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PubMed1993

Role of the complement system in antigen-induced bronchoconstriction and changes in blood pressure in the guinea pig.

Systemic anaphylaxis involves life-threatening bronchoconstriction and a serious hypotensive response often complicated by cardiac arrhythmias. The purpose of the present study was to determine whether complement system activation is essential to the bronchoconstriction and the changes in blood pressure seen in guinea pig models of anaphylaxis. The soluble complement receptor 1 (sCR1; BRL 55730) was used to inhibit activation of the classical and alternative pathways of complement in the guinea pig, and to determine whether this inhibition prevents bronchoconstriction and changes in blood pressure induced by i.v. antigen injection in guinea pigs that are either passively or actively sensitized to the antigen ovalbumin. sCR1 at 15 mg/kg did not affect significantly either the antigen-induced bronchoconstriction or the changes in blood pressure in a guinea pig passively sensitized with immunoglobulin G antibody to ovalbumin. However, it shortened the duration of the antigen-induced increase in blood pressure and inhibited the antigen-induced decrease in circulating platelets in an actively sensitized guinea pig. Continued studies using a cumulative dose of sCR1 of 105 mg/kg administered over a 24-hr period demonstrated that sCR1 attenuated the bronchoconstrictor response and the decrease in circulating platelets and prevented the hypotension induced by antigen in an actively sensitized guinea pig. At a cumulative dose of 105 mg/kg, sCR1 did not inhibit the bronchoconstrictor or blood pressure response to either histamine or bradykinin, indicating that its attenuation of cardiovascular and respiratory reactivity is specific for complement-related processes. The anaphylactic response was accompanied by complement activation as evidenced by cleavage of the C3 molecule. In the presence of sCR1, no C3 cleavage products were detectable in the plasma. Our studies demonstrate that complement activation is an essential step in the antigen-induced bronchoconstriction and the changes in blood pressure in an actively sensitized guinea pig model of anaphylaxis. Continued studies of the differing mechanisms and mediators of anaphylaxis are of importance, and the complement system clearly warrants consideration as a source of those mediators.

Animals↗
PubMed1993

A sensitive peroxidase staining immunoblotting method for measuring total protein S in human plasma.

In plasma, protein S is found in its free form and as a complex with C4b-binding protein. After 125I-protein S was added to normal human plasma and applied to SDS-8% polyacrylamide gel electrophoresis, the autoradiogram of the gel showed only one single band at free protein S position. Applying this evidence, we have developed a peroxidase staining Western Blotting method to quantitate total protein S in human plasma which consists of sodium dodecyl sulfate polyacrylamide gel electrophoresis followed by blotting to nitrocellulose membrane and a sensitive avidin-biotinylated peroxidase staining method (ABC technique). The measurement of protein S by the immunoblotting was reproducible and the coefficient of variation was 7%. As little as 1 ng of protein S could be detected. C4b-binding protein did not affect the measurement of protein S. Compared to other immunoassays, this peroxidase staining immunoblotting method has the advantage of directly estimating the apparent molecular weight of protein of interest, eliminating nonspecific stain and having high sensitivity without using radioisotope.

Avidin↗
PubMed1996

Local inflammation caused by a monoclonal antibody that blocks the function of the rat membrane inhibitor of C3 convertase.

The participation of membrane inhibitors in C-mediated inflammation in vivo was analyzed in rats with the use of mAbs against membrane inhibitors of C. 512Ag inhibits C3 convertase of homologous rat C and rat CD59 prevents the formation of homologous membrane attack complexes. The histologic distributions of 512Ag and CD59 in rat skin were essentially the same. However, although intracutaneous administration of mAb against 512Ag (anti-512Ag) in the form of F(ab')2 induced a remarkable inflammatory response visualized by exudation of Evans blue that had been previously injected i.v., the mAb against CD59 caused no inflammatory exudate. Furthermore, anti-512Ag F(ab')2 caused deposition of C3 followed by intense polymorphonuclear leukocyte infiltration and hemorrhage at the injection sites within 24 h. This reaction was completely abrogated by depletion of C. Therefore, spontaneous C activation on self cell membranes requires amplification at the C3 convertase step, which is restricted by membrane inhibitors such as 512Ag, thus preventing inflammation. A type II allergic response might preferentially occur at sites that exhibit an impairment of membrane inhibitor(s) of C3 convertase. However, although depletion of leukocytes by preadministration of cyclophosphamide did not reduce C3 deposition by anti-512Ag. Evans blue exudation was appreciably reduced, indicating that infiltrated leukocytes play a role in enhancing and prolonging inflammation initiated by local C activation.

Animals↗
PubMed1996

Expression of CD46, CD55, and CD59 on renal tumor cell lines and their role in preventing complement-mediated tumor cell lysis.

