Am. J. Respir. Crit. Care Med., Volume 161, Number 4, April 2000, 1332-1339

Blockade of Complement Inhibits Obliterative Bronchiolitis in Rat Tracheal Allografts

ERKKI A. KALLIO, KARL B. LEMSTRÖM, PEKKA J. HÄYRY, UNA S. RYAN, and PETRI K. KOSKINEN

Cardiopulmonary Research Group of the Transplantation Laboratory, University of Helsinki and Helsinki University Central Hospital, Helsinki, Finland; and AVANT Immunotherapeutics, Needham, Massachusetts

The role of complement activation in the development of obliterative bronchiolitis, a manifestation of chronic lung allograft rejection, was investigated in the heterotopic rat tracheal allograft model. An increase in intragraft complement components C3 and C5b-9 (membrane attack complex) as well as IgM and IgG deposits were demonstrated during the progressive loss of respiratory epithelium and airway occlusion in nontreated allografts compared with syngeneic grafts. A 7-d treatment with recombinant human soluble complement receptor type 1 (sCR1; 20 mg/kg/d, intraperitoneal), an inhibitor of both the classic and alternative complement pathways, significantly decreased epithelial necrosis and intragraft neutrophil infiltration, and reduced obliterative changes by 40%. Immunohistochemical analysis of the grafts showed that sCR1 treatment significantly decreased early C5b-9 and IgG deposits, neutrophil chemoattractant IL-8 immunoreactivity, and ICAM-1 expression. Treatment with sCR1 was associated with increased staining for Th2 cytokines, in particular IL-10, with concomitant downregulation of IL-2 and TNF- immunoreactivity. In contrast, sCR1 treatment did not affect the number of graft-infiltrating CD4⁺ and CD8⁺ T cells, CD45⁺ B cells, ED1⁺ and ED3⁺ macrophages, or immune activation with expression of IL-2R or MHC class II. In conclusion, this is the first study to demonstrate that blockade of complement activation attenuates the development of OB and suggests that in addition to T cell-driven responses, humoral and antigen-independent immune responses also operate in the disease process. A blockade of complement activation renders the chemokine milieu unattractive to neutrophils and also modulates the alloimmune response toward Th2 cytokines, which may have an antiproliferative role in fibroproliferative disorders.

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