A pilot study to evaluate the effects of C1 esterase inhibitor on the toxicity of high-dose interleukin 2

Ogilvie, A. C.; Baars, Johanna W.; Eerenberg, A. J. M.; Hack, C. E.; Pinedo, H.M.; Thijs, L. G.; Wagstaff, John

doi:10.1038/bjc.1994.109

Cited by 23 publications

(5 citation statements)

References 10 publications

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“…One study suggested that the C1 inhibitor-mediated effect was independent of inhibition of classical pathway activation; a role for inhibition of lectin pathway activation was not examined (De Simoni et al, 2004b). In addition, limited experience in human disease suggests that C1 inhibitor may prove to be a useful addition to therapy of diseases including vascular leak syndromes, sepsis, and shock syndromes (Bauernschmitt et al, 1998;Bauernschmitt et al, 2000;de Zwaan et al, 2002;Hack et al, 1993;Hack et al, 1994;Niederau et al, 1995;Ogilvie et al, 1994;Tassani et al, 2001) (Table 1). Two studies have suggested a beneficial effect in humans with ischemiareperfusion injury (Bauernschmitt et al, 1998;de Zwaan et al, 2002).…”

Section: Introductionmentioning

confidence: 99%

C1 inhibitor: Biologic activities that are independent of protease inhibition

Davis

Cai

2007

Immunobiology

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C1 inhibitor therapy improves outcome in several animal models of inflammatory disease. These include sepsis and gram negative endotoxin shock, vascular leak syndromes, hyperacute transplant rejection, and ischemia-reperfusion injury. Furthermore, some data suggest a beneficial effect in human inflammatory disease. In many inflammatory conditions, complement system activation plays a role in pathogenesis. The contact system also very likely is involved in mediation of damage in inflammatory disease. Therefore, the beneficial effect of C1 inhibitor has been assumed to result from inhibition of one or both of these systems. Over the past several years, several other potential anti-inflammatory effects of C1 inhibitor have been described. These effects do not appear to require protease inhibition and depend on non-covalent interactions with other proteins, cell surfaces or lipids. In the first, C1 inhibitor binds to a variety of extracellular matrix components including type IV collagen, laminin, entactin and fibrinogen. The biologic role of these reactions is unclear, but they may serve to concentrate C1 inhibitor at extravascular inflammatory sites. The second is a noncovalent interaction with C3b that results in inhibition of formation of the alternative pathway C3 convertase, a function analogous to that of factor H. The third is an interaction with E and P selectins on endothelial cells that is mediated by the Lewis x tetrasaccharides that are expressed on C1 inhibitor. These interactions result in suppression of leukocyte rolling and transmigration. The fourth interaction is the binding of C1 inhibitor to gram negative bacterial endotoxin that results in suppression of endotoxin shock by interference with the interaction of endotoxin with its receptor complex on macrophages. Lastly, C1 inhibitor binds directly to gram negative bacteria, which leads to suppression of the development of sepsis, as demonstrated in the cecal ligation and puncture model. These observations suggest that C1 inhibitor is a multi-faceted anti-inflammatory protein that exerts its effects through a variety of mechanisms including both protease inhibition and several different non-covalent interactions that are unrelated to protease inhibition.

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Section: Introductionmentioning

confidence: 99%

C1 inhibitor: Biologic activities that are independent of protease inhibition

Davis

Cai

2007

Immunobiology

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“…While the levels of a negative APP (alpha2‐HS) decreased after IL‐2 treatment (similar to the changes of CRP and d ‐dimer levels), no significant differences occurred in the serum levels of other three APPs (C3, C9 and C1‐inh) belonging to the complement system. The failure of IL‐2 to increase C1‐inh concentration is an apparently important observation, as the administration of C1‐inhibitor is known to attenuate the vascular leakage syndrome induced by high doses of IL‐2 [34,35].…”

