Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UMLS:C0155339 (Brown)
 12,436 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Nervous tissue expression of immunological signal and recognition molecules, as well as lymphoid tissue immune responses after facial nerve trauma was studied in male rats of the Lewis and Brown Norway (BN) strains. In both rat strains nerve transection caused within four days the appearance of IFN-gamma-like immunoreactivity in the cytoplasm of axotomized motor neurons and an induction of MHC class I and II, and CD4 molecules on surrounding glial cells to a similar extent. T lymphocytes also infiltrated the facial nuclei ipsilateral to the axotomy in all animals. The number of autoreactive T cells in superficial cervical lymph nodes, which in response to whole myelin or peptides of myelin basic protein (MBP) secreted IFN-gamma increased markedly after axotomy. This response was more conspicuous in Lewis rats, which are susceptible to experimental allergic encephalomyelitis (EAE), than in BN rats, which are EAE resistant. A proportion of the axotomized Lewis rats also developed widespread perivascular infiltration of mononuclear cells in the CNS, reminiscent of EAE. Hypothetically, a strong expansion of myelin autoreactive IFN-gamma producing T cells secondary to nerve trauma may have immunopathological consequences in genetically predisposed individuals. It is also possible that myelin reactive T cells, whether recruited to the lesioned nerve, could have impact on macrophage function during Wallerian degeneration in the distal stump.
 ...
PMID:Facial nerve transection causes expansion of myelin autoreactive T cells in regional lymph nodes and T cell homing to the facial nucleus. 128 78

ZME-018 monoclonal antibody (MAb, IgG2a subclass, 0.04 mg), recombinant human tumor necrosis factor-alpha (rHuTNF-alpha, 10(4) units), and recombinant human interferon-gamma (rHuIFN-gamma, 10(6) units) were injected intravenously into athymic nude mice bearing human malignant melanoma (Brown C5513) xenografts. Sixty-four animals were injected subcutaneously with 0.2 ml tumor chunks 4 days prior to administration of one or more of the treatments. The mice were randomized into eight groups so that mean tumor volume/group before initiation of treatment was similar (212-360 mm3); (a) saline, 2X; (b) rHuTNF-alpha, 1X; (c) rHuIFN-gamma, 1X; (d) ZME-018, 1X; (e) rHuIFN-gamma + rHuTNF-alpha, 1X each; (f) rHu-IFN-gamma + ZME-018 + rHuTNF-alpha, 1X each; (g) rHuTNF-alpha + ZME-018, 2X each; (h) rHuTNF-alpha + ZME-018, 3X each. The order of administration of the agents in those groups given more than one modality is as shown above and each injection was separated by a 24 h period. Tumor volume was measured daily for 9 days after the beginning of treatment. Compared to control mice, minimal suppression of tumor growth was noted when ZME-018, rHuTNF-alpha, or rHuIFN-gamma was used singly, but significantly (p less than or equal to 0.05) slower tumor progression occurred in animals given rHuIFN-gamma + rHuTNF-alpha or ZME-018 + rHuTNF-alpha when compared to controls. Histopathologic analyses of tumor biopsies obtained at 1 and 4 days after the last treatment for each group indicated that 15-95% necrosis was present. Necrosis was most striking in the animals given rHuIFN-gamma + rHuTNF-alpha or the ZME-018 MAb alone. However, the group receiving all three agents exhibited a tumor growth rate similar to that seen in the controls and demonstrated minimal necrosis. These results suggest that ZME-018, rHuIFN-gamma, and rHuTNF-alpha may be useful in the treatment of human melanoma. However, the effects of administration of all three of these agents in a single host needs to be evaluated further.
 ...
PMID:Effects of monoclonal antibody, recombinant interferon-gamma, and tumor necrosis factor-alpha in the treatment of human melanoma xenografts. 251 78

In search of a phenotypic marker determining genetically controlled susceptibility to delayed-type hypersensitivity (DTH) reactions in the brain--in particular, experimental autoimmune encephalomyelitis (EAE)--we have compared the gamma-interferon (IFN-gamma) induction of Ia molecules on astrocytes and macrophages from rat and mouse strains that are susceptible or resistant to this disease. We focused on Ia expression because DTH reactions to self or foreign antigens are largely mediated by lymphocytes restricted by class II (Ia) antigens of the major histocompatibility complex (MHC). Our data demonstrate that Lewis (fully susceptible) and Brown Norway (BN) (fully resistant) rats are very different in that Lewis astrocytes express much higher levels of Ia than BN astrocytes. Similar data were obtained from an analysis of EAE-susceptible and -resistant mouse strains (SJL and BALB/c, respectively), which suggests that this phenomenon may be universal and not limited to only one mammalian species. At least one gene responsible for Ia hyperinduction is located outside the rat RT-1 or the mouse MHC locus. Animals congenic at the RT-1 or MHC locus of the resistant strain but with background genes of the susceptible strain exhibit intermediate levels of Ia compared to fully resistant and susceptible rodents, which fits well with the reduced EAE susceptibility of these congenic animals. Furthermore, hyperinduction of Ia is astrocyte specific, since peritoneal macrophages of susceptible and resistant strains exhibit identical profiles of Ia induction. Thus, astrocyte Ia hyperinducibility may be a major strain- and tissue-specific factor that contributes to Ia-restricted DTH reactions in the brain.
 ...
PMID:Hyperinducibility of Ia antigen on astrocytes correlates with strain-specific susceptibility to experimental autoimmune encephalomyelitis. 349 2

