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Biomedical subjects

R J Wedgwood

Publications and source records attributed to R J Wedgwood.

At least 19 recordsLinked to original sources
PubMed1993

Regulation of antibody responses: the role of complement and adhesion molecules.

To analyze the importance of cell surface-associated molecules in modulating the immune response by facilitating T/B cell interaction, we used the T cell-dependent antigen, bacteriophage phi X174. Taking advantage of "experiments of nature", we studied specific antibody synthesis in patients with deficiencies of complement components or of the adhesion molecule CD11/CD18 (leukocyte adhesion defect, LAD) and guinea pigs and dogs with early complement component deficiency. Following intravenous injection of bacteriophage phi X174 into normal subjects or animals, a primary response consisting of IgM, a secondary response consisting of IgM and IgG, and a tertiary, predominantly IgG response can be distinguished. Patients and guinea pigs deficient of early complement component and LAD patients responded to repeated phage immunization with depressed antibody titers, lack of or inadequate amplification, and failure to switch from IgM to IgG, suggesting a defect in generating antigen-specific memory cells. Several mechanisms have to be considered: (i) The complement portion of the antigen-antibody complement complex facilitates the accumulation and trapping of antigen in lymphoid organs, thus improving the response to Ag at low concentrations. (ii) Immune complexes preferentially bind to antigen-specific B cells, cells expressing Fc receptors, or CR2 and CR3, the receptors for C3bi. (iii) The weak binding established between the MHC-II/Ag complex and the TCR complex is strengthened through the binding of several adhesion molecule pairs. (iv) Receptor-ligand binding initiates activation signals. The concept of binding/signaling via interacting molecules is further supported by the observation that mAb 60.3, recognizing the beta chain of CD11/CD18, blocks in vitro synthesis of antibody to bacteriophage by primed PBMC.

Animals↗
PubMed1991

Decreasing severity of chronic uveitis in children with pauciarticular arthritis.

We compared the current prevalence and severity of chronic uveitis in children with pauciarticular juvenile rheumatoid arthritis in Seattle, Wash, with that of children with the same condition in the same area in 1975. The prevalence of eye disease decreased from 45% in 1975 to 13% in 1989, and the proportion of patients with severe visual loss decreased from 21% in 1975 to none in 1989. We could not attribute these findings to differences in known risk factors for iritis, such as age, sex, or presence of antinuclear antibodies. There was no difference in the duration of follow-up between the two groups. It is possible that the decline in prevalence of uveitis reflects a referral bias for eye disease in the 1975 population. However, the decrease in disease severity remains unexplained and may represent more effective treatment, earlier surveillance for ocular disease, or a change in the frequency of ocular manifestations of this disease in the 1989 group.

Arthritis, Juvenile↗
PubMed1991

The pharmacokinetics of total IgG, IgG subclasses, and type specific antibodies in immunodeficient patients.

The advent of immunoglobulin concentrates suitable for intravenous administration has greatly improved the clinical management of patients with a primary immunodeficiency syndrome. However, proper treatment requires understanding of the pharmacokinetics of the infused IgG and its components. We review here the work that has been conducted in this area. In particular, two studies have shown that these concentrates have adequate catabolic properties with regards to total IgG, IgG subclasses, and specific antibodies. We conclude that careful evaluation of the pharmacokinetics of a given IgG preparation is necessary in order to determine an appropriate treatment regimen.

Female↗
PubMed1989

Toxicity and serum levels of methotrexate in children with juvenile rheumatoid arthritis.

Twenty-three children with destructive polyarticular juvenile rheumatoid arthritis (JRA) were treated for 0.5-4.3 years (median 1.6 years) with weekly doses of methotrexate (MTX) (0.11-0.6 mg/kg/week). Serum levels of MTX at 1 hour and at 24 hours after drug administration were obtained at each dosage level and every 3 months after a stable dosage was achieved. No patient had serum levels of MTX that were in the toxic range nor evidence of hematologic, skin, mucous membrane, gastrointestinal, or pulmonary abnormalities. Ten patients had transiently elevated serum transaminase levels. Arthritis symptoms improved in 21 of these JRA patients, and the improvement was significantly associated with a mean 1-hour serum MTX level of greater than or equal to 5.8 x 10(-7)M (P = 0.008) and a dosage of greater than or equal to 0.3 mg/kg/week (P = 0.004). The 1-hour serum level of MTX was correlated with the MTX dosage (r = 0.28, P = 0.005). Our observations suggest that with close monitoring, MTX can be used safely at dosages as high as 0.6 mg/kg/week, and improvement in the symptoms of JRA will become evident when the serum levels of MTX 1 hour after administration approach 6.0 x 10(-7)M.

