PubMed Health⌕ Search

Biomedical subjects

S Thiru

Publications and source records attributed to S Thiru.

At least 37 records · Page 2Linked to original sources
PubMed1995

Inflammatory polyarthritis induced by mercuric chloride in the Brown Norway rat.

BACKGROUND: Mercuric chloride (HgCl2) induces an autoimmune syndrome in susceptible strains of rodent. In the Brown Norway (BN) rat, this is characterized by autoreactive T cells, high levels of total IgE, IgG autoantibodies, including anti-collagen types I and II, and tissue injury, including glomerulonephropathy and necrotizing vasculitis of the gut. The high total IgE levels and evidence showing ex vivo down-regulation of IFN gamma and in vivo up-regulation of IL-4 suggest that HgCl2-induced autoimmunity occurs in a Th2 lymphokine environment. EXPERIMENTAL DESIGN: HgCl2-autoimmunity was induced in BN rats using standard methods. Anti-collagen (types I and II) Ab and IgG subclasses were measured by ELISA. Arthritis was scored on Days 13 to 17 after HgCl2 treatment. Ankle joints and synovium were examined with standard histologic and immunohistochemical techniques. The incidence and severity of arthritis were compared in normal and R73 (anti-alpha/beta T cell receptor mAb)-treated BN rats. After R73 treatment, T cell function was assessed by measuring the total IgE and anti-type II collagen response to HgCl2, and FACS was used to assess the number of peripheral blood OX19+ lymphocytes (T cell marker). RESULTS: A self-limiting inflammatory arthritis develops in more than 82% of animals and is more severe in males. Histologically, there is a predominant ED1+ macrophage synovial infiltrate, areas of fibrinoid necrosis, and vasculitis and erosions of cartilage. The peak anti-collagen (type I and II) Ab titer does not correlate with arthritis incidence or severity. Treatment with R73 markedly reduces the rise in total IgE and IgG anti-type II collagen, reduces OX19+ peripheral blood lymphocytes, and abolishes the arthritis. CONCLUSIONS: HgCl2 induces a T cell-dependent inflammatory arthritis in the BN rat. In contrast with other animal models, HgCl2-induced arthritis is associated with an apparent Th2 lymphokine response.

Animals↗
PubMed1995

Hydrogen peroxide-induced endothelial retraction is accompanied by a loss of the normal spatial organization of endothelial cell adhesion molecules.

Treatment of confluent monolayers of human umbilical vein endothelial cells with sublethal concentrations of hydrogen peroxide (H2O2) produces reversible cell retraction that opens gaps between adjacent cells. Despite the retraction, adjacent cells remain in contact through a network of dendrite-like processes. Retraction depends on cellular metabolism but not new protein synthesis or protein kinase C. Shape changes induced by H2O2 are accompanied by partial redistribution of actin filaments from the cell periphery in resting endothelial cells to a tangled network of centrally located filaments in H2O2-treated endothelial cells. This change in actin organization is associated with a loss of the normal distribution pattern of surface protein expression. Specifically, beta 1 and beta 3 integrins partly escape from focal adhesion plaques and migrate to the lateral and apical surface of the cell; PECAM-1 redistributes from the lateral borders to the basal surface; and ICAM-1 and ICAM-2 spread from apical caps to the basal surface and to the dendrite-like processes. The likely consequence of endothelial retraction accompanied by abnormal membrane protein distribution is a loss of normal endothelial cell functions. These changes are best considered manifestations of H2O2-induced sublethal injury that may cause endothelial dysfunction.

Actins↗
PubMed1995

Cyclosporin A exacerbates mercuric chloride-induced vasculitis in the brown Norway rat.

