Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0243026 (sepsis)
 52,417 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Although hemorrhage depresses splenocyte (SPL) functions and increases susceptibility to sepsis, it is not known whether increased tumor necrosis factor (TNF) or prostaglandin (PG) production are responsible for it. To study this, mice (C3H/HeN) were bled to a mean blood pressure of 35 mm Hg, maintained at that pressure for 60 min, resuscitated, and treated with ibuprofen (1.0 mg/kg body weight) or vehicle (saline). Hemorrhage reduced (P less than 0.05) SPL proliferation by 60%, SPL release of interleukin-2 (IL-2) by 47%, interferon-gamma (IFN-gamma) by 67%, TNF by 54%, and interleukin-6 (IL-6) by 46% compared to sham. In addition, splenic macrophage (sM phi) release of interleukin-1 (IL-1) and TNF was decreased by 58 and 67% (P less than 0.05), respectively. However, ibuprofen treatment increased (P less than 0.05) SPL proliferation, lymphokine (IL-2, IFN-gamma, and IL-6) synthesis, and IL-1 release by sM phi compared to hemorrhage alone. Furthermore, ibuprofen enhanced the release of TNF by SPL (+175%, P less than 0.05) and sM phi (+68%) compared to the vehicle group. Ibuprofen also decreased (P = 0.011) the susceptibility to sepsis following hemorrhage. These results indicate that PGs are involved in hemorrhage-induced suppression of cellular immunity and in the increased mortality of such animals following a septic challenge.
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PMID:Ibuprofen restores cellular immunity and decreases susceptibility to sepsis following hemorrhage. 140 92

The presence of increased levels of suppressor T cells after thermal injury and their relevance remain controversial. It is unclear whether suppressor T cells are the cause or result of sepsis complicating thermal injury. Spleen cells from a standardized murine burn model and sham burn controls were studied and the relationship between the levels of suppressor cytotoxic T cells (CD8, Lyt-2+), helper T cells (CD4, L3T4+), response to concanavalin A (ConA) and to phytohemagglutinin (PHA) and interleukin-2 (IL-2) production was examined. Mortality following infection via cecal ligation and puncture (CLP) of matched controls was also studied. At day 7 postburn, mean ConA (70 +/- 12% of control) and PHA response (58% +/- 5.2% of controls) and IL-2 production (43% +/- 5.4%) were significantly less than sham burn values (100%; p less than 0.05). However, the mean percentage of cells staining with anti-Lyt-2 and anti-L3T4 (9.1 +/- 0.59 and 13.9 +/- 0.65) was similar to the mean percentage in sham burn animals (9.4 +/- 0.65 and 16.6 +/- 1.1). Furthermore, no significant differences were observed between burned mice and controls in helper (17.3% +/- 1.8% burn vs. 21.2% +/- 1.7% sham) or suppressor cell levels (7.8% +/- 1.2% burn vs. 8.6% +/- 0.7% sham) or helper-suppressor ratios on day 10 postburn. Mortality of 20 litter-matched controls subjected to CLP on day 10 postburn was 90%, which was significantly greater than the sham burn mortality of 20%.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Suppressor T-cell levels are unreliable indicators of the impaired immune response following thermal injury. 153 80