Nucleated cells are protected from complement-mediated injury by the expression of membrane-bound regulators of complement activation (mRCA) CD46, CD55, and CD59. Increased expression of these mRCA may be a mechanism by which tumor cells protect themselves from complement-mediated injury and prevent an inflammatory response. In the present study, we have investigated whether human renal tumor cell lines and cultured proximal tubular epithelial cells express CD46, CD55, and CD59 and whether these mRCA influence complement-mediated lysis of these cells. The expression of CD46, CD55, and CD59 was measured by flow cytometry. To determine the effect of mRCA on lysis, tumor cells were opsonized with complement activating anti-HLA class l mAb. Lysis was measured in the presence or absence of anti-CD46, anti-CD55 or anti-CD59 mAb and serum as a source of complement, using a 51Cr release assay. Flow cytometric analysis revealed that renal tumor cell lines and proximal tubular epithelial cells all express CD46, CD55, and CD59. Lysis of renal tumor cell lines in the presence of rabbit serum depended on the number of HLA class I molecules expressed by the tumor cells. Using human serum, complement-mediated lysis was decreased by at least one-third as compared with rabbit serum. The susceptibility of renal tumor cells for complement-mediated lysis could be increased up to the level observed with rabbit serum by inhibiting the function of CD59. Inhibition of the function of CD46 or CD55 with mAb directed against these mRCA had no substantial effect on lysis. We conclude from this work that renal tumor cells and proximal tubular epithelial cells express CD46, CD55, and CD59. Of these mRCA, CD59 is most efficient in preventing complement-mediated lysis of these cells. Expression of mRCA on tumor cells may influence the effectiveness of immunotherapy with tumor-associated mAb.

Amino Acid Sequence↗
PubMed1996

In vitro anti-complementary activity of flavonoids from olive (Olea europaea L.) leaves.

From extracts of olive (Olea europaea L., Oleaceae) leaves showing anti-complementary activity, the flavonoids apigenin, apigenin-4'-O-rhamnosylglucoside, apigenin-7-O-glucoside, luteolin, luteolin-4'-O-glucoside, luteolin-7-O-glucoside, chrysoeriol, chrysoeriol-7-O-glucoside and quercetin-3-O-rhamnoside were isolated. Major isolated constituents strongly inhibited the classical pathway of the complement system.

Complement Inactivator Proteins↗
PubMed1996

Effects of complement inhibition with soluble complement receptor-1 on vascular injury and inflammation during renal allograft rejection in the rat.

Complement is both an effector of the humoral immune response and a stimulator of leukocyte activation. To examine the influence of complement on the allograft response, we inhibited complement using recombinant human soluble complement receptor-1 (sCR1; TP10), in an unsensitized model of rat renal allograft rejection. Lewis to DA renal transplant recipients were treated daily with 25 mg/kg sCR1 or saline and sacrificed on days 1 to 5 after transplant. Transplanted organs were examined histologically and immunohistochemically for leukocyte subset markers and for the third component of complement, C3, and membrane attack complex deposition. A second set of recipients was followed from day 5 to day 9 to assess graft survival. sCR1-treated recipients displayed > 90% inhibition of plasma complement activity and a marked reduction in tissue C3 and membrane attack complex deposition. Inactivation of complement reduced the vascular injury such that there was almost complete sparing of vascular damage in day 5 sCR1-treated rats. There was a significant reduction in infiltrating leukocytes by day 5 after transplant, and complement inhibition delayed the time to reach a histologically defined end point of graft survival from 5 days in controls to 9 days in the sCR1-treated group. These results imply that the vascular and cell-mediated injury arises, in part, from complement activation. The partial inhibition of these injuries by sCR1 may have functional implications for strategies to inhibit allograft rejection.

Acute Disease↗
PubMedDate not supplied

Anticomplement activity of lysine complexes of propolis phenolic constituents and their synthetic analogs.

Several phenolic constituents of propolis and their synthetic analogs were derivatized with L-lysine. The ability of these complexes to alter complement activity was estimated in vitro in human serum. The influence of selected complexes on C3 hemolytic activity via classical pathway (CP) and alternative pathway (AP) and on zymosan-induced AP activation was determined. The results suppose that the anticomplement effect of the complexes might be related to the interaction with C3 complement component.

Complement Inactivator Proteins↗
PubMed1997

Role of complement in acute tubulointerstitial injury of rats with aminonucleoside nephrosis.

The present work was designed to elucidate the in vivo role of complement in the proteinuria-associated tubulointerstitial injury. Rats were intravenously injected with puromycin aminonucleoside, and massive proteinuria was observed within 5 days. Prominent tubulointerstitial injury characterized by proximal tubular degeneration, tubular dilatation, and leukocyte infiltration were observed 7 days after injection. C3 and C5b-9 were observed in the luminal side of proximal tubular cells. Renal function, assessed by inulin and para-aminohippurate clearance, was significantly decreased. To-assess the role of complement in this model, rats were injected with either cobra venom factor or soluble recombinant human complement receptor type 1 starting at day 3. These manipulations significantly improved tubulointerstitial pathology and para-aminohippurate clearance without affecting the degree of proteinuria. Deposition of C3 and C5b-9 was not detected in the kidney of rats depleted of complement by cobra venom factor. In rats treated with soluble complement receptor, C3 was still detected in the tubules, but deposition of C5b-9 was not observed. Soluble complement receptor was detected at the site of C3 deposition and in the urine. These data strongly suggest that complement plays a pivotal role in proteinuria-associated tubulointerstitial injury and that systemic complement depletion or inhibition of complement in the tubular lumen may diminish the tubulointerstitial damage.