BACKGROUND: Administration of mercuric chloride (HgCl2) to the Brown Norway (BN) rat induces a necrotizing leukocytoclastic vasculitis (most marked in the gut) and anti-myeloperoxidase (anti-MPO) antibodies. The development of autoimmunity in the BN rat is a T cell-dependent phenomenon, and there is evidence that the induction of autoantibodies and tissue injury is a Th2-driven process. Cyclosporin A (CyA) is an anti-T cell agent with a dose-dependent differential effect on Th cell subsets that can ameliorate or enhance autoimmune responses. In the BN it can suppress HgCl2-induced autoantibody production, but the effect on tissue injury has not been previously examined. EXPERIMENTAL DESIGN: We have studied the effect of CyA given "early" (Days 1-10, concurrently with the HgCl2) or "late" (Days 11-14) on tissue injury and autoantibody response. Serial blood samples were taken for anti-glomerular basement membrane, anti-MPO, and IgE antibody levels. Necropsies were performed on animals killed on Day 15. The presence and extent of vasculitis was scored macroscopically and histologically. Controls were incorporated to assess the effect of vehicle and of CyA alone. RESULTS: CyA given early delayed the rise in anti-MPO and anti-glomerular basement membrane levels and ameliorated tissue injury, whereas CyA given late, although suppressing the rise in anti-MPO and anti-glomerular basement membrane antibodies, caused a marked exacerbation of vasculitis. CONCLUSIONS: The effect of CyA depends on the timing of treatment with respect to HgCl2. Anti-MPO antibodies are not of primary importance in the pathogenesis of tissue injury. The late effect may be due to a direct toxic effect on the endothelium or to loss of a protective T cell subset. These observations have implications for the use of CyA in the treatment of systemic vasculitis in humans.

Animals↗
PubMed1995

Disparate localization of 55-kd and 75-kd tumor necrosis factor receptors in human endothelial cells.

We have used confocal immunofluorescence microscopy and immunogold electron microscopy to localize tumor necrosis factor (TNF) receptors in cultured human umbilical vein endothelial cells. The 75-kd receptor is largely expressed on the cell surface and undergoes endocytosis and transport to lycosomes through coated pits and coated vesicles. TNF may accelerate receptor clustering and internalization. The 55-kd receptor is expressed at much lower levels on the cell surface than the 75-kd receptor but is more abundant overall. It is predominantly localized to the Golgi apparatus and, to a lesser extent, cytoplasmic vacuoles. The cellular distribution of the 55-kd receptor is largely unaffected by TNF. These results have implications for TNF-mediated endothelial cell activation and for interactions between 75- and 55-kd TNF receptors.

Antibodies, Monoclonal↗
PubMed1994

Does truly 'idiopathic' crescentic glomerulonephritis exist?

Crescentic glomerulonephritis is usually classified into antiglomerular basement membrane (GBM) disease, immune-complex disease, or pauci-immune crescentic nephritis. The last category includes patients with systemic vasculitis as well as 'idiopathic' isolated crescentic nephritis. The presence of anti-neutrophil cytoplasmic antibodies (ANCA) in many patients with apparently isolated crescentic nephritis suggests that this represents a renal-limited form of vasculitis, and that truly 'idiopathic' crescentic nephritis is a very rare entity. We reviewed all renal biopsies with extracapillary proliferation seen at our centre since the availability of an ANCA assay (4-year period). There were 89 such biopsies of a total of 1240, of which 82 had sufficient details for further analysis. Of these, 10 had anti-GBM disease, 35 had epithelial proliferation associated with a variety of other diseases, and 36 had ANCA-associated disease. Nine of this last group had no extrarenal features and would previously have been classified as 'idiopathic' crescentic glomerulonephritis. The single remaining patient had an inactive glomerulonephritis with a scarred crescent; the predominant lesion was an interstitial nephritis. We therefore conclude that truly 'idiopathic' crescentic nephritis is very rare, if it exists at all. The ability to provide a practically complete classification of crescentic nephritis has important prognostic and therapeutic consequences.

Adolescent↗
PubMed1994

Endothelial cell activation in patients with systemic vasculitis.

Vascular endothelial cells respond in vitro to a number of stimuli, and in particular to cytokines, by undergoing functional and morphological alterations which endow them with the capacity to promote inflammatory reactions. We studied this process of endothelial cell activation in 20 skin biopsies from 18 patients with systemic vasculitis. At sites of cutaneous inflammation, blood vessels were lined with swollen endothelial cells which expressed increased levels of intercellular adhesion molecule-1 (ICAM-1) and vascular cell adhesion molecule-1 (VCAM-1), and were associated with a mononuclear cell inflammatory infiltrate. Neutrophil infiltration was only found in the presence of endothelial leucocyte adhesion molecule-1 (ELAM-1), which was expressed in 15/20 biopsies. ELAM-1 and VCAM-1 were associated with the presence of inflammatory cytokines which induce expression of these molecules in cultured endothelial cells. Endothelial activation in vivo appears to parallel that observed in vitro, and is likely to be important in determining the nature of an inflammatory response.

