Blockade of complement inhibits obliterative bronchiolitis in rat tracheal allografts.
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-alpha 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-2Ralpha 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.
Kallio
E A
EA
Cardiopulmonary Research Group of the Transplantation Laboratory, University of Helsinki and Helsinki University Central Hospital, Helsinki, Finland. Erkki.Kallio@Helsinki.Fi
Lemström
K B
KB
Häyry
P J
PJ
Ryan
U S
US
Koskinen
P K
PK
D000818:Animals; D001989:Bronchiolitis Obliterans / Q000276:immunology / Q000517:prevention & control*; D018925:Chemokines / Q000378:metabolism; D003167:Complement Activation / Q000276:immunology / Q000502:physiology*; D015938:Complement Membrane Attack Complex / Q000378:metabolism; D016207:Cytokines / Q000378:metabolism; D006084:Graft Rejection / Q000276:immunology / Q000517:prevention & control; D006801:Humans; D007074:Immunoglobulin G / Q000378:metabolism; D008297:Male; D009852:Omentum; D051381:Rats; D011920:Rats, Inbred WF; D011951:Receptors, Complement / Q000627:therapeutic use; D011994:Recombinant Proteins / Q000627:therapeutic use; D014132:Trachea / Q000637:transplantation*; D016042:Transplantation, Heterotopic
D018925:Chemokines; D015938:Complement Membrane Attack Complex; D016207:Cytokines; D007074:Immunoglobulin G; D011951:Receptors, Complement; D011994:Recombinant Proteins