Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UMLS:C0004364 (autoimmune disease)
 24,845 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Chemokines are a family of low molecular mass proteins with chemotactic and cell activating activities. Reverse transcription-polymerase chain reaction and Northern hybridization were used to examine their expression during murine experimental allergic encephalomyelitis (EAE), an autoimmune disease used as a model of multiple sclerosis. The mRNAs encoding RANTES, MIP-1 alpha, MIP-1 beta, TCA3 (I-309), IP-10, JE (MCP-1), KC (MGSA/gro), and MARC (MCP-3) were induced in the spinal cord 1-2 days before clinical signs were apparent. SDF, a cDNA predicted to encode a chemokine-like product, was expressed in normal as well as diseased spinal cords. No expression of C10 or MIP-2 was detected. Activated encephalitogenic T cells expressed message for RANTES, MIP-1 alpha, MIP-1 beta, and TCA3. These results define a subset of chemokines that may play an important role in the inflammatory process during murine EAE.
 ...
PMID:Chemokine expression in murine experimental allergic encephalomyelitis. 753 12

Experimental autoimmune encephalomyelitis (EAE) is a CD4+ T cell-mediated, inflammatory demyelinating disease of the central nervous system (CNS) that serves as a model for the human demyelinating disease, multiple sclerosis. A critical event in the pathogenesis of EAE is the entry of both Ag-specific T lymphocytes and Ag-nonspecific mononuclear cells into the CNS. In the present report we investigated the role of two C-C chemokines (macrophage inflammatory protein-1 alpha (MIP-1 alpha) and monocyte chemotactic protein-1) and a C-x-C chemokine (MIP-2) in the pathogenesis of EAE. Production in the CNS of MIP-1 alpha, but not that of MIP-2, a rodent homologue of IL-8, or monocyte chemotactic protein-1, correlated with development of severe clinical disease. Administration of anti-MIP-1 alpha, but not that of anti-monocyte chemotactic protein-1, prevented the development of both acute and relapsing paralytic disease as well as infiltration of mononuclear cells into the CNS initiated by the transfer of neuroantigen peptide-activated T cells. Ab therapy could also be used to ameliorate the severity of ongoing clinical disease. Anti-MIP-1 alpha did not affect the activation of encepahlitogenic T cells as measured by cytokine secretion, surface marker expression, and ability to adoptively transfer EAE. These results demonstrate that MIP-1 alpha plays an important role in directing the chemoattraction of mononuclear inflammatory cells in the T cell-mediated autoimmune disease, EAE.
 ...
PMID:An important role for the chemokine macrophage inflammatory protein-1 alpha in the pathogenesis of the T cell-mediated autoimmune disease, experimental autoimmune encephalomyelitis. 759 7

The normal migration route of B cells into follicular areas of spleen and lymph nodes is altered in the case of autoreactive cells that have bound self-antigen. To begin characterizing the molecular requirements for B cell migration into follicles, cells were treated with pertussis toxin (PTX), an inhibitor of signaling by many G protein-coupled chemokine receptors. Lymphocyte accumulation in the spleen is not inhibited by PTX and, therefore, the distribution of transferred cells was examined in this tissue. In contrast to untreated cells that localized predominantly in follicular areas within white pulp cords, PTX-treated B cells failed to enter white pulp areas altogether and accumulated in the splenic red pulp. T cells were also excluded from white pulp cords and in the case of both cell types, the adenosine diphosphate-ribosylating subunit of the toxin was required to block white pulp entry. These findings implicate a G protein-coupled receptor in lymphocyte migration into splenic white pulp cords. Exclusion of PTX-treated cells from all organized areas of secondary lymphoid tissues raises the possibility that the association observed between PTX treatment and predisposition to autoimmune disease results from inhibition of tolerance mechanisms that normally operate within secondary lymphoid tissues.
 ...
PMID:Pertussis toxin inhibits migration of B and T lymphocytes into splenic white pulp cords. 762 15

Monocyte chemoattractant protein-1 (MCP-1) is a member of the chemokine beta family of chemoattractants that has been shown to play a major role in the initiation of monocyte and T cell inflammation to sites of tissue injury. In this study, we have examined the distribution of MCP-1 expression in inflammation in the central nervous system (CNS) associated with the autoimmune disease experimental autoimmune encephalomyelitis (EAE) and compared the results with those detected in inflammation associated with trauma. In EAE, MCP-1 expression was detected at the onset of inflammation, prior to clinical expression of disease, in lymphocytes and endothelial cells in subarachnoid locations. Monocyte infiltration into these areas appeared 24 h later. After the onset of clinical signs, MCP-1 expression was widely distributed in the spinal cord with levels increasing and decreasing in association with disease activity. Lymphocytes, macrophages, astrocytes, and endothelial cells could be identified as sources of MCP-1 by immunoreactivity and in situ hybridization. A similar close correlation between macrophage infiltration and the levels of mRNA for MCP-1 was found in the CNS of rats subjected to trauma, and in these animals MCP-1 was detected by immunohistochemistry in macrophages and endothelial cells. The results support the conclusion that MCP-1 is an important mediator of inflammation in the CNS.
 ...
PMID:Localization of monocyte chemoattractant peptide-1 expression in the central nervous system in experimental autoimmune encephalomyelitis and trauma in the rat. 860 24

