Cytokine syndrome

IL-2 has been evaluated therapeutically as an enhancer of the immune system in the treatment of both eancer and infectious diseases. When a high dose of IL-2 is administered over a 3- to 5-day period, severe systemic toxicity, termed cytokine syndrome, is observed. However, this therapy does provide an antitumor response by an unestablished mechanism in 15% of treated patients (401). 

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). 

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Hypoperfusion of skeletal muscles leads to fatigue, weakness, and exercise intolerance. Decreased perfusion of the central nervous system (CNS) is related to confusion, hallucinations, insomnia, and lethargy. Peripheral vasoconstriction due to SNS activity causes pallor, cool extremities, and cyanosis of the digits. Tachycardia is also common in these patients and may reflect increased SNS activity. Patients will often exhibit polyuria and nocturia. Polyuria is a result of increased release of natriuretic peptides caused by volume overload. Nocturia occurs due to increased renal perfusion as a consequence of reduced SNS renal vasoconstrictive effects at night. In chronic severe HF, unintentional weight loss can occur which leads to a syndrome of cardiac cachexia. This results from several factors, including loss of appetite, malabsorption due to gastrointestinal edema, elevated metabolic rate, and elevated levels of proinflammatory cytokines. 

Cl 2, Casey, L. C., Balk, R. A., and Bone, R, C., Plasma cytokine and endotoxin levels correlate with survival in patients with the sepsis syndrome. Ann. Intent. Med. 119,771-778 (1993). 

G3. Gando, S., Kameue, T., Nanzaki, S and Nakanishi, Y., Cytokines, soluble thrombomodulin and disseminated intravascular coagulation in patients with systemic inflammatory response syndrome. Thomb. Res. 80,519-526 (1995). 

Compensatory physiologic response to systemic inflammatory response syndrome that is considered secondary to the actions of antiinflammatory cytokine mediators. 

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... 

Priliximab (cM-T412) is an anti-CD4 chimeric monoclonal antibody that was evaluated in the clinic for the treatment of autoimmune diseases. Priliximab binds to CD4 on the surface of T cells and leads to a profound and sustained decrease in circulating CD4+ T cells decreased counts have been reported to be below normal levels at 18 and 30 months following single- and multiple-infusions.81 Similar findings were observed in preclinical studies in chimpanzees.82 The administration of priliximab was also associated with a cytokine-release syndrome that caused transient fever, myalgia, chills, headache, nausea, and/or hypotension that was accompanied by an increase in serum IL-6. Although evidence of efficacy was observed in clinical trials for CD, the... 

The anticonvulsant phenytoin, and to a lesser degree carbamazepine, can inhibit the synthesis of antibodies, and in some cases these drugs can result in lymphoproliferation [77-79]. These effects on the immune system could be viewed as a type of autoimmunity. The relationship between such effects and autoimmunity are still not clear, although the more recent observations that cytokines and anti-cytokines can cause autoimmunity support the existence of such a relationship. The previous edition of this book contained an extensive discussion of the possible relationship between immunosuppression and autoimmunity [80], Phenytoin and carbamazepine can also cause a lupus-like syndrome although the incidence is lower than with many other drugs. 

Azuma, M. et al., Role of cytokines in the destruction of acinar structure in Sjogren s syndrome salivary glands, Lab. Invest., 77, 269,1997. 

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