摘要:

Macrophages (MØ) from prediseased autoimmune-prone MRL/ + and MRL/lpr mice produce markedly decreased levels of IL-1in vitroin response to LPS. In contrast, tissues from diseased MRL/lpr mice overexpress IL-1in vivo.To determine whether IL-1 underproduction in the MRL strains is solely anin vitrophenomenon, we comparedin vivocytokine mRNA expression from prediseased age-matched MRL/ + and MRL/lpr mice to that from normal BALB/c and C3HeB/FeJ mice. Like mØin vitro, whole organ RNA from the spleen, liver, and kidney of MRL/ + and MRL/lpr mice showed down-regulation of IL-1 RNA following intraperitoneal injection of LPS. This abnormality in inducible IL-1 expression was present in all MRL mice, irrespective of disease stage or the presence of theIprgene. On the other hand, only diseased MRL/lpr mice displayed elevated and constitutive expression of IL-1 in their livers and kidneys. We suggest that inducible expression is most indicative of the intrinsic, or genetic, capacity of cells to produce cytokine, whereas constitutive expression reflects extracellular disease-related inflammatory stimuli present only in the diseased MRL/lpr strains. By restricting our studies to prediseased MRL mice, we have tried to eliminate the effects of disease and to focus on the predisposing genetic background. The existence bothin vitroandin vivoof a defect in inducible IL-1 expression by prediseased MRL mice suggests that the molecular abnormality underlying this defect may be a part of this predisposing background to autoimmunity.

ISSN:0891-6934    

DOI:10.3109/08916939608995345

出版商:Taylor&Francis    

年代:1996

数据来源: Taylor

摘要:

CD4 + T cells play a crucial role in the development of lupus in MRL-lpr/lprmice: incomplete deletion/silencing of self-reactive CD4 + T cells leads to T cell activation, which causes both polyclonal B cell activation and T cell infiltration of multiple organs. Furthermore, anti-CD4 antibody therapy ameliorates disease and prolongs survival. Because CD4 is normally involved in both tolerance induction and T cell activation, we questioned whether signaling through CD4 was normal among T cells in this strain. For this purpose, signal transduction in CD4+ T cells derived from MRL-lpr/lprand normal mice were compared, using an autoreactive CD4+ T cell clone and freshly isolated CD4 + T cells derived from mice of varying ages.Tyrosine phosphorylation was similar among MRL and normal CD4+ T cells after cross-linking with either anti-TCR antibody or ant-LCD3 antibody, and following co-culture with Con A. In constrast, cross-linking of surface CD4 resulted in deficient tyrosine phosphorylation of cellular proteins in MRL T cells. By comparison,lckprotein expression in MRL CD4 + T cells was found to be lower than normal. However, following stimulation with Con A,lckenzyme activity, as detected by autophosphorylation oflck, was comparable in MRL and normal T cells. The observed differences were present in the autoreactive T cell clone as well as in T cells isolated from both pre-diseased and diseased mice, and they could not be explained by variation in surface density of CD4. These results raise the possibility that abnormal signaling through CD4 may contribute to impaired tolerance and expansion of autoreactive T cells exhibited in MRL-lpr/lprmice.

ISSN:0891-6934    

DOI:10.3109/08916939608995346

出版商:Taylor&Francis    

年代:1996

数据来源: Taylor

摘要:

A quantitative and sensitive cellular enzyme-linked immunosorbent assay was developed for determining the number of molecules of IgG of each subclass bound to the surface of murine red blood cells (RBC). To develop standard titration curves, RBC from normal mice were treated with tannic acid and coated with a known concentration of purified myeloma of each IgG subclass. The quantity of each subclass bound to the surface of erythrocytes was determined by calculating the protein concentration of the bound IgG, which was then converted into number of molecules of IgG/RBC. The assay was used to quantify the number of autoantibodies of all four IgG subclass bound to the erythrocytes of mice injected with rat RBC. Twenty one days after the first immunisation, a mean number of 84,000 molecules of IgGI/RBC were detected, which increased to 114,500 molecules/RBC on day 28. On days 56 and 96 the mean concentration of IgG1 remained high, however by day 110 the mean level of IgG1 had decreased sligihtiy to 69,500 molecules/RBC. By contrast, the mean concentration of IgG2a autoantibodies was considerably lower throughout the experiment, starting at 40,200 molecules/RBC on day 21 and dropping to 2,500 molecules/RBC by day 110. The mean quantities of IgG2b and IgG3 autoantibodies were similar to each other, and intermediate between the levels of IgG1 and IgG2a autoantibodies.

