Complement inhibition by FUT-175 and K76-COOH in a pig-to-human lung xenotransplant model.
Two complement inhibitors, FUT-175 (FUT) and K76-COOH (K76), were studied as single agents in an ex vivo, in situ model of pig lung rejection by human blood. Pulmonary toxicity (primarily increased pulmonary vascular resistance [PVR]) was seen with FUT at a dose which inhibited complement in vitro (0.4 mg/ml); a lower dose (0.1 mg/ml) was therefore used. K76 had little apparent toxicity at a dose which inhibited complement in vitro (6 mg/ml), but activated complement, leading to C3a elaboration. Efficacy was then assessed by 1) deposition of complement pathway components in the lung and 2) lung survival during perfusion with human blood. Neither agent consistently prolonged median lung survival (FUT: 50 min. +/- 28 SEM; K76: 37 +/- 16), blocked thromboxane production, or prevented PVR elevation compared to experiments using unmodified human blood (survival 9 min. +/- 2). At the doses used, both agents prevented deposition of terminal complement complex (TCC) in the lung. This finding demonstrates that the various phenomena associated with hyperacute lung rejection (thromboxane release, PVR elevation, capillary leak, and intraalveolar hemorrhage) can all occur despite abrogation of membrane attack complex formation. We can not exclude a contribution by drug toxicity or complement damage (mediated by C3a or other complement pathway components proximal to TCC) to the observed lung injury. We conclude that, although both FUT and K76 inhibit deposition of TCC in the lung, at the dose tested neither drug is useful as a single agent to prolong survival in a pig-to-human lung xenograft model.
Blum
M G
MG
Department of Cardiac and Thoracic Surger, Vanderbilt University School of Medicine, Nashville, Tennessee 37232-5734, USA.
Collins
B J
BJ
Chang
A C
AC
Zhang
J P
JP
Knaus
S A
SA
Pierson
R N
RN
D000818:Animals; D001550:Benzamidines; D003169:Complement Inactivator Proteins / Q000008:administration & dosage / Q000494:pharmacology* / Q000633:toxicity; D015938:Complement Membrane Attack Complex / Q000378:metabolism; D003165:Complement System Proteins / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D005455:Fluorescent Antibody Technique; D006084:Graft Rejection / Q000276:immunology / Q000473:pathology / Q000517:prevention & control; D006146:Guanidines / Q000008:administration & dosage / Q000494:pharmacology* / Q000633:toxicity; D006801:Humans; D066298:In Vitro Techniques; D016040:Lung Transplantation / Q000009:adverse effects / Q000276:immunology* / Q000473:pathology; D008954:Models, Biological; D010477:Perfusion; D011652:Pulmonary Circulation / Q000187:drug effects; D012717:Sesquiterpenes / Q000008:administration & dosage / Q000494:pharmacology* / Q000633:toxicity; D013552:Swine; D014183:Transplantation, Heterologous / Q000009:adverse effects / Q000276:immunology* / Q000473:pathology; D014655:Vascular Resistance / Q000187:drug effects
D001550:Benzamidines; D003169:Complement Inactivator Proteins; D015938:Complement Membrane Attack Complex; D006146:Guanidines; D012717:Sesquiterpenes; C038797:K 76 carboxylic acid; D003165:Complement System Proteins; C032855:nafamostat