Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: HUMANGGP:036187 (gut)
 73,132 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Adoptive immunotherapy with tumor-infiltrating lymphocytes (TIL) and interleukin-2 (IL2) can induce regression of tumor metastases in animal models and in human metastatic malignant melanoma. We investigated the potential of colorectal cancer TIL as a source of killer cells and the effect of tumor necrosis factor alpha (TNF alpha) in combination with IL2 on their cytotoxic activity. Tumor-infiltrating lymphocytes were isolated from surgical specimens using a mechanical and enzymatic dissociation process. Autologous lamina propria mononuclear cells (LPMC) were used as control. Tumor-infiltrating lymphocytes and LPMC were cultured in the presence of IL2 with/without TNF alpha (1000 U/ml each) for 5 to 8 weeks. Cytotoxicity (% lysis) was tested against Daudi target cells in a 4-hr 51Cr-release assay. The combination of IL2 and TNF alpha resulted in a significantly greater-fold expansion of TIL than IL2 alone (P less than 0.01). Lamina propria mononuclear cells expanded less than TIL, and TNF alpha had an inhibitory effect on their growth (P less than 0.05). Tumor-infiltrating lymphocytes and LPMC showed comparable cytotoxicity when cultured with IL2 alone. However, the addition of TNF alpha augmented the killer activity of TIL while inhibiting that of LPMC (P = 0.035). These results indicate that TNF alpha selectively increases the IL2-induced growth and cytotoxic function of colorectal cancer TIL, but not those of gut mucosal lymphoid cells, suggesting that TIL and LMPC differ in their response to TNF alpha. Therefore, this combination of cytokines may hold more promise than single agents for the immunotherapy of colorectal cancers with TIL.
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PMID:Resident research award: tumor necrosis factor alpha selectively enhances growth and cytotoxic activity of tumor infiltrating lymphocytes from human colorectal cancer. 154 66

Protein kinase (PK) C has been implicated in a number of cellular events, many of which are also known to be affected by ethanol (ETOH). ETOH intoxication is also known to impair immune function, thereby increasing the host's susceptibility to infection. The purpose of this study was to assess the effect of acute ETOH intoxication on PKC activity and its intracellular distribution in nonparenchymal liver cells following an E. coli lipopolysaccharide (LPS) challenge. The liver was chosen for the study because it is the primary site both for metabolism of ETOH and detoxification of gut derived bacterial products. Catheterized conscious rats were administered saline or ETOH (175 mg/100 g body weight as a bolus followed by a continuous, 7 hr infusion of 28 mg/100 body weight/hr). LPS was injected intravenously (100 micrograms/100 g body weight) 3 hr before the end of the saline or ETOH infusion. Kupffer and endothelial cells were isolated by collagenase-pronase digestion followed by centrifugal elutriation. PKC was assayed after extraction with digitonin containing buffer and partial purification on DE-52 cellulose minicolumns. LPS decreased PKC activity by 69% from control values. Although ETOH infusion alone did not affect PKC activity in Kupffer cells, it completely abrogated the LPS effect. A similar trend was observed for the endothelial cells. No significant differences were observed between groups with respect to the intracellular distribution of PKC. The down-regulation of PKC by LPS may represent a mechanism of functional adaptation of the immunocompetent cells to one of the cytokines, i.e., TNF, whose receptors are down regulated by activation of PKC.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Acute ethanol intoxication prevents lipopolysaccharide-induced down regulation of protein kinase C in rat Kupffer cells. 155 4