The well-established importance of helper T (Th)-cell subsets in immunity and immunoregulation of many experimental helminth infections prompted a detailed study of the cellular immune response against Fasciola hepatica in the natural bovine host. T-cell lines established from two cattle infected with F. hepatica were characterized for the expression of T-cell surface markers and proliferative responses against F. hepatica adult worm antigen. Parasite-specific T-cell lines contained a mixture of CD4+, CD8+, and gamma/delta T-cell-receptor-bearing T cells. However, cell lines containing either fewer than 10% CD8+ T cells or depleted of gamma/delta T cells proliferated vigorously against F. hepatica antigen, indicating that these T-cell subsets are not required for proliferative responses in vitro. Seventeen F. hepatica-specific CD4+ Th-cell clones were examined for cytokine expression following concanavalin A stimulation. Biological assays to measure interleukin-2 (IL-2) or IL-4, gamma interferon (IFN-gamma), and tumor necrosis factor and Northern (RNA) blot analysis to verify the expression of IL-2, IL-4, and IFN-gamma revealed that the Th-cell clones expressed a spectrum of cytokine profiles. Several Th-cell clones were identified as Th2 cells by the strong expression of IL-4 but little or no IL-2 or IFN-gamma mRNA. The majority of Th-cell clones were classified as Th0 cells by the expression of either all three cytokines or combinations of IL-2 and IL-4 or IL-4 and IFN-gamma. No Th1-cell clones were obtained. All of the Th-cell clones expressed a typical memory cell surface phenotype, characterized as CD45Rlow, and all expressed the lymph node homing receptor (L selectin). These results are the first to describe cytokine responses of F. hepatica-specific T cells obtained from infected cattle and extend our previous analysis of Th0 and Th1 cells from cattle immune to Babesia bovis (W. C. Brown, V. M. Woods, D. A. E. Dobbelaere, and K. S. Logan, Infect. Immun. 61:3273-3281, 1993) to include F. hepatica-specific Th2 cells.
 ...
PMID:CD4+ T-cell clones obtained from cattle chronically infected with Fasciola hepatica and specific for adult worm antigen express both unrestricted and Th2 cytokine profiles. 750 19

Both CD8+ T cells and IFN-gamma (IFN-gamma) are important components in the regulation of inducible-nitric oxide synthase (iNOS) which contribute to liver stage anti-malarial activity in rodents immunized with irradiated sporozoites. IFN-gamma, provided by malaria-specific CD8+ T cells, stimulates liver cells to produce nitric oxide (NO) for the destruction of infected hepatocytes or the parasite within these cells. To identify the cell source of iNOS in livers from Brown Norway rats challenged with Plasmodium berghei sporozoites, we probed tissue sections with antisera that recognize iNOS and the malarial exoerythrocytic stage parasite. Immunofluorescence analysis of parasitized livers demonstrate that 1) iNOS was found in infected hepatocytes, not Kupffer or endothelial cells; and 2) a higher proportion of infected hepatocytes express iNOS in immunized rats compared with naive animals after challenge. There was no immunoreactivity to the iNOS antisera in liver sections of immunized rats 15 h after sporozoite challenge, however, iNOS activity was present in 18% of the infected hepatocytes by 24 h and reached 81% by 31 h. In contrast, < 10% of the infected hepatocytes displayed iNOS activity in naive or immune animals 48 h after challenge. We also found a significant decrease in the ability of the immunized animals to express iNOS in response to sporozoite challenge by accelerating the removal of pre-existing irradiated-attenuated parasites from hepatocytes with the antimalarial drug, primaquine. Therefore, induction and maintenance of iNOS activity were dependent on intrahepatic persistence of the irradiated-attenuated parasite. These results suggest that liver-iNOS expression following sporozoite challenge is restricted to the infected hepatocyte and dependent on the presence of the irradiated-attenuated parasite in immune animals.
 ...
PMID:Co-localization of inducible-nitric oxide synthase and Plasmodium berghei in hepatocytes from rats immunized with irradiated sporozoites. 753 96