Unusual gram positive bacteremia has been reported in non granulopenic patients receiving recombinant human interleukin-2 (IL-2) suggesting a beneficial effect of anti gram positive prophylaxis in such patients. We report here studies on granulocyte functions examined during the course of high dose IL-2 therapy (16 to 24 million IU/m2/days for 11 to 18 days) administered during a period of 35 days in 14 patients including 4 solid tumors, 5 chronic myeloid leukemias, 4 recipients of autologous bone marrow transplant (ABMT) and 1 recipient of syngeneic bone marrow transplant. Neutrophils functions were studied before IL-2 administration (d 0), after the first cycle (d 8) and after the third cycle (d 36). Nylon fiber adherence, superoxide production, random migration, phagocytosis, nitroblue tetrazolium reduction, lysozyme and elastase release were not impaired significantly throughout therapy. However N-Formyl-Methionyl-Leucyl-Phenylalanine (FMLP) stimulated chemotaxis of granulocytes, normal before therapy, was significantly impaired as early at d 8 and severely inhibited at d 36 (p less than 0.001). Three septicemia, one corynebacteria parvum septicemia and two gram-negative septicemia despite normal neutrophil counts and oxacillin or Penicillin G plus Pefloxacin prophylaxis, occurred among the 14 patients studied. Although neutrophil functions were not more depressed in transplanted patients than in the other non transplanted patients, special attention should be paid to such patients in whom delayed immune reconstitution could increase the risk of sepsis.
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PMID:Interleukin-2 induces chemotactic deficiency in patients with onco hematologic malignancies and autologous bone marrow transplantation. 166 18

Plasma samples from cancer patients undergoing immunotherapy with high-dose recombinant interleukin-2 (IL-2) were obtained over a 5-day course of treatment and assayed by radioimmunoassay or enzyme-linked immunosorbent assay for the complement degradation products, C3a, iC3b, Ba, Bb, C4d, and SC5b-9. In the majority of patients, pretreatment C3a, Ba, Bb, and SC5b-9 plasma levels were comparable with those measured in normal donor plasma. However, by the end of the 5-day treatment course, C3a levels had increased 15.6-fold. In several patients, peak concentrations of C3a were as high as those reported in patients with sepsis or burn injury. Plasma levels of alternative pathway components Ba and Bb also increased, 8.0- and 5.0-fold, respectively, during IL-2 treatment. Likewise, levels of one of the terminal complexes, SC5b-9, increased 5.0-fold and the plasma C4d and iC3b concentrations increased 4.8- and 2.9-fold, respectively, by the fifth day of treatment. To determine whether activated lymphocytes participate in IL-2-induced complement activation, peripheral blood mononuclear cells (PBMC) obtained from IL-2 recipients before and 5 days after beginning therapy were reacted with monoclonal antibodies (MoAbs) against C3c and the terminal complement complex SC5b-9. Dual-color cytofluorographic analysis showed that within the CD3(+) population, the percentage of cells binding the anti-C3c and anti-SC5b-9 MoAbs increased 6.2-fold and 5.1-fold, respectively, by day 5. The anti-C3c MoAb also bound to CD3(+) cells stimulated in vitro with IL-2 and then exposed to serum. Moreover, fluid-phase iC3b was generated from purified C3 by PBMC activated in vitro with IL-2, but not by unstimulated cells. Serum levels of C-reactive protein (CRP) are markedly elevated in patients undergoing IL-2 immunotherapy. This hepatic acute phase reactant has been shown to activate the classical pathway when bound to cell surfaces. Because levels of the classical component C4d increase markedly during IL-2 treatment, we sought to determine if CRP became bound to PBMC during IL-2 treatment and found that during therapy, the percentage of CD3(+) cells reactive with an anti-CRP MoAb increased from less than 2% to greater than 18%. When PBMC were activated with IL-2 in vitro and then exposed to exogenous CRP, greater than 20% of the CD3(+) cells reacted with the anti-CRP MoAb.(ABSTRACT TRUNCATED AT 400 WORDS)
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PMID:Complement activation in cancer patients undergoing immunotherapy with interleukin-2 (IL-2): binding of complement and C-reactive protein by IL-2-activated lymphocytes. 182 47