In a multicenter pilot study, 19 patients with severe acute graft-versus-host disease (aGVHD) refractory to conventional therapy and serotherapy with a monoclonal anti-interleukin-2 receptor antibody were treated by in vivo infusion of a monoclonal anti-tumor necrosis factor alpha (TNF alpha) antibody (B-C7). Ten patients were grafted from a genotypically identical sibling, five from an HLA-mismatched family member, and four from an HLA-matched unrelated donor. Before B-C7 treatment, 15 patients had grade IV and four had grade III GVHD. In all cases, patients received cyclosporine/methotrexate as aGVHD prophylaxis. Patients were administered increasing doses of antibody (from 0.1 to 0.4 mg/kg). The antibody was infused in bolus daily for 4 days and then every other day twice (6 doses). No side effects were observed during treatment regardless of the dose level used. Changes in peripheral blood cell counts occurred in 8 of the 19 patients and appeared to be unrelated to B-C7. No truly complete response was observed; eight patients achieved a very good partial response (42.6%) and six a partial response (31.5%). The treatment was ineffective in five patients (26.4%). When present, the response occurred early (less than 3 days). In the 14 responding patients, gut lesions responded best (100%), followed by skin (85%) and liver (35.7%) lesions. In 9 of 11 evaluable patients (81%), GVHD recurred when treatment was discontinued in a median delay of 3 days (range, 2 to 120 days). All except one died from aGVHD. Two patients did not experience GVHD recurrence and are still alive 13 and 18 months post-bone marrow transplantation. This pilot study shows that a monoclonal anti-TNF alpha antibody may be of benefit to some patients with severe refractory aGVHD, but is ineffective to prevent GVHD recurrence in the majority of cases.
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PMID:Phase I-II trial of a monoclonal anti-tumor necrosis factor alpha antibody for the treatment of refractory severe acute graft-versus-host disease. 159 76

The effects of cytokines on intestinal glutamine metabolism were studied to gain further insight into the regulation of altered glutamine metabolism that occurs during severe infection. One hundred thirteen adult rats were given a single dose of interleukin-1 (IL-1, 50 micrograms/kg), tumor necrosis factor (TNF, 50 micrograms/kg or 150 micrograms/kg), or saline (controls), and flux studies were performed 4 or 12 hours later. Intestinal blood flow was not different between control and cytokine-treated animals at either time point. At the 4-hour time point, arterial glutamine fell by 16% to 21% in the cytokine-treated animals (p less than 0.05); at the 12-hour time point, the arterial glutamine concentration had returned to normal. Intestinal glutamine extraction decreased in the animals treated with IL-1 at both time points (4 hours: 13% +/- 1.3% in IL-1 versus 20% +/- 1.6% in controls, p less than 0.05; and 12 hours: 9% +/- 2% in IL-1 versus 17% +/- 2% in controls, p less than 0.05). Consequently, net intestinal glutamine uptake fell in the animals treated with IL-1 at both time points (p less than 0.05). Similarly, the activity of mucosal glutaminase, the principal enzyme of glutamine hydrolysis in the gut, fell by 50% in the 4-hour study (6.1 +/- 0.6 mumol/h/mg protein in IL-1 versus 9.6 +/- 0.8 mumol/h/mg protein in controls, p less than 0.01) and by 40% in the 12-hour study (5.4 +/- 0.5 mumol/h/mg protein in IL-1 versus 8.8 +/- 0.4 mumol/h/mg protein in controls, p less than 0.05). Concomitant with the aforementioned decrease in gut glutamine metabolism was a 25% incidence of positive blood cultures for gram-negative organisms in IL-1 treated rats studied at the 12-hour time point (p = 0.05 versus controls). In the doses administered and at the time points studied, TNF had no effects on the parameters of gut glutamine metabolism examined. The results indicate that IL-1 is a potential mediator of the alterations in gut glutamine metabolism observed in sepsis and endotoxemia.
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PMID:Cytokine regulation of intestinal glutamine utilization. 173 66

The effect of sepsis on plasma levels of various gut peptides was studied in rats. Sepsis was induced by cecal ligation and puncture (CLP); control animals underwent sham operation. Sixteen hours after CLP or sham operation, portal and systemic blood was drawn, and plasma levels of gastrin, vasoactive intestinal peptide (VIP), secretin, peptide YY (PYY), gastrin-releasing peptide (GRP), and substance P were determined by radioimmunoassay. Plasma levels of gastrin, VIP, PYY, and secretin were elevated in septic rats compared with nonseptic animals, with the highest levels noted in portal blood. There was no effect of sepsis on GRP or substance P levels. In other experiments, human recombinant interleukin 1 alpha (IL-1 alpha) or recombinant tumor necrosis factor alpha (TNF alpha) was injected intraperitoneally (300 micrograms/kg body weight in 3 divided doses over 16 hours). There was no change in plasma levels of gut peptides after IL-1 alpha injection. TNF alpha induced elevation of PYY levels in portal plasma with no change in other gut peptide levels. The results suggest that sepsis stimulates release of certain gut peptides and that TNF, but not IL-1, may be partly responsible for this response. The mechanism of the release of gut peptides and its significance in the pathophysiologic changes induced by sepsis remain to be determined.
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PMID:Effect of sepsis or cytokine administration on release of gut peptides. 173 67

