摘要:

The nonobese diabetic (NOD) mouse is a model for human Type 1 diabetes mellitus. Pancreaticβ-cell destruction in NOD mice is mediated by an autoimmune process which can be accelerated by cyclophosphamide (CP). We studied the phenotype of lymphocytes from central, peripheral and regional lymphoid tissues in prediabetic NOD and C3H mice before and after a single large dose of CP. All lymphoid organs showed a greatly diminished cell number and most alterations appeared early after CP and were transient, but an aggressive insulitis was not seen in NOD mice until 14 d after injection. The pancreatic islets in C3H mice remained intact and were not infiltrated. NOD female mice, which are most prone to spontaneous and CP-induced diabetes, exhibited the most unusual lymphoid kinetics after treatment with CP. Their thymus and spleen showed the least relative drop in total cell number and the most rapid rate of recovery. The thymus of these mice was also found to have an increased proportion of CD3+thymocytes while CD4/CD8 double positive thymocytes decreased 7 d after CP. At 14 d after CP the number of IL-2R+thymocytes had surpassed that of normal levels. The most dramatic observation was the rapid recovery and overshoot in the number of pancreatic lymph node cells of female NOD mice which coincided with aggressive insulitis.

ISSN:0891-6934    

DOI:10.3109/08916939309004833

出版商:Taylor&Francis    

年代:1993

数据来源: Taylor

摘要:

The immunoglobulin (Ig) heavy chain variable (VH) gene complexity and the VHgene utilisation pattern of the non-obese diabetic (NOD) mouse were investigated. We found that the NOD mouse displays a VHgene complexity which appears to be identical to that of the C57BL/6 mouse. Thus, Southern hybridisation using probes specific for 9 of the murine VHgene families revealed identical restriction fragment length polymorphism (RFLP) patterns in both mouse strains. As indicated by immunofluorescence analysis using allotype specific monoclonal antibodies the NOD mice were also found to carry the IgCH-1ballele. Collectively, these data suggest that the NOD mice carry an IgVHlocus identical to that carried by C57BL/6. In contrast to the apparent identity at the level of germline VHgene repertoires, the pattern of VHgene utilisation differed considerably between these two mouse strains. Thus, in NOD mice the neonatal preference of D-proximal VHgenes was found to be more pronounced than in C57BL/6 mice. Moreover, in contrast to adult C57BL/6 mice a D-proximal bias was evident also in adult NOD mice. On the basis of these findings we discuss the possibility that the distorted development of B cell repertoires in the NOD mouse could be directly or indirectly related to the T cell mediated, autoimmune process in the NOD mouse.

ISSN:0891-6934    

DOI:10.3109/08916939309004834

出版商:Taylor&Francis    

年代:1993

数据来源: Taylor

摘要:

Splenic T-cells from lupus strain (NZB/W F1, Mrl/lpr) mice lack the ability to respond to concanavalin A (Con A) by secretion of IL-2 and hence expression of IL-2 receptor and proliferation. These defects were found not only in an aged group (>5 months) of mice in which obvious clinical‘SLE like’symptoms and elevated levels of serum autoantibodies were observed, but also in mice as young as 4-wk. We demonstrate here that the defective mitogenic activation of T-cells from lupus mice is due to the inability of T-helper cells to produce IL-2 and this defect can be restored by exogenous IL-2in vitro.Con A-induced cell proliferation and IL-2 receptor expression on CD3+cells from lupus mice occur only in the presence of exogenous IL-2, whereas normal T-cells from BALB/c and CBA control mice are activated by the mitogen and undergo complete cell cycling in the absence of exogenous IL-2, as they are able to secrete sufficient endogenous IL-2. The detection of impaired T-helper function in young lupus mice, before development of overt disease, and the reversible nature of the defect indicate that defective IL-2 activity may be fundamental to the mechanism of development of pathology in SLE.

