Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0024312 (lymphopenia)
 4,859 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

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 the beta-cells leading to IDDM. This study was undertaken to investigate the influence of Linomide on IL-1beta induced diabetogenic and hormonal changes in the rat in vivo, and on IL-1beta mediated synthesis of NO and inhibition of insulin secretion in isolated islets of Langerhans ex vivo. Normal male Wistar Kyoto rats received 4.0 microg/kg of recombinant human IL-1beta (rhIL-1beta) 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 for ex vivo studies. Linomide alone caused significant hypercorticosteronemia, hypoglucagonemia, lymphopenia and neutrophilia. Linomide had no effect on IL-1beta induced hyperglycemia, hyperglucagonemia, lymphopenia, neutrocytosis, or hypercorticosteronemia on day three and hypocorticosteronemia on day five. Further, Linomide did not prevent rhIL-1beta mediated reduction in insulin secretion or increase in NO synthesis ex 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.
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PMID:Linomide increases plasma corticosterone in normal rats, but does not prevent the inhibitory action of IL-1 on beta-cells in vivo or ex vivo. 891 32

Much of our present knowledge concerning the etiopathogenesis, treatment and prevention of human diabetes would never have been acquired without the study of animal models of diabetes. The main models of IDDM may be divided into two groups: induced (through pancreatectomy, chemicals such as alloxan and streptozotocin, viruses and others) and spontaneous (mainly using BB rats and NOD mice). The latter, at different ages, develop a diabetic syndrome, with clinical characteristics, genetics and immunology that are very similar to the human disease. Among the more significant differences are lymphopenia (in BB rats) and the predominance of diabetes in females (in NOD mice). Studies aimed at preventing IDDM have advanced by leaps and bounds by using the two spontaneous models. These include various methods such as genomic modification, an influence over some environmental agents, immunosuppression, immunotherapy, immunomodulation and tolerance induction as well as protection of the beta-cell from autoimmune attack. The conclusions drawn from animal experiments have allowed some human trials to be carried out with encouraging results.
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PMID:Animal models of type I (insulin-dependent) diabetes mellitus. 964 24

Cyclophosphamide (CY), an alkylating cytostatic drug, is known for its ability to accelerate a number of experimental autoimmune diseases including spontaneous diabetes in NOD mice. The mechanism(s) by which CY renders autoreactive lymphocytes more pathogenic is largely unknown, but it has been postulated that the drug preferentially depletes regulatory (suppressor) T cells. It has been suggested that in cell-mediated autoimmune diseases, Th2-like lymphocytes secreting IL-4 and/or IL-10 provide protection, while Th1-like cells secreting IFN-gamma are pathogenic. In this study, we analysed the effects of CY on autoimmune diabetes and cytokines in two mouse models: the spontaneous diabetes of NOD mice and the diabetes induced in C57BL/KsJ mice by multiple injections of low dose streptozotocin (LD-STZ). In both models, CY induced severe lymphopenia and accelerated the progression to hyperglycemia. This was associated with changes in splenic cytokine patterns indicating a shift towards the IFN-gamma-secreting phenotype. We provide here evidence that IFN-gamma producers are relatively resistant to depletion by CY and that Th0 clones can be shifted towards Th1. However, direct exposure of T lymphocytes to CY may not be a necessary condition for exacerbation of diabetes; NOD.scid mice treated with CY before adoptive transfer of NOD splenocytes developed diabetes at a higher rate than did controls. Thus, the acceleration of diabetes by CY seems to be a complex event, which includes the relatively high resistance of IFN-gamma producers to the drug, their rapid reconstitution, and a Th1 shift of surviving T cell clones.
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PMID:Acceleration of autoimmune diabetes by cyclophosphamide is associated with an enhanced IFN-gamma secretion pathway. 1058 54

Apoptosis is essential for the development, function and homeostasis of the immune system. Experiments with transgenic and gene knock-out mice have shown that defects in the control of apoptosis in the hematopoietic system can promote the development of autoimmunity or hematological malignancy. In contrast, excessive apoptosis of normally long-lived hemopoietic cells can lead to lymphopenia and immunodeficiency. In mammals, cell death in response to developmental cues and many cell stress signals is regulated by the opposing factions of the Bcl-2 family of proteins. In particular, the pro-apoptotic subgroup called BH3-only proteins, which includes Bim, is critical in the initiation of apoptosis in response to many death stimuli. Bim has been found to be an important regulator of the negative selection of B lymphocytes in the bone marrow and of T lymphocytes both in the thymus and the periphery. Mice lacking Bim accumulate self-reactive lymphocytes, develop autoantibodies and on certain genetic backgrounds succumb to SLE-like autoimmune disease. Abnormalities in Bim expression and the thymic deletion of auto-reactive lymphocytes have also been implicated as a component of the complex, polygenic predisposition to autoimmune diabetes seen in NOD mice. Bim is also an essential regulator of T lymphocyte apoptosis during the termination of an immune response. This chapter focuses on the role of Bim in the development and function of the immune system and its potential role in autoimmunity. Degenerative disorders due to increased apoptosis mediated by Bim are also discussed.
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PMID:Role of Bim and other Bcl-2 family members in autoimmune and degenerative diseases. 1639 56