Chemokines are secreted peptides that exhibit selective chemoattractant properties for target leukocytes. Two subfamilies, alpha- and beta-chemokines, have been described, based on structural, genetic, and functional considerations. In acute experimental autoimmune encephalomyelitis (EAE), chemokines are up-regulated systemically and in central nervous system (CNS) tissues at disease onset. Functional significance of this expression was supported by other studies; intervention with an antichemokine antibody abrogated passive transfer of EAE, and chemokines expressed in brains of transgenic mice recruited appropriate leukocyte populations into the CNS compartment. Chemokine expression in the more relevant circumstance of chronic EAE has not been addressed. We monitored the time course and cellular sources of chemokines (monocyte chemoattractant protein-1, macrophage inflammatory protein-1 alpha, interferon-gamma-inducible protein of 10 kd, KC, and regulated on activation, normal T-cell expressed and secreted cytokine) in CNS and peripheral tissues during spontaneous relapses of chronic EAE. We found coordinate chemokine up-regulation in brain and spinal cord during clinical relapse, with expression confined to CNS tissues. Monocyte chemoattractant protein-1, interferon-gamma-inducible protein of 10 kd, and KC were synthesized by astrocytic cells, whereas macrophage inflammatory protein-1 alpha and regulated on activation, normal T-cell expressed and secreted cytokine were elaborated by infiltrating leukocytes. The results demonstrate stringent regulation of multiple chemokines in vivo during a complex organ-specific autoimmune disease. We propose that chemokine expression links T-cell antigen recognition and activation to subsequent CNS inflammatory pathology in chronic relapsing EAE.
 ...
PMID:Synchronous synthesis of alpha- and beta-chemokines by cells of diverse lineage in the central nervous system of mice with relapses of chronic experimental autoimmune encephalomyelitis. 903 75

DNA vaccination represents a novel means of expressing Ag in vivo for the generation of both humoral and cellular immune responses. The current study uses this technology to elicit protective immunity against experimental autoimmune encephalomyelitis (EAE), a T cell-mediated autoimmune disease of the central nervous system that serves as an experimental model for multiple sclerosis. RT-PCR verified by Southern blotting and sequencing of PCR products of four different C-C chemokines, macrophage-inflammatory protein-1alpha (MIP-1alpha), monocyte-chemotactic protein-1 (MCP-1), MIP-1beta, and RANTES, were performed on brain samples from EAE rats to evaluate mRNA transcription at different stages of disease. Each PCR product was then used as a construct for naked DNA vaccination. The subsequent in vivo immune response to MIP-1alpha or MCP-1 DNA vaccines prevented EAE, even if disease was induced 2 mo after administration of naked DNA vaccines. In contrast, administration of the MIP-1beta naked DNA significantly aggravated the disease. Generation of in vivo immune response to RANTES naked DNA had no notable effect on EAE. MIP-1alpha, MCP-1, and MIP-1beta mRNA transcription in EAE brains peaked at the onset of disease and declined during its remission, whereas RANTES transcription increased in EAE brains only following recovery. Immunization of CFA without the encephalitogenic epitope did not elicit the anti-C-C chemokine regulatory response in DNA-vaccinated rats. Thus, modulation of EAE with C-C chemokine DNA vaccines is dependent on targeting chemokines that are highly transcribed at the site of inflammation at the onset of disease.
 ...
PMID:Long-lasting protective immunity to experimental autoimmune encephalomyelitis following vaccination with naked DNA encoding C-C chemokines. 978 Jan 52

Experimental autoimmune encephalomyelitis (EAE) is a T cell-mediated autoimmune disease of the central nervous system (CNS). RT-PCR verified by Southern blotting and sequencing of PCR products of two C-C chemokines, MIP-1alpha and MCP-1, was performed on brain samples from EAE rats to evaluate mRNA transcription of these chemokines at different stages of disease. mRNA transcription in of each chemokine peaked after the onset of disease and declined during its remission. Each PCR product was then used as a construct for naked DNA vaccination. The subsequent in vivo immune response to MIP-1alpha or MCP-1 DNA vaccines prevented EAE. Immunization of CFA without the encephalitogenic epitope did not elicit an anti-C-C chemokine regulatory response in DNA- vaccinated rats. Thus, modulation of EAE with C-C chemokine DNA vaccines is dependent on targeting chemokines that are highly transcribed at the site of inflammation at the onset of disease.
 ...
PMID:Prevention of experimental autoimmune encephalomyelitis by MIP-1alpha and MCP-1 naked DNA vaccines. 1044 Nov 64