Brown Norway (BN) rats given gold salts develop an autoimmune syndrome with an immune complex-type glomerulonephritis in the context of a polyclonal B cell activation that was suspected to be due to the emergence of anti-self major histocompatibility complex (MHC) class II T cells. In the present study, six anti-self MHC class II T cell lines have been derived from six gold salt-treated rats by repeated stimulations with normal syngeneic MHC class II-bearing cells. The T cell lines proliferated in the presence of self MHC class II-positive B cell-enriched or B cell-depleted cells and the proliferation was inhibited by preincubating stimulator cells with an anti-IA monoclonal antibody. The T cell lines produced interleukin (IL)-4 only or IL-4 and some interferon (IFN)-gamma and could, therefore, be considered as T helper type 2 (Th2) and Th0 cells, respectively. They triggered normal syngeneic B cells to produce in vitro IgE, anti-DNA, anti-laminin and anti-2,4-6-trinitrophenol antibodies through, at least in part, cognate interactions. More interestingly, these lines when transferred into normal BN rats induced an autoimmune syndrome similar to or even more severe than the one observed in the active gold model, provided the recipients were CD8 depleted. These manifestations included a dramatic increase in serum IgE concentration and the production of anti-DNA and anti-laminin antibodies. In addition, all recipients displayed an autoimmune glomerulonephritis due to anti-laminin antibodies, granular IgG deposits in the interstitium, in the vessel walls and along the tubular basement membranes and a severe tubulointerstitial nephritis with marked mononuclear cell infiltration. An anti-ovalbumin T cell line that produced IL-4 and low amounts of IFN-gamma was used as a control and did not induce autoimmunity. These results demonstrate for the first time the ability of autoreactive Th2 as well as Th0 cell lines to induce antibody-mediated autoimmunity. They also show that CD8+ cells play a crucial role in the control of such autoreactive cells. Finally, this work suggests that Th2 cells could initiate cell-mediated reactions either directly or indirectly.
 ...
PMID:Self-reactive anti-class II T helper type 2 cell lines derived from gold salt-injected rats trigger B cell polycolonal activation and transfer autoimmunity in CD8-depleted normal syngeneic recipients. 762 73

Mercurials may induce immune manifestations in susceptible individuals. Mercuric chloride (HgCl2) induced autoimmunity in the Brown Norway (BN) strain but an immuno-suppression in the Lewis strain with, however, autoreactive anti-class II T cells present in both strains. In the present study we looked at modifications of cytokine production by PCR and cytofluorometric analyses in normal BN and Lewis rat splenocytes, cultured with or without HgCl2. Unfractionated BN rat splenocytes and purified T cells exposed to HgCl2 expressed high levels of IL-4 mRNA. Increase in class II and CD23 molecule expression on B cells was partly inhibited by anti-IL-4 mAb showing that IL-4 was produced. By contrast, no overexpression of IL-4 mRNA could be seen in Lewis rats. Although an increase in class II molecule expression was observed suggesting that other T helper cell 2 cytokines were produced, there was also a concomitant decrease in CD23 molecule expression that was abrogated after addition of an anti-IFN-gamma mAb to the culture. IFN-gamma mRNA production was induced in unfractionated spleen cells and T cells from both strains after HgCl2 exposure. Altogether these findings demonstrate that HgCl2 has very early direct effects on cytokine production and that these effects differ depending on the strain. The early effect on IL-4 production observed on BN rat spleen cells and T cells may explain that the autoreactive anti-class II T cells that are found in HgCl2-injected BN rats have a Th2 phenotype.
 ...
PMID:Mercuric chloride, a chemical responsible for T helper cell (Th)2-mediated autoimmunity in brown Norway rats, directly triggers T cells to produce interleukin-4. 765 19

We have examined several peptidase activities of human multicatalytic protease (MCP) purified from the lymphoblastoid cell line 721.45 and a deletion mutant derivative, 721.174, lacking MCP subunits encoded in the major histocompatibility complex (MHC) class II region. Wild-type lymphoblast MCP hydrolyzed a specific peptide, glutaryl-Gly-Gly-Phe-4-methylcoumaryl-7-amide (-MCA), several times faster than the mutant enzyme did, suggesting that MHC-encoded subunits may provide this activity. Contrary to a recent report [Driscoll, J., Brown, M. G., Finley, D. & Monaco, J J. (1993) Nature (London) 365, 262-264], we did not detect significant aminopeptidase associated with lymphoblast MCPs. Our results also differ markedly from those of Gaczynska et al. [Gaczynska, M., Rock, K. L. & Goldberg, A L. (1993) Nature (London) 365, 264-267], who reported that gamma interferon (IFN-gamma) alters the peptidase activities of lymphoblast MCPs. We found that IFN-gamma did not produce significant differences in the peptidase activities of purified MCPs. Moreover, our measurements of Vmax and Km for succinyl-Leu-Leu-Val-Tyr-MCA hydrolysis differ 600-fold and 15-fold, respectively, from those reported by Gaczynska et al. On balance, the findings presented here do not support the idea that IFN-gamma induces major changes in the peptidase activity of purified MCPs.
 ...
PMID:Effects of interferon gamma and major histocompatibility complex-encoded subunits on peptidase activities of human multicatalytic proteases. 783 34