Crohn's disease and ulcerative colitis are chronic inflammatory bowel diseases (IBD) of unknown etiology. They are characterized by an activation of intestinal mononuclear cells. Cytokines play a crucial role in the regulation of the functions of these cells. An increased synthesis of the cytokines interleukin-1 (IL-1), interleukin-6 (IL-6) and tumor necrosis factor alpha (TNF alpha), which are primarily synthesized by activated monocytes/macrophages has been described in patients with IBD. The synthesis of interleukin-2 (IL-2) and of interferon gamma (IFN gamma), which are produced by lymphocytes, on the other hand, has been found to be decreased. The published data are, however, not quite consistent. In patients with IBD there is not only a stimulation of the local cytokine production in the gut. The blood levels and the synthesis of the cytokines IL-1, IL-6 and TNF alpha by peripheral blood mononuclear cells are also increased, in particular in patients with Crohn's disease. Drugs, which are commonly used for the treatment of IBD impair the synthesis of these cytokines in monocytes/macrophages.
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PMID:Inflammatory mediators in chronic inflammatory bowel diseases. 179 95

In a group of 30 human tumors, comprising 12 lung, 14 ovarian, 2 breast carcinomas, 1 hypernephroma and 1 mid-gut carcinoid, the expression of major histocompatibility complex (MHC) class I molecules and the intercellular adhesion molecule 1 (CAM-1, CD54) was found to vary independently. Some tumors expressed both or neither of these molecules. Among 9/13 ICAM-1+ tumors, in which greater than 50% cells reacted with the anti-ICAM-1 monoclonal antibody (mAb) (LB-2), the class I antigen was also detected on greater than 50% of the cells. Only 2 ICAM-1+ tumors were class-I-. In 5/17 cases the tumors were MHC-class-I+ and ICAM-1-. Lymphocytes collected from the blood or from the tumor site were assayed for recognition on the tumor cells in the auto-tumor cytotoxicity test and in mixed lymphocyte tumor cell culture (MLTC). Positive results were obtained only with the MHC-class-I+/ICAM-1+ tumors. In vitro treatment of the tumor cell suspensions with interferon gamma and tumor necrosis factor alpha (TNF alpha) induced or enhanced the ICAM-1 and/or class I antigen expression in 8/12 cases. Of the tumor samples treatged, 8/9 acquired stimulatory capacity and 3/10 became susceptible to lysis by the lymphocytes. In 6/6 MLTC performed with the cytokine-treated tumor cells, cytotoxicity against the autologous tumor was generated. Three of these MLTC lymphocytes also lysed the untreated targets. mAb directed to class I antigens or to ICAM-1 inhibited both the stimulation by and the lysis of tumor cells when confronted with fresh lymphocytes. The cytotoxicity generated in the MLTC was also inhibited. If, however, the cytotoxic function was induced in MTLC containing interleukin-2 (5 U/ml), inhibition was obtained only by pretreatment of the targets with mAb against ICAM-1. The results show thus (a) that the lymphocytes react in vitro with tumor cells only if these express both MHC class I molecules and ICAM-1; (b) that expression of these molecules can be induced by interferon alpha and TNF alpha; (c) that cytotoxic effectors generated in the MLTC with cytokine-treated tumors can also act on the untreated tumor cells. The requirement of the two surface moieties for the interaction with lymphocytes was also substantiated by blockade with relevant mAb.
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PMID:Expression of the adhesion molecule ICAM-1 and major histocompatibility complex class I antigens on human tumor cells is required for their interaction with autologous lymphocytes in vitro. 196 61

