UMLS:C0155339 - FACTA Search

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Query: UMLS:C0155339 (Brown)
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The efficacy of CTLA4Ig in blocking immune activation and allograft rejection (AR) was tested in an aggressive and rapid model of rat lung AR (Brown Norway [BN]-->Lewis [LEW]). CTLA4Ig is a recombinant soluble protein that binds with high affinity to rat B7/BB1 and other surface molecules on APCs, subsequently blocking the binding of B7/BB1 to CD28/CTLA4 on T cells. This interrupts the costimulatory pathway critical for complete T cell activation and completion of the AR process. Left single-lung transplants were performed between BN-->Lew. Five allograft recipients were examined in each group. At transplantation, animals received 250 micrograms of CTLA4Ig or 250 micrograms of control Ig intraperitoneally daily until sacrifice. Animals were sacrificed on days 2, 4, and 7 after transplant. Control (BN-->Lew) grafts show irreversible rejection by day 7. Syngeneic (Lew-->Lew) grafts show no AR on day 7. AR episodes were graded histologically (stages 0-IV) and pathologic intensity of inflammation was graded on percentage of involvement. Cytokine transcript levels were measured in control and CTLA4Ig-treated animals (n = 5 in each group) on day 7 using reverse transcriptase polymerase chain reaction techniques. The most profound differences were found on day 7 after transplant. The degree of lymphocytic infiltration was greater in the CTLA4Ig group (perivascular: 4 +/- 0 vs. 2.6 +/- 0.6, peribronchial: 4 +/- 0 vs. 2.2 +/- 0.4, and peribronchiolar: 3.6 +/- 0.5 vs. 2 +/- 0.3, P < 0.01). However, in striking contrast, the stage of AR (3 +/- 0 vs. 4 +/- 0, P < 0.01), vasculitis (1 +/- 0.7 vs. 2.6 +/- 0.6, P < 0.05), hemorrhage (0.4 +/- 0.6 vs. 3.2 +/- 0.4, P < 0.01), and necrosis (0 +/- 0 vs. 2.4 +/- 0.5, P < 0.005) were significantly reduced in animals treated with CTLA4Ig. Since CTLA4Ig blocks Th1 cell activation in vitro, we compared the levels of Th1 inflammatory cytokines IL-2, gamma-IFN, and TNF-alpha in the two models. The intragraft ratios (CTLA4Ig/control) were IL-2:0.77, gamma-IFN: 1.29, and TNF-alpha:1.33. Thus, CTLA4Ig did not significantly block intragraft production of Th1 cytokines on day 7.(ABSTRACT TRUNCATED AT 400 WORDS)
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PMID:Soluble CTLA4Ig modifies parameters of acute inflammation in rat lung allograft rejection without altering lymphocytic infiltration or transcription of key cytokines. 753 46

The phosphodiesterase inhibitor oxpentifylline (OXP) has a number of potentially important immunomodulatory actions which include a selective inhibition of the Th1 subset of CD4+ cells in vitro and inhibition of tumor necrosis factor (TNF)-alpha mRNA transcription. In vivo, it has a dramatic protective effect against experimental allergic encephalomyelitis. In this animal model, tissue injury is associated with both a Th1 response and with TNF-alpha production, either of which could be targets for the protective action of OXP. In an attempt to clarify the relative importance of the Th cell subsets and TNF-alpha in pathogenesis, we investigated the effect of OXP on a Th2 model of T cell-dependent disease, mercuric chloride (HgCl2)-induced autoimmunity in the Brown Norway rat. The effects of OXP on the Th1:Th2 response, TNF-alpha mRNA transcription in spleen and ankle joints, and on the incidence and severity of arthritis and cecal vasculitis have been examined and the effects in vivo have been compared with those of a soluble TNF receptor-IgG1 fusion protein (sTNFR) that neutralizes rat TNF-alpha. In two separate experiments, OXP significantly enhanced unstimulated levels of splenic interleukin-4 (IL-4) mRNA (median 62%, of an artificial IL-4 mRNA construct, vs. 36.5% in controls) and in one experiment, exaggerated the total IgE response to HgCl2. OXP inhibited HgCl2-induced TNF-alpha mRNA transcription in spleen and ankle joints. In three separate experiments, OXP had a significant protective effect against arthritis, with the mean incidence reduced from 100% to 30% and mean peak score reduced from 7.2 to 2.59 (experiments 1 and 2). The protection against arthritis was indistinguishable from that produced by sTNFR. There was no such protection against cecal vasculitis with either OXP or sTNFR. These results demonstrate that OXP induces a shift towards a Th2 response, inhibits TNF-alpha mRNA transcription locally in joint and systemically in spleen, and has a protective effect against arthritis similar to that produced by sTNFR in the HgCl2-treated BN rat. We conclude that TNF-alpha is a critical cytokine in the pathogenesis of arthritis but not cecal vasculitis in this model, and that inhibition of TNF-alpha transcription is the most important mode of action of OXP in this situation. OXP may be a potential therapeutic agent in the treatment of other arthritides, such as human rheumatoid arthritis, in which TNF-alpha has been implicated in pathogenesis.
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PMID:Oxpentifylline inhibits tumor necrosis factor-alpha mRNA transcription and protects against arthritis in mercuric chloride-treated brown Norway rats. 758 90

