Role of C5 in the development of airway inflammation, airway hyperresponsiveness, and ongoing airway response.

The role of complement component C5 in asthma remains controversial. Here we examined the contribution of C5 at 3 critical checkpoints during the course of disease. Using an mAb specific for C5, we were able to evaluate the contribution of C5 during (a) the initiation of airway inflammation, (b) the maintenance of airway hyperresponsiveness (AHR), and (c) sustainment of an ongoing airway response to allergen provocation.

Laboratory studies in cross-species lung transplantation.

The lack of sufficient suitable human donor lungs for the many patients requiring pulmonary transplantation as life-saving therapy for end-stage lung diseases has generated extensive interest in cross-species lung transplantation. Ethical concerns and those of animal rights advocates have prompted studies of nonprimate species as potential solid organ donors for humans. This paper provides an overview of some of the laboratory studies of cross-species pulmonary transplantation performed over the past 20 years and focuses, in particular, on more recent work (from our laboratory and others) in the area of porcine-to-primate pulmonary xenotransplantation.

Genetically modified animal organs for human transplantation.

The major barrier to successful discordant xenogeneic organ transplantation is the phenomenon of hyperacute rejection (HAR). Hyperacute rejection results from the deposition of high-titer preformed antibodies that activate serum complement on the luminal surface of the vascular endothelium, leading to vessel occlusion and graft failure within minutes to hours. Here we describe our strategy to overcome HAR in the pig-to-primate transplant setting, which includes the genetic incorporation into transgenic organs and high level expression of both a novel human bifunctional complement inhibitor and a human blood group enzyme.

Humanized porcine VCAM-specific monoclonal antibodies with chimeric IgG2/G4 constant regions block human leukocyte binding to porcine endothelial cells.

Discordant xenografts surviving the initial hyperacute rejection phase may be subject to cellular rejection processes mediated by infiltrating leukocytes including T cells, NK cells and monocytes. The stable adhesion of these cell types to endothelial cells is due to the molecular interaction of the integrins VLA-4 and LFA-1 with their ligands vascular cell adhesion molecule (VCAM) and ICAM-1 present on the endothelial cells. Human VLA-4 binds to porcine VCAM, and blocking mAbs specific for porcine VCAM have been developed.

Inhibition of complement activity by humanized anti-C5 antibody and single-chain Fv.

Activation of the complement system contributes significantly to the pathogenesis of numerous acute and chronic diseases. Recently, a monoclonal antibody (5G1.1) that recognizes the human complement protein C5, has been shown to effectively block C5 cleavage, thereby preventing the generation of the pro-inflammatory complement components C5a and C5b-9.