To study the mechanisms underlying the development of interstitial pneumonia in autoimmune disease, we analyzed bronchoalveolar lavage fluid (BALF) in an animal model of interstitial pneumonia in which an intratracheal instillation of staphylococcal enterotoxin B (SEB) induced interstitial pneumonia in autoimmune-prone mice. Increases in the numbers of total cells, macrophages, lymphocytes, and neutrophils were observed in BALF from SEB-treated MRL +/+ mice, and peaked at 3 d after SEB administration (Day 3). Flow cytometric analyses revealed increases in SEB-reactive Vbeta8(+) T cells, indicating that SEB-reactive cells play an important role in bronchoalveolar space. The expressions of tumor necrosis factor (TNF)-alpha, interferon (IFN)-gamma, JE/monocyte chemoattractant protein-1, regulated on activation, normal T cells expressed and secreted, and KC/gro messenger RNA (mRNA) in BALF cells from SEB-treated mice peaked at Day 3. Increased expression of TNF-alpha mRNA was observed mainly in macrophages and CD8(+) T cells, and the increase in IFN-gamma mRNA was observed mainly in CD8(+) T cells in BALF at Day 3. The expression of platelet-derived growth factor mRNA was very weak at Day 3 but strongly expressed at Day 14. An immunosuppressant, FK506, but not corticosteroid, suppressed SEB-induced T-cell expansion in BALF as well as increased cytokine and chemokine production in the bronchoalveolar space of SEB-treated mice. Histologically, FK506 but not corticosteroid significantly reduced both the cell infiltration to alveolar septal walls and the synthesis of pulmonary collagen fibers. Further, transfer of T cells of MRL +/+ mice with SEB into SCID mice gave rise to interstitial pneumonia. These results suggest that superantigen-reactive T cells in the bronchoalveolar space may trigger the development of interstitial pneumonia in this model.
 ...
PMID:Role of T cells in bronchoalveolar space in the development of interstitial pneumonia induced by superantigen in autoimmune-prone mice. 1057 64

Infiltrating leukocytes may be responsible for autoimmune disease. We hypothesized that the chemokine monocyte chemoattractant protein (MCP)-1 recruits macrophages and T cells into tissues that, in turn, are required for autoimmune disease. Using the MRL-Fas(lpr) strain with spontaneous, fatal autoimmune disease, we constructed MCP-1-deficient MRL-Fas(lpr) mice. In MCP-1-intact MRL-Fas(lpr) mice, macrophages and T cells accumulate at sites (kidney tubules, glomeruli, pulmonary bronchioli, lymph nodes) in proportion to MCP-1 expression. Deleting MCP-1 dramatically reduces macrophage and T cell recruitment but not proliferation, protects from kidney, lung, skin, and lymph node pathology, reduces proteinuria, and prolongs survival. Notably, serum immunoglobulin (Ig) isotypes and kidney Ig/C3 deposits are not diminished in MCP-1-deficient MRL-Fas(lpr) mice, highlighting the requirement for MCP-1-dependent leukocyte recruitment to initiate autoimmune disease. However, MCP-1-deficient mice are not completely protected from leukocytic invasion. T cells surrounding vessels with meager MCP-1 expression remain. In addition, downstream effector cytokines/chemokines are decreased in MCP-1-deficient mice, perhaps reflecting a reduction of cytokine-expressing leukocytes. Thus, MCP-1 promotes MRL-Fas(lpr) autoimmune disease through macrophage and T cell recruitment, amplified by increasing local cytokines/chemokines. We suggest that MCP-1 is a principal therapeutic target with which to combat autoimmune diseases.
 ...
PMID:Monocyte chemoattractant protein 1-dependent leukocytic infiltrates are responsible for autoimmune disease in MRL-Fas(lpr) mice. 1060 56

We recently used a modification of gene therapy (naked DNA vaccination) to induce immunological memory against self-pro-inflammatory chemokines such as macrophage inflammatory protein-1 alpha or monocyte chemoattractant protein-1, and against the pro-inflammatory cytokine tumor necrosis factor-alpha. First, DNA constructs encoding each of the different pro-inflammatory mediators together with a repeated immunostimulatory sequence were prepared. Then, experiment animals were subjected to a repeated administration of each construct. Under these conditions, tolerance to the product of each insert was broken, and immunological memory established. Upon induction of experimental autoimmune encephalomyelitis, a T cell-mediated autoimmune disease of the central nervous system that serves as a model for multiple sclerosis or adjuvant induced arthritis, this memory was "turned on" to provide DNA-vaccinated animals a high state of disease resistance. Antibodies to the product of each inserted gene were isolated form these animals. Each antibody was found capable of neutralizing in vitro the chemoattractive properties of each relevant chemokine, thereby transferring disease resistance. Interestingly, the level of their production was dependent on disease severity, that is, each titer was accelerated in accordance with disease progression. Thus, by using a simple gene therapy technique the immune system could be "re-educated" to restrain its own harmful activities.
 ...
PMID:Gene therapy for T cell-mediated autoimmunity: teaching the immune system how to restrain its own harmful activities by targeted DNA vaccines. 1090 20


1 2 3 4 5 6 7 8 9 10 Next >>