Effect of various forms of the C1 esterase inhibitor (C1‐INH) and DAF on complement mediated xenogeneic cell lysis

Fukuta, Daisuke; Miyagawa, Shuji; Yamada, Mako; Matsunami, Katsuyoshi; Kurihara, Takashi; Shirasu, Akio; Hattori, Hiroyuki; Shirakura, R

doi:10.1034/j.1399-3089.2003.01120.x

Cited by 18 publications

(9 citation statements)

References 45 publications

(49 reference statements)

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“…Soluble C1 inhibitor inhibited the activation of porcine aortic endothelial cells incubated with human serum (Dalmasso and Platt, 1993). Surface bound C1 inhibitor also was shown to protect Chinese hamster ovary cells and pig endothelial cells from lysis by human complement (Fukuta et al, 2003; Matsunami et al, 2000). Ex vivo perfusion of pig kidneys with human blood plus additional C1 inhibitor prolonged survival by greater than four fold (Fiane et al, 1999).…”

Section: C1 Inhibitor-mediated Modulation Of Inflammatory Diseasementioning

confidence: 99%

Biological activities of C1 inhibitor

Davis

Mejia

2008

Molecular Immunology

261

202

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Broadly speaking, C1 inhibitor plays important roles in the regulation of vascular permeability and in the suppression of inflammation. Vascular permeability control is exerted largely through inhibition of two of the proteases involved in the generation of bradykinin, factor XIIa and plasma kallikrein (the plasma kallikrein-kinin system). Anti-inflammatory functions, however, are exerted via several activities including inhibition of complement system proteases (C1r, C1s, MASP2) and the plasma kallikrein-kinin system proteases, in addition to interactions with a number of different proteins, cells and infectious agents. These more recently described, as yet incompletely characterized, activities serve several potential functions, including concentration of C1 inhibitor at sites of inflammation, inhibition of alternative complement pathway activation, inhibition of the biologic activities of gram negative endotoxin, enhancement of bacterial phagocytosis and killing, and suppression of the influx of leukocytes into a site of inflammation. C1 inhibitor has been shown to be therapeutically useful in a variety of animal models of inflammatory diseases, including gram negative bacterial sepsis and endotoxin shock, suppression of hyperacute transplant rejection, and treatment of a variety of ischemia-reperfusion injuries (heart, intestine, skeletal muscle, liver, brain). In humans, early data appear particularly promising in myocardial reperfusion injury. The mechanism (or mechanisms) of the effect of C1 inhibitor in these conditions is (are) not completely clear, but involve inhibition of complement and contact system activation, in addition to variable contributions from other C1 inhibitor activities that do not involve protease inhibition.

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Section: C1 Inhibitor-mediated Modulation Of Inflammatory Diseasementioning

confidence: 99%

Biological activities of C1 inhibitor

Davis

Mejia

2008

Molecular Immunology

261

202

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“…The molecule is an approximately 140 kDa glycoprotein and belongs to the superfamily of serine‐protease inhibitors (serpin). The reactive site of C1‐INH is located around the R444‐T445 region, and the first 98 amino acids, which are rich in N ‐linked sugars, do not play a role in the interaction of the inhibitor with target proteases [89,90]. C1‐INH represents the only known inhibitor in plasma which is capable of inactivating C1r & C1s and MASP‐1 & MASP‐2, and then plays an important role in the regulation of the classical and lectin pathway complement activation cascades [91].…”

Section: Attempts To Prepare Suitable Complement Regulatory Moleculesmentioning

confidence: 99%

Complement regulation in the GalT KO era

Miyagawa

Yamamoto

Matsunami

et al. 2010

Xenotransplantation

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A number of institutes have reported on the successful production of alpha-galactosyltransferase knockout (GalT-KO) pigs. After producing such pigs, hyperacute rejection appeared to no longer be a problem. However, acute vascular rejection (AVR)/acute humoral xenograft rejection (AHXR) is defined as a rejection that begins within 24 h after transplantation and gradually destroys the graft. The origin of AVR/AHXR continues to be a controversial topic, but is generally thought to be initiated by xeno-reactive antibodies, including non-Gal antibodies and subsequent activation of the graft endothelium, the complement and the coagulation systems. The complement is activated via the classical pathway by non-Gal antigens and ischemia-reperfusion injury, via the alternative pathway, especially on islets, and via the lectin pathway. Therefore the complement system is still an important recognition and effector mechanism of AVR/AHXR. In addition, quite recently, based on the relationship between complement and coagulation systems, a new pathway has been proposed. All complement regulatory proteins (CRPs) have the ability to regulate complement activation in different ways. Therefore, to effectively protect xenografts against AVR/AHXR, it appears reasonable to employ not only one but several CRPs including anti-complement drugs. Non-Gal antigens, such as the Hanganutziu-Deicher antigen, is still present on GalT-KO grafts. The further assessment of antigens continues to be an important issue in the area of clinical xenotransplantation. The above conclusions suggest that the expression of human CRPs on GalT-KO grafts is necessary. Moreover, multilateral inhibition of complement activation is required in conjunction with the regulation of the coagulation system.

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“…Treatment with C1 inhibitor improves outcome in a number of animal models of inflammatory disease including gram negative bacterial sepsis and endotoxin shock, vascular leak syndromes, hyperacute transplant rejection, and ischemia-reperfusion injury (Akita et al, 2003;Buerke et al, 1995;Buerke et al, 1998;Dalmasso and Platt, 1993;De Simoni et al, 2003;De Simoni et al, 2004a;Fiane et al, 1999;Fukuta et al, 2003;Giebler et al, 1999;Guerrero et al, 1993;Hecker et al, 2002;Henze et al, 1997;Horstick et al, 1997;Horstick et al, 2001a;Jansen et al, 1998;Khorram-Sefat et al, 1998;Matsunami et al, 2000;Nielsen et al, 2002;Przemeck et al, 2002;Radke et al, 2000;Schelzig et al, 2001;Scherer et al, 1996;Schmidt et al, 1999a;Schmidt et al, 1999b) (Table 1). For example, in myocardial ischemia-reperfusion injury, treatment with C1 inhibitor resulted in decreased infarct size, decreased myocardial neutrophil accumulation, decreased plasma levels of creatine kinase, C3a and C5a, and decreased expression of P-selectin and ICAM-1 within the cardiac endothelium (Buerke et al, 1995;Buerke et al, 1998;Horstick et al, 1997;Horstick 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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Effect of various forms of the C1 esterase inhibitor (C1‐INH) and DAF on complement mediated xenogeneic cell lysis

Cited by 18 publications

References 45 publications

Biological activities of C1 inhibitor

Biological activities of C1 inhibitor

Complement regulation in the GalT KO era

C1 inhibitor: Biologic activities that are independent of protease inhibition

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