ISSN:0891-6934    

DOI:10.3109/08916939309004835

出版商:Taylor&Francis    

年代:1993

数据来源: Taylor

摘要:

Lymphoid cell infiltrates were analyzed using immunohistochemical techniques on 5 normal fetal and 6 normal neonatal pancreases. Data were compared to data obtained analyzing the lymphoid cell infiltrates in the pancreas of an 8 months old diabetic infant.In the normal fetal and neonatal pancreases islets were intact and not infiltrated. In the diabetic infantβ-cells had vanished in almost all islets, the remaining islets showed a minor infiltration with primarily T-cells, a few B-cells, and some classical marcrophages.It appeared that a widespread infiltration of the exocrine pancreas with single dendritic-like cells, andβ-cells, and little clusters of these cells were normal features of fetal and neonatal pancreases. In the diabetic case these infiltrative patterns were more pronounced.Larger accumulations of such lymphoid cells could also be detected in the normal fetal and neonatal pancreases and these consisted mainly of T-cell zones, sometimes containing HEV's, with intermingled interdigi-tating dendritic cells and a few macrophages. This architecture is reminiscent of peripheral lymphoid tissue, such as bronchus-or gut-associaled lymphoid tissue. The function of this fetal/neonatal intrapancreatic lymphoid tissue (which disappears in later life) is unknown. Various possibilities are suggested such as a yet unknown ubiquitous fetal/neonatal microbial infection, tolerance induction towards islet cell antigens, an endocrine regulatory function of infiltrated lymphoid cells, and a normal ontogenetic process.

ISSN:0891-6934    

DOI:10.3109/08916939309004836

出版商:Taylor&Francis    

年代:1993

数据来源: Taylor

摘要:

We previously reported that rheumatoid factors (RFs) might bear the internal image of Feγ-binding proteins (FcBPs) of herpes family viruses, suggesting the possibility that some RFs may be produced as antiidiotypic antibodies to anti-viral FcBP antibodies. Since human cytomegalovirus (HCMV) has been implicated in the pathogenesis of RA, we made an attempt to detect antibodies to 65 KD major HCMV FcBP in sera and synovial fluid from patients with RA. Western blotting was performed using HCMV-infected MRC-5 cell lysate as the antigen. Eleven of 23 patients with RA possessed strong serum antibodies to HCMV-65 KD protein, whereas such antibodies were found in only 2 of 23 normal controls. In the synovial fluid, 10 of 19 RA patients showed anti-HCMV 65 KD reactivity. Pepsin-digested IgG retained anti-65 KD reactivity, indicating that false-positive reaction due to the presence of igG Fc portion and/or RF was unlikely. 65 KD protein was shown to be different from human heat shock proteins (h'sps) using monoclonal antibodies against human lisps. Patients' IgG F(ab'): also reacted with the 65 KD protein of purified HCMV virion itself. These results support the possibility that some RFs could be produced as antiidiotypic antibodies to anti-viral FcBP antibodies.

ISSN:0891-6934    

DOI:10.3109/08916939309004837

出版商:Taylor&Francis    

年代:1993

数据来源: Taylor

摘要:

Evidence is growing that autoimmune reactivity results from a combination of endogenous (e.g. MHC type) and environmental factors. Our experimental study focuses on the induction of autoimmune reactivity by microbial factors. Splenic formalion and serum levels of antierythrocyte antibodies and circulating immune complexes were taken as parameters. It was found that experimental infection of mice withEscherichia caliandSalmonella typhimuriumwas accompanied by clear signs of autoimmune reactivity, smooth bacteria being almost ten times as potent as rough mutant strains. An attempt was made to correlate the data obtained with live bacteria to their corresponding endotoxins. It was concluded that the induction of more prominent autoimmune reactivity by smooth bacteria must be ascribed to a longer survival timein vivo.Our data support the view that bacterium-derived factors are involved in the etiology (and possibly also the course) of autoimmune diseases.

ISSN:0891-6934    

DOI:10.3109/08916939309004838

出版商:Taylor&Francis    

年代:1993

数据来源: Taylor

摘要:

It has previously been shown that the administration of cyclosporine A to newborn mice results in the development of autoimmunity later in life. It has been proposed that the neonatal administration of cyclosporine A results in altered thymic selection or inhibition of the development of suppressor cells. In the present study, treatment of day 3 thymectomized C3H/HeN mice with cyclosporine A (20 mg/kg/day) for 9 d post surgery increased the prevalence of antigastric autoantibodies. In contrast, the administration of IL-2 (300–600 Units/g/day) for 7 days after thymectomy inhibited the development of antigastric antibodies. We hypothesize that CsA may act by causing transient lymphokine abnormalities in the extrathymic environment during the first few weeks of life which lead to the development of antigastric antibodies. In contrast to the inhibition of development of antigastric anlibodies, the administration of a similar course of IL-2 produced only a transient suppression of diabetes in NOD mice. These results and other data suggest that diabetes in NOD mice is probably due to a different immunologic defect.