Adolescent↗
PubMed1994

Effects of decomplementation with cobra venom factor on experimental vasculitis.

Mercuric chloride (HgCl2) induces autoimmunity in susceptible rat strains, with hyper-IgE, appearance of a number of autoantibodies, and widespread tissue injury, including necrotizing vasculitis in the gut. In the early phase of tissue injury there is granulocyte infiltration; later there is immunoglobulin deposition along basement membranes in vessels. We have analysed the role of complement in this model using cobra venom factor (CVF), which causes decomplementation lasting around 5 days. The characteristic time course when HgCl2 is given over 10 days is that tissue injury and autoantibody levels reach a peak at around day 15 (start of HgCl2 = day 0). We therefore gave CVF either early (day 0), intermediate (day 5) or late (day 10); a fourth group (controls) received HgCl2 but no CVF. At each time point, CVF caused complete decomplementation which lasted for at least 5 days. Serum IgE and autoantibody levels were similar in all four experimental groups. Tissue injury in the 'early' CVF group and in the 'late' CVF group was not significantly different from controls, but in the intermediate group tissue injury was significantly more severe than in controls. These data indicate that the complement system does not play a major role in the induction of autoantibodies by HgCl2, nor in the effector phase of tissue injury. We speculate that the exacerbation of tissue injury by CVF in the group given this agent at an intermediate stage of the model is explained by the presence of products of C3 activation which have proinflammatory effects during the phase of active granulocyte-mediated tissue injury.

Animals↗
PubMed1994

Use of methyl prednisolone and antioxidants in mercuric chloride-induced experimental vasculitis.

The systemic vasculitides are characterized by necrotizing inflammation of blood vessels. Neutrophils are implicated in tissue damage by their presence at the site of injury. They can mediate injury by release of cellular contents including proteinases, cytokines and reactive oxygen species. Antioxidants such as vitamin E and N-acetyl cysteine (NAC) may therefore be predicted to ameliorate oxidative damage in vivo and could be a cheap and non-toxic form of therapy. We examined this hypothesis in an experimental model of vasculitis which has some similarities to human disease, and in which depletion of neutrophils ameliorates tissue injury. Mercuric chloride (HgCl2) treatment induces an autoimmune syndrome and necrotizing leucocytoclastic vasculitis in the Brown Norway (BN) rat; anti-myeloperoxidase (MPO) and anti-glomerular basement (GBM) antibodies are present, and vasculitis is reduced by antimicrobials. Methyl prednisolone given intravenously was effective in reducing tissue injury, demonstrating that the model was responsive to a treatment used in man. Vitamin E and NAC were given as daily injections intraperitoneally to BN rats either before, during or after HgCl2 administration. Serial blood samples were taken for anti-MPO and IgE antibodies, which were assayed by ELISA. Necropsies were performed on animals killed at peak disease. At doses of 50-200 mg/kg per day vitamin E had no beneficial effect on tissue injury, regardless of timing of treatment. NAC at 100 or 200 mg/kg also had no significant protective effect on vasculitis. Autoantibody and IgE levels were not affected by either methyl prednisolone or the antioxidants. The lack of benefit of vitamin E and NAC suggests that oxidative damage, whether generated by neutrophils or other cells, does not play a major role in the pathogenesis of vasculitis, and that antioxidant therapy is unlikely to be of benefit in systemic vasculitis in man.

Acetylcysteine↗
PubMed1994

Immunosuppression of canine renal allograft recipients by CD4 and CD8 monoclonal antibodies.