Administration, Oral↗
PubMed1989

Human antibody responses to bacteriophage phi X 174: sequential induction of IgM and IgG subclass antibody.

We studied the appearance of antigen-specific immunoglobulin classes and IgG subclasses in normal adult human subjects in response to primary, secondary, and tertiary immunization with the T-cell-dependent neo-antigen bacteriophage phi X 174. To complete the study we developed a sensitive, specific, and reproducible ELISA assay which was closely comparable to the widely used neutralization assay for total antibody (r = +0.97) and for IgG antibody (r = +0.93), and reasonably comparable for IgM antibody (r = +0.76). We confirmed that the initial response to primary immunization was predominantly, but not exclusively, IgM antibody. The secondary and tertiary responses demonstrated memory, amplification, and switch from IgM to IgG antibody. There was an orderly appearance of phage-specific IgG subclasses. IgG3 and IgG1 antibodies appeared 2 to 6 weeks after primary immunization. In all subjects there was a marked increase in IgG1 and IgG3 antibody after secondary immunization, and IgG2 antibody followed closely; IgG4 antibody appeared in some subjects. IgM antibody persisted in significant amounts (approx 50%) throughout the secondary response period. Following tertiary immunization, IgG1, IgG2, and IgG3 antibody consistently increased, and IgG4 antibody appeared in all subjects; IgG1 antibody predominated. Low levels of IgM antibody (approx 1% of total) persisted during the tertiary response. The persisting antibody on long-term follow-up (median 4 years after immunization) was virtually all (greater than 90%) IgG1.

Adult↗
PubMed1989

Intravenous immunoglobulin: a review.

Intramuscular immunoglobulin products developed for the prophylaxis of viral diseases and used in replacement therapy in immunodeficiency diseases have been superseded by products suitable for intravenous administration. Modified and intact immunoglobulin preparations are available for therapeutic use; only the intact products express full Fc-mediated function and the biological half-life of IgG (3-4 weeks). While adverse reactions to intravenous immunoglobulin (IVIG) do occur, they are infrequent. Rare clusters of non-A, non-B hepatitis after the use of some lots of IVIG have been reported. Transmission of HIV has never been documented. The administration of IVIG in replacement therapy in primary immunodeficiency syndromes and in secondary immunodeficiencies, as well as for the prevention and treatment of infectious diseases, is discussed, and reports of the use of IVIG for immune modulation in autoimmune and immune-complex disease are summarized.

Antibodies, Bacterial↗
PubMed1988

Abnormal antibody responses in patients with persistent generalized lymphadenopathy.

Persistent, generalized lymphadenopathy (PGL) is a recognized component of human immunodeficiency virus (HIV) infection. We conducted longitudinal studies of B and T cell function in seven homosexual men with HIV infection and PGL. All seven had abnormal antibody-mediated immunity as studied by sequential assessment of in vivo antibody responses after immunization with the T-dependent neoantigens bacteriophage phi X 174 and keyhole limpet hemocyanin (KLH), the T-independent tetradecavalent pneumococcal polysaccharide vaccine, and the recall antigens diphtheria and tetanus toxoid. Compared to HIV-negative heterosexual controls, PGL patients responded with lower antibody titers and, following immunization with phage, failed to develop immunologic memory and to switch from IgM- to IgG-isotype antibody. In vitro antigen-induced antibody production was markedly diminished; and some patients showed depressed mitogen responses. There was a correlation between the degree of compromised immunity and the clinical condition; those with the most severe symptoms showed the most extensive immune deficiency. Yet despite obvious immunologic impairment five of the seven men have remained clinically stable over a 3-year follow-up period.

AIDS-Related Complex↗
PubMed1988

The half-lives of IgG subclasses and specific antibodies in patients with primary immunodeficiency who are receiving intravenously administered immunoglobulin.

