Cytokine release

Inhibition of immunomodulatory cytokines (Fig. 1) Anti-T-cell receptor antibodies Muromonab (OKT3, Orthoclone ) binds to the CD3 complex of the T-cell receptor and induces depletion of T-lymphocytes. It is applied to prevent acute rejection of kidney, liver, and heart allografts. Rapid side effects (within 30-60 min) include a cytokine release syndrome with fever, flu-like symptoms, and shock. Late side effects include an increased risk of viral and bacterial infections and an increased incidence of lymphproliferative diseases due to immunosuppression. 

Treatment with specific antibodies (ALG, ATG, anti-CD3, anti-CD25) is indicated during the induction phase after transplantation and in the case of acute rejection for short time periods. Therapy with nonhuman antibodies may cause sensitization. Muromonab-CD3 might initiate a cytokine release syndrome (fever, chills, headache). 

Genes involved in the uptake and degradation of tocopherols - Genes implicated with lipid uptake and. Mi / °f J - Protein kinase C (PKC) - Cyclooxygenase - 5-Lipoxygenase - Cytokine release (IL-1P)... 

Attaching some short peptidic sequences to adamantane makes it possible to design novel antagonists. The bradykinin antagonist, which is used as an anticancer agent, is an example. The adamantane-based peptidic bradykinin analog was utilized in strucmre-activity relationship (SAR) studies on the bradykinin receptors and showed a potent activity in inhibition of bradykinin-induced cytokine release and stimulation of histamine release [142]. 

At cellular level each stage of atheroma development is accompanied by the expression of specific glycoproteins by endothelial cells which mediate the adhesion of monocytes and T-lymphocytes. Their recruitment and migration is triggered by various cytokines released by leukocytes and possibly by smooth muscle cells. Atheroma development continues with the activation of macrophages, which accumulate lipids and become, together with lymphocytes, so-called fatty streaks. The continuous influx, differentiation and proliferation finally leads to more advanced lesion and to the formation of the fibrous plaque. ... 

T cells control these learned responses and decide which tools to use in the reaction. Sometimes they choose several different tools at once, and multiple reactions ensue, such as when a person becomes sensitized to penicillin and has not only anaphylaxis but hemolytic anemia and serum sickness. There are different types of T cells, and they communicate either directly with other cells or by chemical messages called cytokines. The pattern of cytokines released is one way T cells have of determining which kind of response will occur. They are broadly called Thl andTh2 responses, with Thl mostly responding to infections and Th2 often producing allergy or asthma. 

After T cell lysis, there is a cytokine release. Owing to this phenomenon, ATG is associated with several adverse reactions.7,8,11 The most common include fever (63%), chills (43%), headache (35%), back pain (43%), nausea (28%), diarrhea (32%), dizziness (25%), malaise (4%), and myelosuppression [leukopenia (30%) and thrombocytopenia (44%)]. Overall incidence of opportunistic infections is 27%, with cytomegalovirus (CMV) disease occurring in 11% of patients.7,8,11... 

Owing to its ability to cause widespread T cell lysis after the first dose, OKT-3 has several severe adverse effects that manifest within 3 hours after administration.10,11,14 These adverse reactions often are referred to as the first-dose effect and usually are secondary to cytokine release. The adverse-reaction profile of OKT-3 includes fever (77%), chills (43%), dyspnea (16%), nausea (32%), vomiting (25%), diarrhea (37%), and tachycardia (26%). One of the major complications of OKT-3 is the development of severe pulmonary edema.11,15,16 In reported cases of this complication, patients were fluid overloaded at the time of the initial dose. Another problematic adverse reaction is the development of nephropathy.11,17... 

Azelastine Hrreceptor antagonist, mast cell stabilizer May inhibit cytokine release... 

In endotoxinemic mice IL-10 treatment inhibits proinflammatory cytokine release and leads to a reduction in LPS toxicity (G8, H28). IL-10 does not influence the LPS-induced production of IL-6 in vivo (M9). This suggests that IL-10 could differentially regulate TNF and IL-6 production by macrophages in vivo, in contrast to data obtained in vitro (Wl), or that cell types other than macrophages are a major source of IL-6 in vivo and are resistant to IL-10 (S23). 

Bogdan, C., Paik, J., Vodovotz, Y. and Nathan, C. (1992) Contrasting mechanisms for suppression of macrophage cytokine release by transforming growth factor-beta and interleukin-10. Journal of Biological Chemistry 267, 23301-23308. 

From 4 to 8 hours after the initial exposure to an allergen, a late-phase reaction may occur, which is thought to be due to cytokines released primarily by mast cells and thymus-derived helper lymphocytes. This inflammatory response likely is responsible for persistent, chronic symptoms including nasal congestion. 

Theophylline appears to produce bronchodilation by inhibiting phosphodiesterases, which may also result in antiinflammatory and other nonbronchodilator activity through decreased mast cell mediator release, decreased eosinophil basic protein release, decreased T-lymphocyte proliferation, decreased T-cell cytokine release, and decreased plasma exudation. 

Pacifici R, Brown C, Puscheck E, Friedrich E, Slatopolsky E, Maggio D, McCracken R, Avioli LV (1991) Effect of surgical menopause and estrogen replacement on cytokine release from human blood mononuclear cells. Proc Nad Acad Sci USA 88 5134-5138... 

Langezaal, I. et al., Evaluation and prevalidation of an immunotoxicity test based on human whole-blood cytokine release, Altern. LabAnim., 30, 581, 2002. 

Stimulation for 24 hours with LPS leads to the release of interleukin-1 [3, IL-6, IL-8, TNF-a and by prolonging the incubation period from 48 to 72 hours, the whole blood model can detect the release of other lymphokines [45], including IL-2, IL-4, IL-13 and IFN-y. Skewing of the T-helper cell response to antigens can likewise be detected by evaluating the pattern of cytokine release, corresponding to a predominance of Th 1 or Th2 cytokine production. The predictive value of these approaches is currently under investigation. 

House, D. et al., Cytokine release by lipopolysaccharide-stimulated whole blood from patients with typhoid fever, J. Infect. Dis., 186, 240, 2002. 

Heagy, W. et al., Lower levels of whole blood LPS-stimulated cytokine release are associated with poorer clinical outcomes in surgical ICU patients, Surg. Infect (Larchmt.), 4, 171, 2003. 

CD8+CD69+ T cells was not observed in vivo. NK cells appeared to increase during the recovery period and an expansion of B cells was observed that persisted longer than that observed for T cells in individual animals. Transient, moderate elevations of serum IL-2, IL-5 (anti-inflammatory TH2-type cytokine), and IL-6 (inflammatory cytokine) was observed in individual animals at 2 or 24 hours following the initial dose but were not observed on Days 17 or 62 no changes in TNFa or IFNy (major pro-inflammatory cytokines) were observed. Thus, TGN1412 did not appear to be associated with a cytokine-release syndrome that has been observed in humans with upon administration of agonistic anti-CD3 antibodies.78... 

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