The immune system has evolved elaborate mechanisms to respond to diverse antigens while minimizing the risk for autoimmune reactivity. During lymphopenia, however, some mechanisms that normally serve to maintain host tolerance are temporarily suspended. Peripheral T cells proliferate in response to self-antigens in lymphopenic hosts, but proliferation toward these same antigens is prevented when T cell numbers are normal. This process, termed homeostatic peripheral expansion, augments peripheral T cell number and limits repertoire skewing during recovery from lymphopenia and also predisposes lymphopenic hosts to autoimmune disease. This paper reviews murine and human settings in which autoimmunity occurs in the context of lymphopenia. We propose a two-hit model, in which lymphopenia plus another insult is sufficient to induce autoimmune disease. Among the secondary insults that appear sufficient to induce autoimmunity during lymphopenia are overproduction of IL-21 as occurs in the NOD.SCID mouse, depletion of Tregs as demonstrated in murine colitis and gastritis models, and tissue inflammation as seen in HIV infected patients who develop immune reconstitution inflammatory syndrome (IRIS). Delineating critical cofactors which result in autoimmune disease during lymphopenia can provide insight into the pathophysiology of naturally occurring autoimmune diseases as well as generating testable hypothesis for inducing tumor-specific autoimmunity in lymphopenic hosts with cancer.
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PMID:Autoimmunity during lymphopenia: a two-hit model. 1676 27

A series of recent studies in humans and the NOD mouse model have highlighted the central role that autoimmunity directed against insulin, in particular the insulin B chain 9-23 peptide, may play in the pathogenesis of type 1 diabetes. Both pathogenic and protective T-cell clones recognizing the B:9-23 peptide have been produced. This report describes the successful creation of BDC12-4.1 T-cell receptor (TCR) transgenic mice with spontaneous insulitis in F1 mice (FVB x NOD) and spontaneous diabetes in NOD.RAG(-/-) (backcross 1 generation). Disease progression is heterogeneous and is modified by a series of genetic factors including heterozygosity (H-2(g7)/H-2(q)) versus homozygosity for H-2(g7), the presence of additional T-/B-cell receptor-rearranged genes (RAG(+) versus RAG(-/-)), and the insulin 2 gene knockout (the insulin gene expressed in the NOD thymus). Despite lymphopenia, 40% of H-2(g7/g7) BDC12-4.1 TCR(+) RAG(-/-) Ins2(-/-) mice are diabetic by 10 weeks of age. As few as 13,500 transgenic T-cells from a diabetic TCR(+) RAG(-/-) mouse can transfer diabetes to an NOD.scid mouse. The current study demonstrates that the BDC12-4.1 TCR is sufficient to cause diabetes at NOD backcross 1, bypassing polygenic inhibition of insulitis and diabetogenesis.
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PMID:Transgenic insulin (B:9-23) T-cell receptor mice develop autoimmune diabetes dependent upon RAG genotype, H-2g7 homozygosity, and insulin 2 gene knockout. 1680 66

T cells undergoing lymphopenia-driven proliferation acquire effector and memory properties that can be pathogenic. Indeed, generalized lymphopenia is associated with a variety of autoimmune diseases such as type 1 diabetes. The current study was carried out to determine how CD8(+) T cells undergoing acute lymphopenic expansion respond to antigen under tolerizing conditions in vivo. Adoptive transfer of diabetes by TCR-transgenic CD8(+) T cells was enhanced following treatment of NOD. scid recipients with a high dose of soluble peptide. Furthermore, whereas TCR-transgenic CD8(+) T cells underwent clonal deletion and failed to differentiate into CTL in peptide-treated lymphoreplete recipient mice, TCR-transgenic CD8(+) T cells in a lymphopenic environment were resistant to clonal deletion, and CTL differentiation was enhanced by a high dose of soluble peptide. Moreover, peptide treatment had distinct effects on expression of the anti-apoptotic protein Bcl-X(L) in TCR-transgenic CD8(+) T cells under lymphopenic versus lymphoreplete conditions. These results demonstrate that CD8(+) T cells undergoing lymphopenia-driven expansion in NOD. scid recipients are resistant to antigen-induced tolerance, and readily differentiate into CTL upon stimulation with a high dose of soluble peptide.
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PMID:Lymphopenia-driven CD8(+) T cells are resistant to antigen-induced tolerance in NOD.scid mice. 1682 Dec 36

