Recombinant human C1-inhibitor prevents acute antibody-mediated rejection in alloimmunized baboons

• Published in: Kidney international Vol. 78; no. 2; pp. 152 - 159
• Main Authors: Tillou, Xavier, Poirier, Nicolas, Le Bas-Bernardet, Stéphanie, Hervouet, Jeremy, Minault, David, Renaudin, Karine, Vistoli, Fabio, Karam, Georges, Daha, Mohamed, Soulillou, Jean Paul, Blancho, Gilles
• Format: Journal Article
• Language: English
• Published: Basingstoke Elsevier Inc 01.07.2010; Nature Publishing Group; Elsevier Limited
• Subjects: Acute Disease; alloantibodies; Animals; Antibodies - immunology; antibody-mediated rejection; Biological and medical sciences; Complement C1 Inhibitor Protein - therapeutic use; Complement Inactivating Agents - therapeutic use; complement regulation; Disease Models, Animal; Graft Rejection - immunology; Graft Rejection - prevention & control; Immunization; kidney allograft; Kidney Transplantation - immunology; Medical sciences; Nephrology. Urinary tract diseases; nonhuman primate; Papio; Recombinant Proteins - therapeutic use; complement regulation; kidney allograft; nonhuman primate; alloantibodies; antibody-mediated rejection; Graft(material); Nephrology; Complement C1; Monkey; Transplantation; Homotransplantation; Urology; Isoimmunization; Prevention; Regulation(control); Surgery; Primates; Graft; Recombinant protein; Human; Antibody; Acute; Nonhuman primate; Baboon; Rejection; Vertebrata; Mammalia; Treatment; Alloantibody; Inhibitor
• ISSN: 0085-2538; 1523-1755
• DOI: 10.1038/ki.2010.75

Acute antibody-mediated rejection is an unsolved issue in transplantation, especially in the context of pretransplant immunization. The deleterious effect of preformed cytotoxic anti-HLA antibodies through complement activation is well proven, but very little is known concerning complement blockade to prevent/cure this rejection. Here, we used a baboon model of preimmunization to explore the prevention of acute antibody-mediated rejection by an early inhibition of the classical complement pathway using human recombinant C1-inhibitor. Baboons were immunized against peripheral blood mononuclear cells from allogeneic donors and, once a specific and stable immunization had been established, they received a kidney from the same donor. Rejection occurred at day 2 posttransplant in untreated presensitized recipients, with characteristic histological lesions and complement deposition. As recombinant human C1-inhibitor blocks in vitro cytotoxicity induced by donor-specific antibodies, other alloimmunized baboons received the drug thrice daily intravenously during the first 5 days after transplant. Rejection was prevented during this treatment but occurred after discontinuation of treatment. We show here that early blockade of complement activation by recombinant human C1-inhibitor can prevent acute antibody-mediated rejection in presensitized recipients. This treatment could also be useful in other forms of acute antibody-mediated rejection caused by induced antibodies.