ISSN:0891-6934    

DOI:10.3109/08916939608995347

出版商:Taylor&Francis    

年代:1996

数据来源: Taylor

摘要:

Recently, the synthetic immunomodulator Linomide (quinoline-3-carboxamide, LS 2616) was reported to prevent IDDM and insulitis in NOD mice. The mechanism for this protective effect is not known. The cytokine interleukin 1 (IL-1) may be a pathogenetic factor in the initial destruction of theβ-cells leading to IDDM. This study was undertaken to investigate the influence of Linomide on IL-1βinduced diabetogenic and hormonal changes in the ratin vivo, and on IL-1βmediated synthesis of NO and inhibition of insulin secretion in isolated islets of Langerhansex vivo.Normal male Wistar Kyoto rats received 4.0μg/kg of recombinant human IL-1β(rhIL-1β) i.p. daily for 5 days with or without Linomide (8-9 mg/kg/day) in the drinking water. Litters of neonatal Wistar rats were pretreated for 3 days with injections of 10 mg/kg of Linomide i.p., and pancreatic islets of Langerhans were isolated forex vivostudies. Linomide alone caused significant hypercorticosteronemia, hypoglucagonemia, lymphopenia and neutrophilia. Linomide had no effect on IL-1βinduced hyperglycemia, hyperglucagonemia, lymphopenia, neutrocytosis, or hypercorticosteronemia on day three and hypocorticosteronemia on day five. Further, Linomide did not prevent rhIL-1βmediated reduction in insulin secretion or increase in NO synthesisex vivo.In conclusion, Linomide does not seem to exert its protective effect on IDDM development via inhibition of interleukin 1 action on islet insulin release or NO production, but the increase in plasma corticosterone may contribute to the understanding of the immunomodulatory effects of Linomide.

ISSN:0891-6934    

DOI:10.3109/08916939608995348

出版商:Taylor&Francis    

年代:1996

数据来源: Taylor

摘要:

In an attempt to elucidate the mechanism of development of organ-specific autoimmune lesions resembling human Sjogren's syndrome of MRL/lpr mice, we have analyzed local cytokine gene expressions and organ-specific autoantibody productionin vivo.We have demonstrated that a major proportion of T cells bearing CD4 and Vp8 molecules are essentially responsible for triggering the autoimmunity in the salivary glands of MRL/lpr mice. The local cytokine gene expressions including interferon(1FN)-γ, IL-12(p40) mRNAs were observed during the course of murine Sjogren's syndrome in MRLApr autoimmune strain. In particular, a high level of local expressions of IL-12 mRNA was detected earlier in the proinflammatory stage of autoimmune lesions. A significant level of local expression of MHC class-II(I-Ak) mRNA was detected before the onset of inflammatory lesions in the salivary glands, and I-Ak-positive epithelial duct cells were frequently observed in the salivary glands of MRL/lpr mice. In addition, we found the salivary gland-specific autoantibody in sera from MRL/lpr mice with early phase of autoimmune lesions by immunoblot analysis. These results suggest that cytokine gene stimulation and autoantibody production are essentially involved in the development of organ-specific autoimmune lesions in Sjogren's syndrome of MRL/lpr mice.

ISSN:0891-6934    

DOI:10.3109/08916939608995349

出版商:Taylor&Francis    

年代:1996

数据来源: Taylor

摘要:

The role of stress proteins in the pathology of autoimmune thyroid disease (AITD) has aroused considerable controversy in recent years1. Thyroid cells in tissue culture are known to synthesise a range of stress proteins (hsp) in response to elevated temperatures or toxic chemicals2. Hsp70 over expression has been demonstrated in thyroid tissue from patients with Graves' disease3and intra-thyroidal T-cells from these patients can also be induced to expand in response to hsp70 from a variety of sources4. Unpublished data from our own laboratory shows that the incorporation of [3H] thymidine into peripheral lymphocytes from patients with AITD is also enhanced when these cells are cultured in the presence of stressed thyroid cells. However, in the same experiments, lymphoproliferation was also enhanced by PPD, a preparation rich in Mycobacterial hsp, which is a common immunogen in the population.

ISSN:0891-6934    

DOI:10.3109/08916939608995350

出版商:Taylor&Francis    

年代:1996

数据来源: Taylor

ISSN:0891-6934    

DOI:10.3109/08916939608995351

出版商:Taylor&Francis    

年代:1996

数据来源: Taylor