With the increased use of immunoglobulin for intravenous use (IGIV) as replacement therapy for patients with primary immunodeficiencies, a natural concern is whether such preparations demonstrate a normal turnover rate with regard to total IgG, individual IgG subclasses, and specific antibody titers. We have conducted such a pharmacokinetic study on a cohort of eight patients with an IGIV preparation, Gammagard. For total IgG, the half-life found was 25.8 days; for IgG1 it was 29.7 days; for IgG2 it was 26.9 days; and for IgG3 it was 15.7 days. The results are similar to those reported for endogeneous IgG. Half-lives for antibodies to S. minnesota (Re 595 mutant), cytomegalovirus, and S. pneumoniae were of the same order of magnitude as that for total IgG. We conclude that this IGIV preparation is catabolized in patients with primary immunodeficiency at a rate similar to that of native IgG in normal individuals.

Adolescent↗
PubMed1988

Survival of antigen-specific antibody following administration of intravenous immunoglobulin in patients with primary immunodeficiency diseases.

To measure the survival of IgG, IgG subclasses and antigen-specific antibody in immune-deficient patients, we infused 4 patients with X-linked agammaglobulinemia (XLA) and 6 patients with common variable immune deficiency (CVID) with modified immunoglobulin at a dose of 400 mg/kg per month until steady state was reached. Following the 8th monthly infusion, serial samples were obtained and analyzed for serum concentration of IgG, IgG subclasses and for specific antibody activities against a battery of antigens. Half-lives for IgG and IgG subclasses were between 30 and 40 days except for IgG3 which appeared to consist of two populations of molecules, one showing a rapid decay, the other disappearing at a rate suggesting a half life of 22-24 days. Antigen-specific antibodies, including antibodies to HBsAg, cytomegalovirus, pneumococcal polysaccharides and streptococcal group A carbohydrate were similar to that for total IgG. These studies demonstrate that protective antibody titers to infective agents can be maintained for several weeks following high-dose intravenous immunoglobulin infusion.

Adolescent↗
PubMed1987

IgG subclass deficiencies.

IgG subclasses represent distinct immunoglobulin types, each defined by unique primary structures of the constant region of the heavy-chain molecule, and each with characteristic biological and functional properties. New methods and reagents to measure serum concentrations have contributed to the study of the ontogeny, antigen restriction, and deficiencies of IgG subclasses. Distinct clinical entities of single or multiple IgG subclass deficiencies have been identified and the efficacy of immunoglobulin replacement therapy has been demonstrated in several instances.

Adolescent↗
PubMed1987

Impaired in vivo and in vitro antibody responses to bacteriophage phi X 174 in juvenile rheumatoid arthritis.

Immunologic abnormalities described in juvenile rheumatoid arthritis (JRA) have been largely confined to mitogen or antigen driven proliferation assays. We studied antigen specific antibody production using the neoantigen bacteriophage phi X 174 in vivo and in vitro; defective responses were found in all 8 patients with JRA studied. These could not be attributed to circulating anti-T cell antibodies, but may relate to lymphocyte subset abnormalities found by 2 color analyses. These immunologic aberrations may play a direct role in the pathogenesis of JRA or, alternatively, may be a secondary event.

Adolescent↗
PubMed1987

Efficacy of a new intravenous immunoglobulin preparation in primary immunodeficient patients.

The safety and efficacy of a new second-generation intravenous immunoglobulin manufactured using ion-exchange chromatographic methods was studied in 17 patients with primary immunodeficiency. In assessing safety, the incidence of adverse reactions during the first 48 hours after each infusion and long-term changes in laboratory values were considered. Efficacy was determined by the number of acute and new chronic infections as well as by the number of prescriptions filled for antibiotics. These results were compared with those reported for similar preparations. Results showed a low (4.4%) incidence of acute adverse reactions, and no serious reactions or significant changes were noted in any of the laboratory test results. The incidences of infection and antibiotic usage were as low as or lower than those reported with other preparations. Thus we conclude that this new intravenous immunoglobulin product is a safe, effective prophylactic treatment for patients who have primary immunodeficiency.

Adolescent↗