Patients treated with high doses of interleukin-2 (IL-2) because of cancer, develop hemodynamic and vasopermeability changes, that resemble those observed in sepsis. These patients thus provide a unique opportunity to study the early events in the development of septic shock. We analysed the changes that occurred in the contact system of coagulation in plasma from 4 patients, who together received seven 12-day cycles of high doses of IL-2. Levels of factor XII and prekallikrein during the cycles progressively fell to 50 and 30% of their initial levels, respectively, whereas significant increases in plasma factor XIIa- and kallikrein-C1-inhibitor complexes were not observed (in 3 out of 211 samples slightly increased levels of both complexes were found). The reductions in factor XII and prekallikrein were only in part due to protein leakage, since levels were still significantly lower, i.e., 80 and 50%, respectively, when corrected for albumin decreases. Levels of high molecular weight kininogen (HMWK) also decreased during IL-2 therapy, however, this decrease paralleled that of albumin. SDS-PAGE analysis of plasma HMWK did not reveal increased cleavage of this protein. The reduction of factor XII and prekallikrein, corrected for protein leakage, significantly correlated with albumin levels and inversely with daily cumulative weight gain in the patients. Thus, we demonstrate that factor XII and prekallikrein decrease during IL-2 therapy. As these decreases, already observed after 1 day treatment, were disproportional to that of albumin, a negative acute phase reactant, and correlated with signs of the vascular leak syndrome, we favor the explanation that they reflected activation rather than a decreased synthesis of the contact system proteins.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Studies on the contact system of coagulation during therapy with high doses of recombinant IL-2: implications for septic shock. 187 10

Twenty-five assessable patients with metastatic melanoma have been entered in a multicenter phase II study of two induction cycles of human recombinant interleukin-2(IL2), 18 x 10(6) IU/m2/d continuous intravenous (IV) infusion on days 1 to 5 and days 12 to 17. Dacarbazine (DTIC), 850 mg/m2 IV bolus was given on day 26. The cycle was repeated at 5 weeks. Maintenance therapy was scheduled 3 weeks after the completion of induction treatment, consisting of IL2, 18 x 10(6) IU/m2/d for 5 days alternating with DTIC, 850 mg/m2 IV every 3 weeks, for a total of 18 weeks. Six patients responded (24%); two complete and four partial. Stable disease was seen in five patients. None of the six patients with more than two sites of metastases responded. Maximum response was observed in the first 3 months of treatment. Progression-free periods of 6 months and longer were seen in the two complete responders (8 and 17+ months), in two of the four partial responders (7 and 12+ months), and in three of the five patients with stable disease (9+, 15, and 17+ months). Toxicity included fever, skin rash, fatigue, anorexia, and diarrhea in most patients. Two patients had a weight gain of more than 10%. Eight patients needed intensive care for the observation and treatment of a myocardial injury (one patient), ventricular tachycardia (one), hypotension and oliguria (four), and sepsis (two). Sequential treatment with IL2 and DTIC appears to be effective but not clearly better than could be expected of IL2 alone.
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PMID:Sequential administration of recombinant human interleukin-2 and dacarbazine in metastatic melanoma: a multicenter phase II study. 187 25

To evaluate immune cell activation in patients with melioidosis, serum samples were assayed for interferon-gamma (IFN-gamma), soluble interleukin-2 receptors (sIL-2R), and soluble CD8 protein (sCD8). Forty patients with sepsis (23 fatal cases, 17 survivors) and 13 with localized disease were studied during acute illness; 12 additional patients were studied after discharge while on maintenance antimicrobial therapy. Serum concentrations of IFN-gamma and sIL-2R were greatly elevated, but sCD8 concentrations were not. These levels increased with disease severity and were associated with fatal outcomes. Macrophage activation by high concentrations of the cytokine IFN-gamma may contribute to pathophysiology and death in septicemic patients. Both IFN-gamma and sIL-2R seem to be predictive of outcome in patients with severe melioidosis and may prove useful in detection of relapse.
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PMID:Immune cell activation in melioidosis: increased serum levels of interferon-gamma and soluble interleukin-2 receptors without change in soluble CD8 protein. 190 47