The immunological therapy of cancer has been proposed in a number of neoplasms (Borden, Sondel, 1989; Foon, 1989; Rosenberg, 1992) and has recently been adopted in the treatment of Central Nervous System (CNS) tumors in combination with conventional surgical and radiotherapeutical approach. In this context, loco-regional administration of immunomodulating agents (for instance in post-surgical cavity) allows to achieve much higher in situ concentrations than by systemic route. Since these treatments have potential adverse effects, careful assessment of clinical and immunological parameters in phase I trials is needed. CNS tumors disseminating via Cerebrospinal Fluid (CSF) pathways offer a stimulating opportunity for intrathecal immunotherapy. In this context, alpha-IFN and IL2 (alone or in combination with LAK cells) have been employed either loco-regionally or intrathecally (Merchant, Mc Vicar, Merchant & Young, 1992; Schiller, Hank, Storer, Borchert, Moore, Albertini, Bechhofer, Wesley, Brown, Bastin & Sondel, 1993). The rationale for the use of both these substances includes the known anti-tumor action of alpha-IFN (Mahaley, Urso, Whaley, Blue, Williams, Guaspari & Selker, 1985; Nagai, 1988) and the ability of r-IL2 to generate activated cells effective in lysing tumor cell targets (Hayes, Moore, Pierz, Chen, Da Rosso, Nirenberg & Allen, 1993). We treated 3 patients (2 affected by disseminating cerebellar medulloblastoma, 1 by disseminating thalamic glioblastoma) by intrathecal r-IL2 via recervoir. In the first 2 patients, this treatment was preceded by alpha-IFN (also intrathecally). Monitoring of immunological effects of the treatment schedule involved kinetics of CSF and serum TNF-alpha, IL2s and IL2R during the first day of r-IL2 treatment, as well as on day +2 and +4 of both r-IL2 cycles, and assessment of CSF cells, protein and CSF and PB NK cell activity and CD3-CD56+ cells during the course of all treatment cycles. We also assessed clinical and neuroradiological effects of immunotherapy.
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PMID:Immunological fluctuations during intrathecal immunotherapy in three patients affected by CNS tumours disseminating via CSF. 798 57

Mast cells have been traditionally associated with an acute allergic response. However, their role in regulating chronic inflammatory processes must also be considered in view of evidence that mast cells synthesize and release a number of cytokines. In this study, we have examined the effect of cholera toxin (CT) on peritoneal mast cell IL-6 and TNF-alpha production. Highly purified, freshly isolated, rat peritoneal mast cells from Brown Norway rats were cultured in the presence of CT or its B subunit (CTB) alone or in combination with anti-IgE or bacterial LPS. Histamine release was measured after 10 min; IL-16 and TNF-alpha production was assessed in supernatants after 18 h. We found that CT or CTB alone did not affect histamine release; however, mast cell IL-6 production was significantly enhanced by CT but not by CTB. In contrast, constitutive production of TNF-alpha was inhibited by CT. The effects of CT were similar to our previous observations of the actions of prostaglandin E2 on mast cells. We also examined the effects of CT in combination with other mast cell activating agents. CT had no significant effect on anti-IgE-induced histamine release. An additive effect on IL-6 production was observed in the context of LPS. Forskolin, an agent known to increase intracellular cAMP levels, also induced a significant increase in IL-6 production, whereas TNF-alpha production was decreased. These data have important implications for our understanding of the regulation of mast cell cytokine production and the effects of CT on local cytokine production.
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PMID:Cholera toxin increases IL-6 synthesis and decreases TNF-alpha production by rat peritoneal mast cells. 859 79

