Biomedical subjects

D B G Oliveira

Publications and source records attributed to D B G Oliveira.

7 recordsLinked to original sources

PubMed2005

A role for alphabeta T cells in the resistant phase of the Brown Norway rat model of vasculitis.

Administration of mercuric chloride (HgCl(2)) to Brown Norway rats causes Th2 dominated autoimmunity including a caecal vasculitis. Disease peaks 14 days after starting HgCl(2) after which animals immunoregulate spontaneously. In a third phase, if animals are rechallenged with HgCl(2) 6 weeks later they appear resistant, developing only attenuated disease. Previous studies suggested a role for CD8(+) cells as partial mediators of resistance but no groups had studied the role of alphabeta T cells, gammadelta T cells or natural killer (NK) cells in resistance. We used adoptive transfer and in vitro cell depletion to show that alphabeta T cells are also partially responsible for resistance. Donor animals were treated with HgCl(2) or saline and killed 21 days later. Cells from donor spleens were transferred into recipient animals which were challenged with HgCl(2) and killed 14 days later. Test recipients received spleen cells from HgCl(2)-treated donors after in vitro depletion of one subset of cells. Recipients receiving spleen cells from saline-treated donors remained susceptible to HgCl(2)-induced vasculitis; those receiving spleen cells from HgCl(2)-treated donors were resistant. Animals receiving alphabeta T-cell-depleted spleen cells from HgCl(2)-treated donors showed partial reversal of resistance. Our results suggest a role for alphabeta T cells in the resistant phase of the Brown Norway rat model of vasculitis.

Adoptive Transfer↗

PubMed2004

Desferrioxamine modulates chemically induced T helper 2-mediated autoimmunity in the rat.

A rise in interleukin (IL) 4-dependent immunoglobulin E (IgE) is a hallmark of the mercuric chloride (HgCl2)-induced Th2-mediated autoimmune syndrome in the Brown Norway (BN) rat, and one of the mediators in allergic asthma in human. Oxidative stress, a potential factor related to the pathogenesis of allergy and asthma, has been shown to up-regulate IL-4 in mast cells and predispose to degranulation in vitro. However, it remains unknown whether oxidative/antioxidative imbalance plays a role in this Th2-driven model of autoimmunity in the rat. Here we show that administration of the non-sulphydryl-containing antioxidant desferrioxamine i.p. and s.c. to BN rats reduces HgCl2-enhanced IL-4 gene expression and inhibits HgCl2-induced Th2-mediated autoimmunity. Desferrioxamine treatment suppresses significantly IgE production and lymphoproliferation, and reduces tissue injury in the form of caecal vasculitis in the HgCl2-induced autoimmune syndrome. These results support a role for oxidative stress in the pathogenesis of the HgCl2-induced Th2-dominated autoimmune syndrome. This finding might have implications for understanding the mechanisms involved in Th2 cell responses as seen in allergy and asthma and thereby aid the development of new therapeutic strategies for these diseases.

Animals↗

PubMed2004

Resistance to re-challenge in the Brown Norway rat model of vasculitis is not always complete and may reveal separate effector and regulatory populations.

Administration of mercuric chloride to Brown Norway rats results in T helper type 2 (Th2)- dominated autoimmunity characterized by high immunoglobulin E (IgE) concentrations, the production of multiple IgG autoantibodies, including those to glomerular basement membrane (GBM), arthritis and caecal vasculitis. After 14 days animals immunoregulate and auto-immunity resolves even if mercuric chloride injections are continued. In a third phase, if animals are re-challenged with mercuric chloride 6 weeks later, they show only attenuated autoimmunity with lower anti-GBM antibody concentrations and arthritis scores. Resistance to the induction of anti-GBM antibodies can also be achieved following an initial challenge with low-dose (one-tenth standard dose) mercuric chloride. We have now studied this resistant phase in more detail. We have shown, first, that following an initial full-dose mercuric chloride challenge, resistance also affects susceptibility to caecal vasculitis. Second, following an initial full-dose mercuric chloride challenge, the IgE response upon re-challenge is initially accelerated but subsequently enters a resistant phase and third, following an initial challenge with low-dose mercuric chloride, resistance is also seen to the induction of caecal vasculitis but is not seen in IgE serology (where results suggest competing effector and regulatory cell populations). Studying such regulatory phases in animal models of autoimmunity may be of benefit in the future in designing new therapies for human vasculitis.