Endotoxins (lipopolysaccharides, LPS) are biologically active substances present in the outer membrane of gram-negative bacteria. They induce a spectrum of biological effects which may be harmful or beneficiary for the host. Lipid A is the biologically active part of the LPS molecule. This was demonstrated using soluble forms of lipid A and more recently confirmed further by employing synthetic lipid A. LPS administered into experimental animals circulates as LPS/HDL complex and is cleared from the blood mainly into the liver and spleen. In the liver LPS undergoes partial deacylation however without a loss of toxic activity. Its excretion is effected mainly via the bile into the gut. The lethal toxicity and tolerance inducing properties of LPS are mediated by macrophages through tumor necrosis factor alpha (TNF alpha), which is probably the most important endogenous mediator of the lethal effects of LPS. The lethal toxicity of LPS may be completely inhibited by anti-TNF alpha antibodies.
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PMID:Bacterial lipopolysaccharides: structure, metabolism and mechanisms of action. 210 4

Acute lung injury characterized by increased microvascular permeability is one feature of multiple-organ system failure and the adult respiratory distress syndrome. Intestinal ischemia-reperfusion injury has been linked to this type of acute lung injury. The purpose of these experiments was to examine the pathogenic mediators that link the two processes, with particular emphasis on the roles of endotoxin and tumor necrosis factor alpha (TNF alpha). Previously described characteristics of the acute lung injury in this rat model of intestinal ischemia-reperfusion include pulmonary neutrophil sequestration, depletion of lung tissue ATP, alveolar endothelial cell disruption, and increased microvascular permeability. Plasma levels of TNF in the systemic circulation of sham-operated animals and those with intestinal ischemic injury less than 60 minutes in duration were very low or undetectable. Intestinal ischemia for 120 minutes was associated with TNF elevation to 1.19 +/- 0.50 U/mL. Reperfusion for periods of 15 and 30 minutes generated 5- to 10-fold increases in circulating TNF levels (6.61 +/- 3.11 U/mL, p greater than 0.05 and 10.41 +/- 5.41 U/mL, p = 0.004 compared to sham); however this increase in circulating TNF was transient and largely cleared within 60 minutes after initiating reperfusion. Portal vein endotoxin levels were found to increase significantly before the appearance of TNF in systemic plasma, suggesting that gut-derived endotoxin may induce TNF release from hepatic macrophages into the systemic circulation. Anti-TNF antibody attenuated the increase in pulmonary microvascular permeability in this preparation but did not prevent pulmonary neutrophil sequestration. These observations suggest that endotoxin and TNF have pathogenic roles in this acute lung injury, but that mechanisms of adherence of neutrophils to endothelial cells independent of TNF may be involved. The accumulation of neutrophils in the lung but the prevention of a vascular permeability increase in the presence of antibody to TNF may imply an in vivo role for TNF in the process of neutrophil activation. These studies provide additional evidence of the importance of the endogenous inflammatory mediators in the development of systemic injury in response to local tissue injury.
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PMID:Evidence for tumor necrosis factor-induced pulmonary microvascular injury after intestinal ischemia-reperfusion injury. 217 68

The lymphatic transport of recombinant human tumor necrosis factor (rHu-TNF) was investigated after its administration via various routes in anesthetized rats. After intravenous (i.v.) administration, the level of rHu-TNF in the lymph reached a peak at 2 h, and thereafter decreased exponentially in a pattern similar to that of the elimination from plasma. Intramuscular (i.m.) and subcutaneous (s.c.) administrations resulted in low levels of rHu-TNF both in the plasma and in the lymph. On the other hand, intraperitoneal (i.p.), intra-stomach wall (s.w.) and intra-gut wall (g.w.) administrations gave high lymph levels of rHu-TNF. After the s.w., g.w. and i.p. administrations, the ratios of rHu-TNF recovered from the thoracic duct to the cumulative amount estimated from the rHu-TNF concentration in plasma were about 25, 32 and 8 times higher than in the case of i.v. administration, respectively. These results suggest that the routes of local administration of rHu-TNF such as s.w., g.w. and i.p. may be highly effective for the treatment of lymphatic metastasis of cancer.
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PMID:Lymphatic transport of recombinant human tumor necrosis factor in rats. 322 3


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