Immunofluorescent localization of pig complement component 3, regardless of the presence or absence of detectable immunoglobulins, in hyperacutely rejected heart xenografts

Wang, M. W.; Johnston, Peter; Wright, Les; Lim, Susan M. L.; White, David J.

doi:10.1007/bf01082446

Cited by 9 publications

(4 citation statements)

References 18 publications

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“…Inappropriate activation of complement may lead to host cell damage. Complement is implicated in several disease states, including various autoimmune diseases, and has been found to contribute to other clinical conditions, such as adult respiratory syndrome (Robbins et al, 1987), stroke (Vasthare et al, 1993), heart attack (Kilgore et al, 1994), rejection following xenotransplantation (Wang et al, 1992), and bum injuries (Gallinaro et al, 1992). Complement-mediated tissue injury has also been found to result from bioincompatibility situations, such as those encountered in patients undergoing dialysis (Pekna et al, 1993) or cardiopulmonary bypass (Gillinov et al, 1994).…”

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confidence: 99%

Solution structure of Compstatin, a potent complement inhibitor

et al. 1998

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The third component of complement, C3, plays a central role in activation of the classical, alternative, and lectin pathways of complement activation. Recently, we have identified a 13-residue cyclic peptide (named Compstatin) that specifically binds to C3 and inhibits complement activation. To investigate the topology and the contribution of each critical residue to the binding of Compstatin to C3, we have now determined the solution structure using 2D NMR techniques; we have also synthesized substitution analogues and used these to study the structure-function relationships involved. Finally, we have generated an ensemble of a family of solution structures of the peptide with a hybrid distance geometry-restrained simulated-annealing methodology, using distance, dihedral angle, and 3JNH.H,-~o~pling constant restraints. The Compstatin structure contained a type I p-turn comprising the segment GlnS-Asp6-Trp7-Glys. Preference for packing of the hydrophobic side chains of Val3, Val4, and Trp' was observed. The generated structure was also analyzed for consistency using NMR parameters such as NOE connectivity patterns, 3JNH.H,-~o~pling constants, and chemical shifts. Analysis of Ala substitution analogues suggested that Val3, G l d , Asp6, Trp7, and Glys contribute significantly to the inhibitory activity of the peptide. Substitution of Gly' caused a 100-fold decrease in inhibitory potency. In contrast, substitution of Val4, His', His", and Arg" resulted in minimal change in the activity. These findings indicate that specific side-chain interactions and the &turn are critical for preservation of the conformational stability of Compstatin and they might be significant for maintaining the functional activity of Compstatin.The complement system is the first line of immunological defense against foreign pathogens (Muller-Eberhard, 1992). Its activation through the classical, alternative, or lectin pathways leads to the generation of anaphylatoxic peptides C3a and C5a and formation of the C5b-9 membrane attack complex. Complement component C3 plays a central role in activation of all three pathways. Activation of C3 by complement pathway C3 convertases and its subsequent attachment to target surface leads to assembly of the membrane attack complex and ultimately to damage or lysis of the target cells (Frank & Fries, 1991). C3 is unique in that it possesses Reprint requests to:

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confidence: 99%

Solution structure of Compstatin, a potent complement inhibitor

et al. 1998

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“…The current shortage of human organs available for transplantation is an incentive to develop systems in which xenogeneic organs could be used [7,9]. However, the occurrence of natural antibodies directed to endothelial antigens in discordant xenografts [87], or of an alternative pathway activating capability of the xenograft [34, 75,104] causes rapid rejection by a thrombotic process induced by MAC assembly on endothelial cells [13,75,85]. A similar process may account for hyperacute graft rejection that occurs in recipients having alloantibodies specific for donor antigens.…”

Section: Antibody-dependent Complement Activationmentioning

confidence: 99%

Therapeutic uses of recombinant complement protein inhibitors

Kalli

Hsu

Fearon

1994

Springer Semin Immunopathol

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“…But the complement system interacts also with antibodies in humoral immune response and with T-cells (ROITT et al, 1996). Furthermore the complement system is involved in hyperacute xenograft rejection of different species combination (WANG et al, 1992). The complement system consists of more than 30 proteins most of which act as a catalyst for the next.…”

Section: Introductionmentioning

confidence: 99%

Haemolytic complement activity and C3c serum concentration in pigs

et al. 1999

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Abstract. Because of the importance of the complement system in disease resistance through direct lysis of target cells and support of other mechanisms of the immune System, individual Variation in haemolytic complement activity and C3 concentration in pigs prior and after vaccination were evaluated. Possible effects on the variation of these parameters were investigated. Total complement activity was determined based on complement-mediated haemolysis of antibody-sensitised erythrocytes and C3c levels were measured by immunonephelometry in Gemian Landrace pigs and an experimental pig population. Both methods revealed remarkable individual differences. The arithmetic means of total haemolytic complement activity including all pigs were 42.3 ± 28.2 U/ml before vaccination and 59.1 ± 50.6 U/ml after three immunisations. Mean plasma concentrations of C3c were between .102 ± .035 g/1 before immunisation and .126 ± .038 g/1 on day 4 after Aujeszky vaccination. Existing phenotypic variation may be in part influenced by pig genetic factors. Both haemolytic complement activity as well as C3c semm levels are potentially useful measures of complement capacity on the way to improve defence power against many pathogens by breeding.

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Immunofluorescent localization of pig complement component 3, regardless of the presence or absence of detectable immunoglobulins, in hyperacutely rejected heart xenografts

Cited by 9 publications

References 18 publications

Solution structure of Compstatin, a potent complement inhibitor

Solution structure of Compstatin, a potent complement inhibitor

Therapeutic uses of recombinant complement protein inhibitors

Haemolytic complement activity and C3c serum concentration in pigs

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