In Brown Norway to Lewis rat lung transplantation, short-term administration of cyclosporine produces permanent adoption of allografts; however, the adopted grafts show symptoms of chronic rejection. To clarify the difference in cytokine production in acute an chronic rejection of the allografts, an immunohistochemical study was performed. In acute rejection, positive cells for respective cytokines were observed in infiltrating cells, increasing in number as the days after transplantation passed, and reaching a maximum on the fifth day. The strongest reactivity was observed perivenously. In chronic rejection, TNF-alpha positive cells were observed in the perivascular and peribronchial regions, especially around class II positive epithelia. The number of positive cells was, however, less than that in the vascular phase of acute rejection. Few cells were positive for IL-1 beta, IFN-gamma and, unexpectedly, for IL-4. These facts indicate the functional difference of infiltrating cells between acute and chronic rejection.
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PMID:Difference in cytokine production in acute and chronic rejection of rat lung allografts. 895 33

Acute lung allograft rejection is believed to be initiated by passenger leukocytes, such as alveolar macrophages (AM), in the donor organ, which release TNF-alpha, and present alloantigens to host lymphocytes, to up-regulated Th1 cellular and humoral immunity. However, the role of donor AM in local TNF-alpha synthesis, and their ability to induce local Th1 cellular and humoral immunity have not been evaluated. By depleting Brown Norway (BN, RT1n) rat lung allografts of AM before transplantation into Lewis rat (LEW, RT1(1)) recipients, the current study determined the role of donor AM in including the production of TNF-alpha, IFN-gamma (Th1 cytokine), IL-4 (Th2 cytokine), IgG subtypes, and rejection pathology in the allograft. The data show that compared with untreated BN allografts, pretransplant depletion of donor lung AM resulted in significantly less TNF-alpha, and IFN-gamma production in allograft bronchoalveolar lavage fluid with variable effects on local IL-4 production. Depletion of AM in the donor lung before transplantation affected the local production of several IgG subclasses. However, pretransplant depletion of donor AM had no effect on the development of the pathology of severe acute rejection. These data show that donor AM have a central role in the local synthesis of TNF-alpha and induce the production of IFN-gamma and IgG subtypes, locally, during acute lung allograft rejection. However, depletion of AM before transplantation does not prevent the development of severe acute rejection in BN rat lungs, transplanted into LEW recipients.
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PMID:Role of passenger leukocytes in allograft rejection: effect of depletion of donor alveolar macrophages on the local production of TNF-alpha, T helper 1/T helper 2 cytokines, IgG subclasses, and pathology in a rat model of lung transplantation. 937 99

Increased airway resistance and airway hyperresponsiveness induced in rats by infection with parainfluenza type I (Sendai) virus is associated with bronchiolar fibrosis. To determine whether increased tumor necrosis factor (TNF)-alpha gene expression is an important regulatory event in virus-induced bronchiolar fibrosis, pulmonary TNF-alpha mRNA and protein expression was assessed in rat strains that are susceptible (Brown Norway; BN) and resistant (Fischer 344; F344) to virus-induced bronchiolar fibrosis. Virus-inoculated BN rats had increased TNF-alpha pulmonary mRNA levels (P < 0.05) and increased numbers of bronchiolar macrophages and fibroblasts expressing TNF-alpha protein compared with virus-inoculated F344 rats (P < 0.05). Virus inoculation also induced elevated TNF-alpha mRNA and protein levels (P < 0.05) in cultured rat alveolar macrophages (NR8383 cells). A 55-kd soluble TNF receptor-immunoglobulin G fusion protein (sTNFR-IgG) was used to inhibit TNF-alpha bioactivity in virus-inoculated BN rats. Treated rats had fewer proliferating bronchiolar fibroblasts, as detected by bromodeoxyuridine incorporation, compared with virus-inoculated control rats (P < 0.05). There was also increased mortality in p55sTNFR-IgG-treated virus-inoculated rats associated with increased viral replication and decreased numbers of macrophages and lymphocytes in bronchoalveolar lavage fluid (P < 0.05). The results of this study indicate that 1) Sendai virus can directly up-regulate TNF-alpha mRNA and protein expression in macrophages, 2) TNF-alpha is an important mediator of virus-induced bronchiolar fibrosis, and 3) TNF-alpha has a critical role in the termination of Sendai viral replication in the lung.
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PMID:Increased tumor necrosis factor-alpha (TNF-alpha) gene expression in parainfluenza type 1 (Sendai) virus-induced bronchiolar fibrosis. 946 78

