Cytokine release syndrome

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). 

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... 

Cytokine release syndrome (CRS) Temporally associated with the administration of the first few doses of muromonab-CD3 (particularly, the first 2 to 3 doses), most P.1174... 

Alegre, M.L., Vandenabeele, P., Depierreux, M., Florquin, S., Deschodt-Lanckman, M., Flamand, V., Moser, M., Leo, 0 Urbain, J. and Fiers, W. (1991) Cytokine release syndrome induced by the 145-lCll anti-CD3 monoclonal antibody in mice prevention by high doses of methylprednisolone. Journal of Immunology (Baltimore, MD, 1950), 146, 1184-1191. 

Attenuation of cytokine release syndrome in patients treated with muromonab-CD3... 

Cytokine release syndrome, ranging from a mild, self-limited, flu-like syndrome to a less-frequently reported severe, life-threatening shocklike reaction, has been associated with first few doses... 

Evidence suggests that giving 250 mg of methylprednisolone 6 hours prior and 1 hour prior to administration of muromonab-CD3 can decrease the incidence of cytokine release syndrome (CRS). Pentoxifylline has not been shown to attenuate CRS. Indomethacin, however, can be effective. 

A major side effect, a cytokine-release syndrome, is observed within 30-60 min after the administration of muromonoab-CD3. The side effect could last for several days, and is the result of increased production of several cytokines including IL-2, IL-6, TNF-a and IFN-y. TNF-a appears to be responsible for most of the discomfort, and the symptoms are more pronounced after the first administration of muromonoab-CD3. 

Daclizumab is used for the prophylaxis of acute rejection in patients receiving kidney transplants. A dose of 1 mg/kg is sufficient to completely block all the IL-2 receptors. It is administered in five doses at a 2-week interval where its elimination half-life is about 20 days. A combination of several other immunosuppressive agents including cyclosporine (or tacrolimus, rapamycin), mycophenolate mofetil and corticosteroids can be used with daclizumab. When it is used in combination with tacrolimus, the doses of tacrolimus are reduced. After tissue transplantation, the addition of daclizumab to the standard immunosuppressive regimen produces reduction in tissue rejection up to 50%. Daclizumab can cause hypersensitivity reactions, but it does not cause cytokine-release syndrome. There is a low incidence of... 

Additional preclinical data to address potential for specific adverse events, such as cytokine release syndrome, may be required in some cases. 

Winkler U, Jensen M, Manzke O, Schulz H, Diehl V, Engert A. Cytokine-release syndrome in patients with B-cell chronic lymphocytic leukemia and high lymphocyte counts after treatment with an anti-CD20 monoclonal antibody (rituximab, IDEC-C2B8). Blood 1999 94(7) 2217-24. 

Wing MG, Waldmann H, Isaacs J, Compston DAS, Hale G. Ex-vivo whole blood cultures for predicting cytokine-release syndrome dependence on target antigen and antibody isotype. Ther Immunol 1995 2 183-90. 

Wing MG, Moreau T, Greenwood J, Smith RM, Hale G, Isaacs J, Waldmann H, Lachmann PJ, Compston A. Mechanism of first-dose cytokine-release syndrome by CAMPATH 1-H involvement of CD16 (Fc-yRIII) and CDlla/CD18 (LFA-1) on NK cells. J Clin Invest 1996 98 2819-26. 

Compared with placebo, basiliximab was not associated with any specific adverse effects in early studies (3). However, severe h)rpersensitivity reactions can occur and can be associated with the cytokine release syndrome. 

Basiliximab is composed of murine sequences (30%), which can cause IgE-mediated hypersensitivity reactions. Important warnings have been released by the manufacturers regarding the possible risk of severe hypersensitivity reactions within 24 hours of initial exposure or after re-exposure after several months, based on 17 reports that included cardiac and/or respiratory failure, bronchospasm, urticaria, cytokine release syndrome, and capillary leak syndrome. 

A complex of acute systemic symptoms referred to as the cytokine-release syndrome is the most typical adverse effect of muromonab (3). A flu-like reaction is the key component of this complex syndrome, including fever, chills, headache, myalgia, tachycardia, and gastrointestinal symptoms. Other systemic and severe manifestations of the syndrome include acute pulmonary edema and... 

Several humanized CD3 antibodies have been produced and tested, with the aim of reducing the adverse effects associated with the murine orthoclone antibody. The first results in renal transplant patients were encouraging, with promising clinical results, no evidence of antiglobulin response, and no or very few and minimal adverse effects attributable to various humanized monoclonal CD3 antibodies (16,17). In particular, careful patient monitoring failed to identify any significant cytokine release syndrome. 

Cardiovascular manifestations are usually observed during the cytokine-release syndrome. They mostly included tachycardia and transient hypertension or hypotension (4). Fluid overload or volume depletion can also play a role. Chest pain or severe dysrhythmias are infrequent (18). 

Antimuromonab IgE antibodies have been identified after 10-25 days of treatment in six of 181 patients, and only in those with high titers of antimuromonab IgG antibodies (34). Immediate IgE-mediated anaphylactic reactions, namely anaphylactic shock, bronchospasm, urticaria, have been rarely reported and have sometimes been difficult to differentiate from the cytokine-release syndrome (35,36). Late-onset reactions after the first week of treatment, including cutaneous erythema, a fall in blood pressure, or serum sickness-hke reactions, are infrequent (37). 

Jeyarajah DR, Thistlethwaite JR Jr. General aspects of cytokine-release syndrome timing and incidence of symptoms. Transplant Proc 1993 25(2 Suppl l) 16-20. 

Vasquez EM, Fabrega AJ, Poliak R. OKT3-induced cytokine-release syndrome occurrence beyond the second dose and association with rejection severity. Transplant Proc 1995 27(1) 873. ... 

Chatenoud L. OKT3-induced cytokine-release syndrome prevention effect of anti-tumor necrosis factor monoclonal antibody. Transplant Proc 1993 25(2 Suppl 1) 47-51. 

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