Mercuric chloride (HgCl2) injections protect (Lewis x Brown-Norway) F1 (F1) rats against experimental autoimmune uveoretinitis (EAU) induced by immunization with the retinal S antigen (S-Ag); in contrast HgCl2-injected F1 rats develop EAU following transfer of lymph node (LN) cells from rats immunized with S-Ag alone. In the present study we demonstrate that the ability of LN cells from rats protected against EAU to transfer the disease into naive F1 rats was considerably reduced. These LN cells neither produced interleukin (IL)-2 nor (interferon (IFN)-gamma but exhibited mRNA for IL-4. In contrast, LN cells from diseased rats easily transferred EAU into naive F1 rats, produced significant IL-2 and IFN-gamma levels but barely exhibited mRNA for IL-4. Furthermore protected rats predominantly produced IgG1 anti-S-Ag antibodies, while diseased rats produced IgG2b anti-S-Ag antibodies and the increase in expression of MHC class II molecules on B cells was higher in protected rats than in diseased rats. These data suggest that (1) to exert a protective effect, HgCl2 must act at an early stage of differentiation of precursors of S-Ag specific T cells, and (2) this effect is related to the preferential activation of TH2 cells to the detriment of uveitogenic TH1 cells. Finally, these results indicate that activation of TH2 cells protect from a TH1-dependent autoimmune disease.
 ...
PMID:TH2 activated cells prevent experimental autoimmune uveoretinitis, a TH1-dependent autoimmune disease. 825 22

Many groups have reported that preoperative injection of donor-derived whole spleen cells or major histocompatibility complex antigens prolongs organ allograft survival in experimental models, but the immunosuppressive mechanism(s) responsible remains unclear. A central, confounding issue is how to reconcile documentation of comparable levels of mRNA for IL-2 in suppressed versus control groups with obvious host hyporesponsiveness. We used a model of tolerance induction involving perioperative injection of donor spleen cells and injection of CsA at day 2 after transplant to analyze the serial expression of several proinflammatory cytokines relevant to development of alloresponsiveness within cardiac allografts and recipients' spleens. Four experimental groups of Lewis rats receiving vascularized heterotopic cardiac allografts from Brown Norway (BN) donors were evaluated: (1) untreated controls; (2) animals receiving intraoperative injection of donor BN spleen cells; (3) those receiving a single injection of CsA on day 2 post-Tx; and (4) animals given the combination of intraoperative BN spleen cells and CsA on day 2 post-Tx. Graft survival was significantly prolonged in Lewis rats receiving the combined spleen cell/CsA therapy (mean 64 days, with 40% of grafts surviving > 100 days, n = 15) compared with acute rejection at about 8 days (range 6-13, n = 20) in each of the 3 control groups (P < 0.0001). By comparison with acutely rejecting allografts in the control untreated group at day 7 post-Tx, allografts in rats receiving the combined perioperative spleen cell/CsA treatment showed (1) significantly reduced graft cellularity and interstitial edema; (2) significantly decreased features of immune activation, including infiltration by mononuclear cells expressing IL-2R or proliferating cell nuclear antigen; (3) decreased intragraft expression of the cytokines IL-2 and IFN-gamma; and (4) suppression of endothelial activation as evidenced by both failure of up-regulation of intracellular adhesion molecule-1 and maintenance of thrombomodulin expression by graft endothelium. Analysis of sections of recipients' spleens showed that spleen cell/CsA therapy led to significant reductions versus untreated controls, in expression of IL-2, IFN-gamma, and IL-2R. Similarly, mixed lymphocyte response cultures showed that responder cells from rats receiving combined therapy proliferated by 93-95% less than untreated animals. Our results suggest that the efficacy of this clinically relevant protocol is associated with suppression of IL-2 or IFN-gamma protein production, and that in the absence of such molecules, it appears that T cell-receptor occupancy by alloantigens readily induces a state of anergy in vivo.
 ...
PMID:Mechanism of a clinically relevant protocol to induce tolerance of cardiac allografts. Perioperative donor spleen cells plus cyclosporine suppress IL-2 and interferon-gamma production. 827 94


1 2 3 4 5 6 7 Next >>