Section: Discussionmentioning

confidence: 99%

Changes in the levels of some acute-phase proteins in human immunodeficiency virus-1 infected patients, following interleukin-2 treatment

Barbai

Újhelyi

Szlávik

et al. 2010

Clinical and Experimental Immunology

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SummaryIntermittent interleukin (IL)-2 administration to human immunodeficiency virus (HIV)-1 infected patients is well documented and generally used, but there is limited information about the changes of acute-phase protein (APP) levels in response to this treatment. Fifteen patients undergoing highly active anti-retroviral therapy (HAART) treatment, with undetectable viral load, but low CD4+ cell count (<300/ml), have been treated with 3·6 M IU Proleukine® administered twice daily by subcutaneous injection over 5 days. C-reactive protein (CRP), d-dimer, C3, C9, C1-inh and alpha-2HS glycoprotein levels were measured immediately before IL-2 administration, as well as on day 5 and 2-3 weeks thereafter. After IL-2 administration, both mean d-dimer and CRP levels increased significantly (P < 0·001), but returned (P < 0·001) to baseline within the subsequent 2-3 weeks. Alpha-2HS glycoprotein decreased immediately after IL-2 administration. No significant differences were detected in the levels of C3, C9 and C1-inh. A significant, positive correlation (r = 0·5178, P = 0·0008) was ascertained between the changes of CRP level, measured immediately before as well as 5 days after IL-2 administration, and changes in CD4 T cell counts measured 2-3 weeks before and after treatment, respectively. IL-2 administration induces rapid elevation of two major APPs (CRP, d-dimer). The positive correlation observed between the changes of CRP levels and CD4+ cell counts after IL-2 administration may indicate that the abrupt, but transitory overproduction of CRP might contribute to the CD4 + cell count-increasing effect of the drug and/ or may be associated with serious side effects.

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“…Vascular leakage syndrome induced by IL-2 or after bone marrow transplantation has been suggested to result from an activation of inflammatory mediator systems, such as cytokines, neutrophils, and the complement and contact phase systems (8). Administration of C1 inhibitor inhibited the classical complement pathway and improved the clinical picture of vascular leakage syndrome (31,32,34). Hence, the beneficial, although mild, effect of C1 inhibitor on organ dysfunction in the patients included in this study (9) may be mediated via its action on PMN.…”

Section: Discussionmentioning

confidence: 99%

Administration of C1 Inhibitor Reduces Neutrophil Activation in Patients with Sepsis

Zeerleder

Caliezi

Mierlo

et al. 2003

Clin Vaccine Immunol

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Forty patients with severe sepsis or septic shock recently received C1 inhibitor. In the present study we studied the effect of C1 inhibitor therapy on circulating elastase-␣ 1 -antitrypsin complex (EA) and lactoferrin (LF) levels in these patients to gain further insight about agonists involved in the activation of neutrophils in human sepsis. Elevated levels of EA and LF were found in 65 and 85% of the septic patients, respectively. Patients with elevated EA levels had higher organ dysfunction scores, higher levels of cytokines, and higher levels of complement activation products than patients with normal EA levels. C1 inhibitor therapy reduced EA as well as complement activation and IL-8 release in the patients with elevated EA on admission. We conclude that neutrophil activation in human sepsis correlates with the severity of organ dysfunction and involves complement and interleukin-8 as agonists. The effect of C1 inhibitor therapy on neutrophils may provide an explanation for the beneficial, although mild, effects of this treatment on organ dysfunction in sepsis.

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A pilot study to evaluate the effects of C1 esterase inhibitor on the toxicity of high-dose interleukin 2

Cited by 23 publications

References 10 publications

C1 inhibitor: Biologic activities that are independent of protease inhibition

C1 inhibitor: Biologic activities that are independent of protease inhibition

Changes in the levels of some acute-phase proteins in human immunodeficiency virus-1 infected patients, following interleukin-2 treatment

Administration of C1 Inhibitor Reduces Neutrophil Activation in Patients with Sepsis

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