Characterization of transfusion-elicited acute antibody-mediated rejection in a rat model of kidney transplantation.
Animal models of antibody-mediated rejection (ABMR) may provide important evidence supporting proof of concept. We elicited donor-specific antibodies (DSA) by transfusion of donor blood (Brown Norway RT1(n) ) into a complete mismatch recipient (Lewis RT1(l) ) 3 weeks prior to kidney transplantation. Sensitized recipients had increased anti-donor splenocyte IgG1, IgG2b and IgG2c DSA 1 week after transplantation. Histopathology was consistent with ABMR characterized by diffuse peritubular capillary C4d and moderate microvascular inflammation with peritubular capillaritis + glomerulitis > 2. Immunofluorescence studies of kidney allograft tissue demonstrated a greater CD68/CD3 ratio in sensitized animals, primarily of the M1 (pro-inflammatory) phenotype, consistent with cytokine gene analyses that demonstrated a predominant T helper (TH )1 (interferon-γ, IL-2) profile. Immunoblot analyses confirmed the activation of the M1 macrophage phenotype as interferon regulatory factor 5, inducible nitric oxide synthase and phagocytic NADPH oxidase 2 were significantly up-regulated. Clinical biopsy samples in sensitized patients with acute ABMR confirmed the dominance of M1 macrophage phenotype in humans. Despite the absence of tubulitis, we were unable to exclude the effects of T cell-mediated rejection. These studies suggest that M1 macrophages and TH 1 cytokines play an important role in the pathogenesis of acute mixed rejection in sensitized allograft recipients.
Division of Transplantation, Department of Surgery, University of Wisconsin School of Medicine and Public Health, Madison, WI.
G
G
Huang
N A
NA
Wilson
S R
SR
Reese
L M
LM
Jacobson
W
W
Zhong
A
A
Djamali
D000818:Animals; D015153:Blotting, Western; D015935:Complement C4b / Q000276:immunology*; D016207:Cytokines / Q000235:genetics / Q000378:metabolism; D004195:Disease Models, Animal; D006084:Graft Rejection / Q000209:etiology* / Q000473:pathology; D006801:Humans; D007249:Inflammation / Q000209:etiology* / Q000473:pathology; D007518:Isoantibodies / Q000276:immunology*; D016030:Kidney Transplantation; D008297:Male; D010446:Peptide Fragments / Q000276:immunology*; D012333:RNA, Messenger / Q000235:genetics; D051381:Rats; D011914:Rats, Inbred BN; D011917:Rats, Inbred Lew; D060888:Real-Time Polymerase Chain Reaction; D020133:Reverse Transcriptase Polymerase Chain Reaction; D014019:Tissue Donors; D065227:Transfusion Reaction; D014184:Transplantation, Homologous
D016207:Cytokines; D007518:Isoantibodies; D010446:Peptide Fragments; D012333:RNA, Messenger; D015935:Complement C4b; C032261:complement C4d
Animal model; C4d; antibody-mediated rejection; donor-specific antibody; phenotype; transfusion