The expression of IL-6 is greatly enhanced in the twitcher mouse (S. M. LeVine and D. C. Brown, 1997, J. Neuroimmunol. 73, 47-56), which is an authentic animal model of globoid cell leukodystrophy (Krabbe's disease). In order to investigate the role of IL-6 in this disease, twitcher/IL-6-deficient mice were generated and the pathology was compared between them and regular twitcher mice. Twitcher/IL-6-deficient mice had a more severe disease than regular twitcher mice: they had an earlier onset day of twitching, a greater number of PAS-positive cells, a greater susceptibility to LPS, an exaggerated gliotic response around some vessels, an elevated level of TNF-alpha, and a compromised blood-brain barrier, which was evaluated by three independent measures. This latter finding indicates that IL-6 plays a role in maintaining the integrity of the BBB, and it raises the possibility that IL-6 functions in a similar manner in other diseases of the CNS. LPS was found to greatly shorten the life of twitcher and twitcher/IL-6-deficient mice compared to genotyped-matched saline-injected mice. This result indicates that a proinflammatory condition can exacerbate an underlying CNS pathology, which could help explain why some leukodystrophy patients display their initial symptoms following a fever or blow to the head.
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PMID:IL-6 deficiency causes enhanced pathology in Twitcher (globoid cell leukodystrophy) mice. 1041 53

Accelerated myointimal hyperplasia is a major complication of arterial allografts. The aim of our study was to analyze the role of growth factors in the genesis of myointimal hyperplasia in arterial allografts. Two groups of experiments were performed: Isografts and Allografts. The Isograft group consisted of 18 inbred Lewis rats in which a 1-cm long segment of aorta was inserted as abdominal aortic interposition graft. The aortic segments were obtained from syngeneic Lewis rats. The Allograft group consisted of 18 inbred Lewis rats, in which a 1-cm long segment of aorta was interposed at the level of the abdominal aorta. The aortic segments were obtained from allogeneic Brown-Norway rats. No immunosuppression was used. The animals were sacrificed 4 weeks after surgery and the aortic grafts were analyzed by light, electron microscopy (n = 3 for each group) and immunohistochemistry (n = 3 for each group). In addition, aortic segments (n = 12 for each group) were put in an organ culture to assess production of growth factors. All allografts showed evidence of severe myointimal hyperplasia, which was minimal in isografts. PDGF, bFGF and TGF-beta(1) production, generally considered to be the cause of myointimal hyperplasia, was not increased in allografts, whereas IL-1, TNF-alpha and GM-CSF production was increased in allografts and probably lymphocytes were the source of these cytokines (p < 0.001). We conclude that myointimal hyperplasia in aortic allografts is associated with an increase of IL-1, TNF-alpha and GM-CSF produced by lymphocytes.
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PMID:Increased production of cytokines and growth factors by aortic allografts: A possible explanation for myointimal hyperplasia formation. 1044 88

Histamine release and cytokine production by mast cells and basophils are thought to be closely involved in the pathogenesis of allergic diseases. Some reports show that FK506 (tacrolimus hydrate) inhibited histamine release and cytokine production by mast cells and basophils. However, as the effects of FK506 has not been compared with those of clinically used drugs in those reports, the clinical relevancy of FK506 inhibition remained unclear. In this paper, we compared the actions of FK506 with those of steroids or disodium cromoglycate (DSCG) which has been clinically used. FK506 inhibited histamine release by Brown-Norway rat peritoneal mast cells more potently than steroids and especially DSCG. FK506 also inhibited histamine release by a mast rat basophilic leukemia (RBL)-1 cell line and human peripheral blood basophils, whereas steroids failed to inhibit histamine release by human basophils. FK506 as well as steroids inhibited TNF-alpha and IL-4 production by RBL-1 cells. FK506 was therefore more effective than steroids and DSCG in inhibiting histamine release, and it also had the ability of inhibiting cytokine production by mast cells as steroids do. We concluded that FK506 might regulate allergic diseases via these actions, judging from the viewpoint of clinical relevancy.
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PMID:FK506 inhibition of histamine release and cytokine production by mast cells and basophils. 1068 2

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