Animals↗

PubMed2004

Reactive oxygen species in the initiation of IL-4 driven autoimmunity as a potential therapeutic target.

Helper T-lymphocytes have been shown to differentiate into two mutually regulatory subsets. Cells primarily secreting interleukin-2 (IL-2) and interferon-gamma are known as Th1 cells and mediate classical cell-mediated immune responses such as delayed-type hypersensitivity. Cells secreting interleukin-4 (IL-4) are known as Th2 cells and promote humoral immune responses, in particular the production of IgE and IgG4 (human) or IgG1 (rodents). Over-activity of either cell type can result in tissue-damaging autoimmune disease. A number of human diseases including asthma and some kidney diseases are thought to be caused by a Th-2 type autoimmune response. Study of an animal model of Th2-driven autoimmunity (mercuric chloride-induced autoimmunity in Brown Norway rats) has yielded insights into a possible role for oxidant stress in the generation of Th-2 driven autoimmune responses. Mercuric chloride probably causes oxidant stress by the generation of free-radicals, activating NK-kappaB, a transcription factor for the IL-4 gene. Treatment with the antioxidants N-acetlcysteine and desferrioxamine has been shown to suppress vasculitis and IgE production in this model. These findings suggest a possible clinical role for antioxidants in the therapy of human autoimmune disease.

Adjuvants, Immunologic↗

PubMed2003

Acute glomerulonephritis.

Glomerulonephritis is an important cause of renal failure thought to be caused by autoimmune damage to the kidney. While each type of glomerulonephritis begins with a unique initiating stimulus, subsequent common inflammatory and fibrotic events lead to a final pathway of progressive renal damage. In this article the different forms of inflammatory glomerulonephritis and their diagnosis are discussed. In a review of therapy both immediate life saving treatment given when glomerulonephritis causes acute renal failure and more specific treatments designed to modify the underlying mechanisms of renal injury are considered.

Acute Disease↗

PubMed2002

The Th2-response in mercuric chloride-induced autoimmunity requires continuing costimulation via CD28.

Mercuric chloride (HgCl2)-induced autoimmunity in Brown Norway (BN) rats is a highly polarized polyclonal Th2-driven autoimmune response with increased IgE production, lymphoproliferation, vasculitis and proteinuria. The increase in serum IgE concentration is clearly measurable by day 4 after the first HgCl2 injection and peaks between days 15 and 20. Treatment with CD80 and CD86 antibodies prior to administration of HgCl2 completely suppresses the autoimmune process. To determine whether interruption of CD28 signalling after initial stimulation of the Th2-response would be suppressive, antibody treatment was delayed. BN rats were given 5 doses of HgCl2 subcutaneously on alternate days. CD80 and CD86 antibodies, or an isotype control, were given daily for 3 days and then on alternate days until day 12 commencing either on the day of the first HgCl2 injection (day 0) or on days 4 or 8. Treatment from day 0 reduced serum IgE concentrations to below baseline (median 9.34 microg/ml on day 0 versus 4.6 microg/ml, on day 5, P = 0.03) suggesting that ongoing costimulation via CD28 is required to maintain basal serum IgE production. Delaying treatment until day 4 or day 8 after the first HgCl2 injection resulted in significant inhibition of IgE secretion, lymphoproliferation, and vasculitis, although less markedly than when treatment was commenced on day 0. These data indicate that CD28-mediated costimulation is not only required for the initiation of the Th2-response but is required for maintenance of a maximal response, making this an attractive therapeutic target for antibody-mediated autoimmune diseases.

Animals↗

PubMed2002

The immunopathogenesis of membranous nephropathy.

Membranous nephropathy is an important disease: it is one of the leading primary causes of the nephrotic syndrome in adults, and, in up to a third of patients, causes progressive renal impairment resulting in end stage renal failure. Ever since histological techniques demonstrated the presence of glomerular immunoglobulin deposits in this disease the immune system has been implicated in pathogenesis. Initial ideas focussed on the deposition of circulating immune complexes, but the development of an animal model (Heymann nephritis) suggested the alternative mechanism of antibody reacting with an intrinsic glomerular antigen. However, attempts to find evidence for this Heymann type mechanism in the human disease have, in general, been unsuccessful. This article briefly reviews the development of ideas about the pathogenesis of membranous nephropathy, and proposes the hypothesis that the disease is caused by formation of low affinity non-complement fixing IgG4-containing immune complexes.

Animals↗