IL-4 is protective against Type 1 diabetes in the NOD mouse. IL-4 promotes T cell survival in vitro, but little is known about the effect of IL-4 on clonal expansion in vivo. Here, we show that IL-4 only enhances the expansion of autoreactive CD4 T cells during lymphopenia and that neither the presence of islet IL-4 nor IL-4 deficiency affects T cell expansion significantly under conditions of immunosufficiency. The accumulation of proliferating cells induced by IL-4 in a lymphopenic host is inhibited incrementally by increasing the number of bystander cells and is prevented by cell numbers well below that of unmanipulated NOD mice. The ability of IL-4 to promote autoreactive CD4 T cell expansion is therefore sensitive to the degree of host immunodeficiency. Paradoxically, IL-4 receptor-deficient, autoreactive CD4 T cells proliferate more extensively than wild-type T cells in immunodeficient hosts, suggesting that the growth-promoting effect of islet IL-4 acts indirectly. These results suggest that IL-4-mediated protection against autoimmunity and diabetes may be outweighed during immunodeficiency by a pathogenic, IL-4-induced expansion of autoreactive T cells.
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PMID:Distinct regulation of autoreactive CD4 T cell expansion by interleukin-4 under conditions of lymphopenia. 1716 29

The objective of the present study was to determine whether sleep deprivation (SD) would promote changes in lymphocyte numbers in a type 1 diabetes model (non-obese diabetic, NOD, mouse strain) and to determine whether SD would affect female and male NOD compared to Swiss mice. The number of lymphocytes in peripheral blood after 24 and 96 h of SD (by multiple platform method) or equivalent period of time in home-cage controls was examined prior to the onset of diabetes. SD for 96 h significantly reduced lymphocytes in male Swiss mice compared to control (8.6 +/- 2.1 vs 4.1 +/- 0.7 10(3)/microL; P < 0.02). In male NOD animals, 24- and 96-h SD caused a significant decrease of lymphocytes compared to control (4.4 +/- 0.3 vs 1.6 +/- 0.5; P < 0.001 and 4.4 +/- 0.3 vs 0.9 +/- 0.1 10(3)/microL; P < 0.00001, respectively). Both 24- and 96-h SD induced a reduction in the number of lymphocytes in female Swiss (7.5 +/- 0.5 vs 4.5 +/- 0.5, 4.4 +/- 0.6 10(3)/microL; P < 0.001, respectively) and NOD mice (4 +/- 0.6 vs 1.8 +/- 0.2, 1.2 +/- 0.4 10(3)/microL; P < 0.01, respectively) compared to the respective controls. Loss of sleep induced lymphopenia in peripheral blood in both genders and strains used. Since many cases of autoimmunity present reduced numbers of lymphocytes and, in this study, it was more evident in the NOD strain, our results suggest that SD should be considered a risk factor in the onset of autoimmune disorders.
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PMID:Sleep deprivation reduces the lymphocyte count in a non-obese mouse model of type 1 diabetes mellitus. 1746 24

NOD-H2(h4) mice, which express I-A(k) on the NOD background, spontaneously develop autoimmune thyroiditis, a model of Hashimoto thyroiditis in humans, by adding iodide in the drinking water. Parental NOD mice have previously been shown to have intrinsic numerical abnormalities in peripheral lymphocytes and lymphocyte subpopulations such as CD4(+)CD25(+) naturally occurring regulatory T cells (Treg). Therefore we first investigated whether the similar abnormalities exist in NOD-H2(h4) mice. We observed that, compared with other non-autoimmune disease prone BALB/c and C57BL/6 mice, NOD-H2(h4) mice have lower numbers of splenocytes, CD3(+)T, CD4(+)T and CD8(+)T cells but the ratios of Treg to CD4(+)T cells were comparable. Increasing the numbers of peripheral lymphocytes by Complete Freund's Adjuvant immunization or splenocyte transfer did not affect development of thyroiditis, indicating that lymphopenia does not play a critical role in the pathogenesis of thyroiditis. We next examined the significance of Treg by depleting this lymphocyte subset with anti-CD25 antibody. Treg depletion, performed 4days before the administration of NaI water for 8 weeks, significantly exacerbated thyroiditis (p<0.01). Anti-thyroglobulin antibody titers also increased by Treg depletion (p<0.01) without changing the IgG2b to IgG1 ratios. In addition, expression levels of mRNA for IFN-gamma and IL-4 were enhanced in parallel. However, T(4) levels were similar between antibody-treated and untreated groups. Additional anti-CD25 administration at 3 weekly intervals did not influence these results. These data, together with previous studies on other mouse models of inducible thyroiditis and Graves' disease, indicate the role played by Treg in keeping anti-thyroid autoimmune reaction in check in experimental autoimmune thyroid diseases.
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PMID:CD4+CD25+ naturally occurring regulatory T cells and not lymphopenia play a role in the pathogenesis of iodide-induced autoimmune thyroiditis in NOD-H2h4 mice. 1782 32


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