Animals↗
PubMed1976

Immune complexes in chronic hepatitis.

Rheumatoid factors were present in 33.2%, crioglobulins in 47.6%, and anticomplementary assay in 34.2% of cases with chronic active hepatitis. No statistically significant loss of total complement was observed, but its components especially C1 and C3, exhibited lowered titers in 48.6% and respectively 45.7% of 160 cases. The origin, significance and pathogenicity of these factors are discussed in connection with the presence and possible role of the immunologic complexes to the development of chronic liver injury.

Antigen-Antibody Complex↗
PubMed1998

A bispecific monoclonal antibody directed against both the membrane-bound complement regulator CD55 and the renal tumor-associated antigen G250 enhances C3 deposition and tumor cell lysis by complement.

Tumor cells may inhibit the induction of a complement-mediated inflammatory response through overexpression of membrane-bound regulators of complement activation. Therefore, it is of interest to determine the most efficient approach to block these membrane-bound complement regulators on tumor cells. In the present study, we first generated a bispecific mAb directed against both CD55, using the functional blocking mAb MBC1, and the highly expressed HLA class I molecule as a model for a tumor-associated Ag, using the mAb W6/32. Tumor cells opsonized with bispecific mAb W6/32*MBC1, then exposed to complement and subsequently stained for C3 deposition, were assessed by flow cytometric analysis. We found that opsonization with W6/32*MBC1 resulted in a 92% enhancement of C3 deposition on renal tumor cells as compared with opsonization with W6/32 alone and a 17% enhancement of the C3 deposition as compared with incubation with a mixture of both parental mAb. Based on these results, we developed a bispecific mAb recognizing both CD55 and the relatively low expressed renal tumor-associated Ag G250. Increasing concentrations of the bispecific mAb G250*MBC1 resulted in a 25 to 400% increase in C3 deposition on renal tumor cells as compared with C3 deposition in the presence of the parental mAb G250 alone. G250*MBC1 enhanced C3 deposition by 21% in comparison with a mixture of both parentals. Furthermore, opsonization of tumor cells with G250*MBC1 rendered these cells more sensitive to complement-mediated lysis. In conclusion, the bispecific mAb G250*MBC1 induces deposition of C3 and tumor cell lysis more efficiently than G250 alone.

Antibodies, Bispecific↗
PubMed1998

Therapeutic inhibition of the complement system.

The use of powerful methodologies in molecular biology, biochemistry, and physiology in the last 2 decades had led to impressive progress in our understanding of the mechanisms of complement activation and its role as either a protective or a pathogenic factor in human disease. With respect to disease pathogenesis, the complexity of the complement cascade provides opportunities for several different therapeutic targets within the complement pathways. More than a century after complement was first described, we are about to witness in the near future the availability of a variety of complement inhibitors for specific therapies. Progress in the area of xenotransplantation has been substantial, but formidable obstacles remain to selective inhibition of the factors that block successful clinical xenotransplantation. Bispecific antibodies, designed to enhance rather than inhibit existing complement pathways, hold strong promise for the clearance of viral and bacterial pathogens from the circulation.

Animals↗
PubMed1998

Compstatin inhibits complement and cellular activation in whole blood in two models of extracorporeal circulation.

Recently, a C3-binding cyclic synthetic peptide (Compstatin) has been identified that binds to complement component C3 and inhibits complement activation. Here we have examined the influence of Compstatin on complement activation and its indirect effects on cellular responses in whole blood in two models for extracorporeal circulation. Compstatin effectively inhibited the generation of C3a and sC5b-9 and the binding of C3/ C3 fragments to the polymer surface. As a result of the inhibition of complement activation, the activation of polymorphonuclear leukocytes (PMNs; as assessed by the expression of CD11b) and the binding of these cells (CD16(+)) to the polymer surface were almost completely lost. In contrast, blood cell counts were not affected. Using surface plasmon resonance technology, we have confirmed that Compstatin exerts its inhibitory effect on complement activation by binding to native C3. These data show that complement activation, leading to activation and binding of PMNs to the biomaterial surface, can be abolished by the addition of Compstatin. The properties of Compstatin make Compstatin a promising drug for use in extracorporeal circuits to avoid bioincompatibility reactions, eg, during cardiopulmonary bypass, but also a favorable precursor peptide for the development of an anticomplement drug for oral use.

Amino Acid Sequence↗