Posttransplant ischemia-reperfusion injury in transplanted heart is prevented by a minibody to the fifth component of complement.
BACKGROUND
Complement activation has been implicated in the development of posttransplant ischemia-reperfusion (I/R) which is responsible for the delayed function of 20% to 30% of grafts. C5a and the terminal complement complex (TCC) are the complement activation products mainly involved in tissue injury caused by I/R.


METHODS
To control activation of the terminal step of the complement activation pathways, we used a neutralizing minibody to C5 containing a human single-chain fragment variable (scFv) linked to the hinge region, CH2, and CH3 domains of rat IgG1.


RESULTS
The minibody acts on C5 inhibiting the release of C5a and the assembly of TCC and depletes circulating C5 in Sprague-Dawley rats with a therapeutic activity of 4 hr. Administration of the minibody to rats 30 min before heart allotransplantation prevented tissue deposition of TCC, apoptosis, and necrosis of the graft and increase in the levels of serum creatine phosphokinase and tumor necrosis factor-alpha observed in control transplanted rats.


CONCLUSIONS
These data suggest that an anti-C5 therapy is effective in preventing graft injury caused by I/R. A minibody containing the human scFv linked to the hinge region and the CH2 and CH3 domains of human IgG1 is ready for use in clinical transplantation.
Ferraresso
Mariano
M
Department of Surgical Sciences, University of Milan, Milan, Italy. mariano.ferraresso@unimi.it
Macor
Paolo
P
Valente
Marialuisa
M
Della Barbera
Mila
M
D'Amelio
Fabio
F
Borghi
Orietta
O
Raschi
Elena
E
Durigutto
Paolo
P
Meroni
Pierluigi
P
Tedesco
Francesco
F
D000818:Animals; D000906:Antibodies / Q000008:administration & dosage / Q000276:immunology / Q000627:therapeutic use; D001012:Aorta, Abdominal / Q000601:surgery; D001013:Aorta, Thoracic / Q000601:surgery; D003167:Complement Activation / Q000187:drug effects; D003182:Complement C5 / Q000276:immunology / Q000627:therapeutic use*; D016027:Heart Transplantation / Q000009:adverse effects* / Q000473:pathology; D020287:In Situ Nick-End Labeling; D007275:Injections, Intravenous; D008297:Male; D009200:Myocardial Contraction; D009336:Necrosis; D011183:Postoperative Complications / Q000473:pathology / Q000503:physiopathology / Q000517:prevention & control*; D051381:Rats; D017207:Rats, Sprague-Dawley; D015427:Reperfusion Injury / Q000517:prevention & control*; D016042:Transplantation, Heterotopic / Q000379:methods; D014682:Vena Cava, Inferior / Q000601:surgery; D014683:Vena Cava, Superior / Q000601:surgery
D000906:Antibodies; D003182:Complement C5