The clinical and immune modulatory effects of interleukin-2 (IL-2) and interferon (INF) alfa-2a were examined in a phase II study in patients with metastatic renal cell carcinoma (six patients) and melanoma (eight patients). Treatment consisted in IL-2 3 MU/m2 continuous infusion days 1-4 and INF alfa-2a 6 MU/m2 subcutaneously day 1 and 4, both given on alternate weeks. Tumour response was assessed after four cycles of treatment or earlier, if necessary. Patients with stable disease or response were to be continued for another nine cycles or up to disease progression. The 14 patients received a total of 60 cycles of treatment. Major toxicities (WHO Grade III/IV) were fever, capillary leak syndrome with hypotension, nausea and vomiting, erythema with pruritus, leuco- and thrombopenia and sepsis with staphylococcus aureus. Five of 14 patients (36%) developed a self limiting autoimmune thyroiditis with HLA-DR expression on thyrocytes. Long term treatment toxicity was moderate with an average weight loss of 5% and an average fall in Karnofsky index of 10% compared to baseline. No responses were seen in renal cell carcinoma, two patients with melanoma had a partial and two a minor response with a duration of 1-7 months. Serial measurements of immune modulatory parameters showed a functional response to treatment with an increase of NK- and LAK-activity during the first two cycles, followed by a plateau and decrease during the third and fourth cycles. These findings were paralleled by a successive decline in treatment induced INF gamma response. These findings suggest, that alternative weekly treatment with IL-2 and INF alfa-2a results in an exhaustion of lytic capacity of NK- and LAK-cells and an attenuation of secondary cytokine release.
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PMID:Clinical and immune modulatory effects of alternative weekly interleukin-2 and interferon alfa-2a in patients with advanced renal cell carcinoma and melanoma. 199 8

The hearts of eight patients aged 22 to 67 years (mean, 41 years) who died during or within 4 days of interleukin-2 (IL-2) based immunotherapy for treatment of renal cell carcinoma or melanoma were studied at necropsy. Death resulted from combined cardiorespiratory failure in two patients, sepsis in four patients, acute myocardial infarction in one patient, and myocarditis in one patient. Transmural left ventricular necrosis was present in one of the two patients with significant atherosclerotic coronary artery narrowing. Noninfectious myocarditis was present in five patients: the inflammatory infiltrate was lymphocytic in four and composed of a mixture of eosinophils and lymphocytes in one. Although treatment-related deaths associated with high-dose IL-2 therapy are uncommon (1.5% in 652 consecutive patients), the potential for significant myocardial ischemia or myocarditis exists, and careful monitoring for arrhythmias or myocardial failure is warranted.
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PMID:Myocarditis or acute myocardial infarction associated with interleukin-2 therapy for cancer. 220 2

The use of interleukin-2 (IL-2), either alone or in combination with lymphokine-activated killer cells, tumor infiltrating lymphocytes, or other immunotherapeutic agents has added a new list of alternatives to conventional antineoplastic regimens. Little information is available about the pathologic changes occurring in patients treated with these agents. In this study, we reviewed the necropsy materials from 19 patients, 12 men and 7 women, with a variety of malignancies including melanoma, renal cell carcinoma, gastrointestinal and pulmonary adenocarcinoma, and metastatic gastrinoma, who died after receiving IL-2-based immunotherapy. Death occurred at intervals ranging from less than 1 hour to 143 days following the last dose of therapy. All patients dying at or less than 43 days following cessation of therapy had lymphoid infiltrates of varying intensity in residual tumor. At necropsy, the major cause of death unrelated to the presence of metastatic tumor was bacterial sepsis. In addition, we found evidence of significant cardiac and pulmonary toxicity: two patients with acute myocardial infarction, one with and one without significant coronary artery disease, two cases of unexplained lymphocytic myocarditis, and one case of fatal pulmonary capillary plugging following an infusion of lymphokine-activated killer cells. Thus, not unlike other forms of therapy for cancer, IL-2-based immunotherapy does not appear to be without significant toxicity.
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PMID:Pathologic findings associated with interleukin-2-based immunotherapy for cancer: a postmortem study of 19 patients. 233 30


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