A state of tolerance to MHC mismatched allografts can be generated in rodents by treatment with CD4 and CD8 monoclonal antibodies (mAb). In order to transpose this type of therapy to large animals and ultimately to the clinic, a suitable model is required. To this end we have generated a series of mAb to the canine CD4, CD8, and Thy-1 antigens and have tested their ability to prevent rejection of renal allografts. Donor-recipient pairs were selected from a colony of mongrel dogs in which untreated rejection of two haplotype-mismatched kidneys occurred by day 7 (defined as a serum creatinine > 300 mumol/l). Therapy with either the CD4 or the CD8 mAb, using no other immunosuppression, did not prolong graft survival. Depletion of T cells by a Thy-1 mAb prior to surgery only extended graft survival to day 9. However, treating with combinations of mAb up to day 10 (CD4 plus Thy-1; CD4 plus CD8; or CD4 plus CD8 plus Thy-1) prolonged renal allograft function up to 25 days. Combination of the triple mAb therapy with a sub-therapeutic immunosuppressive drug regimen (cyclosporin A plus azathioprine that alone gave a median survival of 15 days) favored survival to a median of 38 days. This protocol also inhibited the antiglobulin response that had curtailed the effects of mAb treatment, opening the way to more extended, and potentially tolerizing, mAb plus drug regimens.

Animals↗
PubMed1993

Long-term remission of intractable systemic vasculitis with monoclonal antibody therapy.

Monoclonal antibodies that target T cells offer an alternative to conventional immunosuppressive drugs in the management of autoimmune disease. "Humanisation" of such monoclonal antibodies makes their clinical use less likely to be prone to the risk of cross-species sensitisation than treatment with rodent antibodies. We describe humanised monoclonal antibody therapy in four patients with severe systemic vasculitis unresponsive to immunosuppressive drugs. Substantial and sustained benefit was seen in three of the four patients, although one of these three patients developed anti-idiotypic antibodies that had to be removed by plasma exchange.

Antibodies, Anti-Idiotypic↗
PubMed1993

Regulatory role of OX22high T cells in mercury-induced autoimmunity in the brown Norway rat.

The monoclonal antibody OX22 defines a functional split within CD4+ T cells in the rat, with OX22high cells mainly producing interleukin 2 (IL-2) and interferon gamma and responsible for delayed-type hypersensitivity responses, and OX22low cells mainly producing IL-4 and -5 and responsible for providing B cell help. There are reciprocal interactions between OX22high and OX22low cells, and it has been suggested that the OX22low subset has a role in the prevention of autoimmunity. We have used OX22 in vivo to define the role of these subsets in mercuric chloride-induced autoimmunity in the Brown Norway rat. In this model, there is polyclonal B cell activation and animals develop widespread tissue injury. Treatment of thymectomized animals with OX22 led to a profound reduction in the number of OX22high T cells in the peripheral blood. OX22-treated animals consistently developed more severe tissue injury than controls given an irrelevant antibody of the same isotype. Control animals pretreated with broad spectrum antimicrobial drugs showed milder tissue injury, but this protective effect of antimicrobials was lost in OX22-treated animals. Transfer of naive T cells to OX22-treated animals provided protection, but if T cells were depleted in vitro of OX22high cells before transfer, this effect was lost. These data provide evidence for a protective immunoregulatory role for OX22high T cells in mercuric chloride-induced autoimmunity.

Animals↗
PubMed1993

Further characterization of an animal model of systemic vasculitis.

The demonstration of vasculitis and anti-myeloperoxidase antibodies in the mercuric chloride treated Brown Norway rat provides a useful, though limited, animal model of systemic vasculitis. We describe some preliminary experiments on the effect of transfer of serum from mercuric chloride treated rats and of two forms of immunotherapy: intravenous immunoglobulin and an anti-CD4 antibody. Transfer of serum did not lead to tissue injury and neither of the two forms of therapy proved beneficial in this model.

Animals↗
PubMed1992

Glomerulonephritis with end-stage liver disease in childhood.

Renal biopsies were done perioperatively in 18 children receiving liver grafts. All specimens showed glomerulonephritis, which was mesangial-proliferative in 15 and mesangio-capillary in 3. Of the 16 children who were alive four or more months after transplantation, only 1 showed progressive deterioration of renal function; 1 other had a subnormal but static glomerular filtration rate. In all 6 children who had proteinuria before operation, the urine became normal.

Adolescent↗