cell lines (CD59>>CD46>CD55), although in variable amounts. With a few exceptions, the cytokines had no effect on m-RCA expression. CD55 expression was not influenced by any of the cytokines. IFN-gamma downregulated expression of CD46 on one cell line (p < 0.01). TNF-alpha upregulated CD59 expression on two of the five cell lines (p < 0.012 and p < 0.001, respectively), which effect was dose dependent. IFN-alpha, IFN-gamma, IL1-beta, IL12, and TNF-alpha had limited effects on m-RCA expression on uveal melanoma cells in vitro.
Membrane-bound regulators of complement activation in uveal melanomas. CD46, CD55, and CD59 in uveal melanomas.
PURPOSE: To identify the presence of membrane-bound regulators of complement activation (m-RCA) on uveal melanomas and uveal melanoma cell lines and to examine their role in the inhibition of complement-mediated lysis in vitro. METHODS: Immunohistochemistry and flow cytometric analysis with monoclonal antibodies directed against m-RCA CD46, CD55, and CD59 were applied to tissue sections of 10 uveal melanomas, three primary uveal melanoma cell lines, and one uveal melanoma metastatic cell line. A microcytotoxicity test was used for measuring antibody-dependent complement-mediated lysis. RESULTS: The tissue sections and all four uveal melanoma cell lines expressed CD46, CD55, and CD59. Complement-mediated lysis in the presence of human complement was increased after partial removal of the m-RCA CD55 and CD59 with phosphatidylinositol-specific phospholipase C from the uveal melanoma cell line 92-1. CONCLUSIONS: These results demonstrate that CD46, CD55, and CD59 are expressed in uveal melanomas and that CD55 or CD59, or both, plays a role in resistance to complement-mediated cytotoxicity. The finding that m-RCA are expressed in uveal melanomas may have implications for the effectiveness of the anti-tumor response and in the therapeutic application of monoclonal antibodies directed against tumor-associated antigens.
Rate of radial bone mineral accretion in healthy children.
Radial bone width and mineral content were measured in 392 healthy Cambridge children aged 6-12 years from a cohort of 420 children studied 2 years previously. The typical rate of bone mineral accretion was 0.044 g/cm/year for boys across the whole age range and 0.042 g/cm/year for girls up to a mean age of 9 years, rising rapidly thereafter in association with changes in body size. The factors best predicting bone mineral accretion rate were mean bone mineral content, mean height, height velocity, weight velocity and bone width velocity. After adjusting for anthropometry, age did not contribute to the model. These are the first available longitudinal reference data for the rate of radial bone mineral accretion in healthy children.
Aprospective study of urinary-tract infections in a Dutch general practice.
In a Dutch general practice the adult female population was screened for asymptomatic bacteriuria (A.B.) by repeated urine culture after vulval cleansing. The prevalence of signficant A.B. was 4.7% and increased with age. Women with significant A.B. were followed up for one year. All symptomatic urinary-tract infections were recorded during the same period (incidence 59 per 1000 population). Women with significant A.B. at screening were divided into three groups according to the pattern of the follow-up results: transitory A.B., symptomatic A.B., and persistent A.B. The last group differed from the penultimate group with regare to the site of their urinary-tract involvement, symptomatic cases having predominantly upper-urinary-tract involvement and persistent cases lower-urinary-tract infection. In the matched control group the acquisition-rate of both symptomatic and asymptomatic 0acteriuria was over 12%, a figure similar to the percentage of women present in the practice population during one year with transient, symptomatic, and persistent A.B. Screening for A.B. in the general non-pregnant female population is not advocated at present. Screening and treatment of existing A.B. should be carried out in pregnant women who run an increased risk.
[Screening for bacteriuria in pregnant women].
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Cloxacillin and nafcillin: serum binding and its relationship to antibacterial effect in mice.
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Pharmacokinetics of cloxacillin in patients on chronic intermittent haemodialysis and in healthy subjects.
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Streptococcal pharyngitis in the general population. I. A controlled study of streptococcal pharyngitis and its complications in the Netherlands.
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Streptococcal pharyngitis in the general population. II. The attack rate of rheumatic fever and acute glomerulonephritis in patients.
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[The significance of leukocyturia, Gram preparation, and the Griess test for the diagnosis of urinary tract infections].
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The relation between M-typability of group A streptococci, virulence and antibody response in general practice.
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[The rational use of antibiotics].
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Streptococci, ABO blood groups, and secretor status.
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Continuous suppressive antimicrobial treatment in chronic infected bronchitis during the winter months.
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