ISSN:0891-6934    

DOI:10.3109/08916939309004839

出版商:Taylor&Francis    

年代:1993

数据来源: Taylor

摘要:

The mechanism ofβ-cell destruction leading to insulin dependent diabetes is probably a cell mediated autoimmune process occurring in genetically susceptible individuals. Since 50–70% of monozygotic twins will not get the disease non-genetic risk factors must play an important role in the etiology of the disease. During the past decade population based epidemiological studies have identified several risk determinants for insulin dependent diabetes. Based on these studies a multifactorial hypothesis of causation is proposed. Some risk determinants (maternal child blood group incompatibility, fetal viral infections, early exposure to cow's milk proteins, a high exposure level of nitrosamines) may independently initiate the autoimmune process by causing the initial damage of theβ-cell, leading to antigen release. Other risk determinants may promote an already ongoing autoimmune destructive process through induction of lymphokine release or by causing an increased work load on theβ-cell. Risk factors that may increase the peripheral need for insulin (infectious diseases, cold environment, a high growth rate and stressful life events) may act as promoters of theβ-cell destruction but also disclose theβ-cell impairment and make the disease clinically overt. Possibilities of different risk profiles in different age groups and of synergism between different risk factors are also discussed.

ISSN:0891-6934    

DOI:10.3109/08916939309004840

出版商:Taylor&Francis    

年代:1993

数据来源: Taylor

摘要:

Multiple sclerosis (MS) is a demyelinating auto-immune disease of the central nervous system with a suspected genetic component.Previous publications have demonstrated that MS susceptibility is influenced by Major Histocompatibility Complex (MHC) genes and recent studies have focused on additional susceptibility genes. The accumulation of activated T-cells in demyelinating MS lesions, the possible auto-immune mechanism of this disease and the functional relationship between MHC and T cell receptor (TCR) molecules support the hypothesis that TCR genes are good candidates to influence MS development. Published results in this domain are conflicting and still a matter of controversy.In the present study we analysed the influence of Vβ, Cβ, PλG3 and Vγgene polymorphisms defined by Restriction Fragments Length Polymorphism (RFLP) on 48 pairs of monozygotic and dizygotic twins with at least one of each pair affected, and also in 63 unrelated MS patients for Vγgene polymorphism. These results have been compared with those in the non affected twins and with data from a control group (Beall et al., 1989) regarding Cβand Vβpolymorphisms and with a local control population for Vγ. No significant correlation between Cβ, Vy or PλG3 polymorphisms and MS was found, only a non significant tendency to reduced PAG3 allele sharing among dizygotic non concordant twin pairs was observed. However one Vβ11, 25 kb allele and a haplotype defined by Vβ11 and Cβalleles showed a correlation with MS susceptibility of borderline significance.These observations are in favor of a slight effect of a genetic factor in the TCRβgene region in MS genetic susceptibility whereas this is not the case for Vγgenes.

ISSN:0891-6934    

DOI:10.3109/08916939309004841

出版商:Taylor&Francis    

年代:1993

数据来源: Taylor

摘要:

Double negative (DN) T cells expanding in peripheral lymphoid tissues in mice bearing lymphoproliferation (Ipr) gene are generally unresponsive to mitogens, antigens, and anti-T cell receptor (TCR) or anti-CD3 monoclonal antibodies (mAb). In response to the stimulation with 0.125–5.0μM ionomycin, control T cells sustained an increase in intracellular free calcium ([Ca2+]i), while DN Ipr T cells showed a gradual fall following initial rapid increase in [Ca2+]i. Such gradual fall in [Ca2+]i was overcome by the addition of endoplasmic and sarcoplasmic reticulum Ca2+-ATPase inhibitor or high dose (10μM) of ionomycin. The requirement of high concentration of calcium ionophore for the sustained increase of [Ca2+]i in Ipr DN T cells is due to the dysfunction of Ca2+-ATPase pump.

ISSN:0891-6934    

DOI:10.3109/08916939309004842

出版商:Taylor&Francis    

年代:1993

数据来源: Taylor