Use of C4d as a diagnostic adjunct in lung allograft biopsies.
OBJECTIVE
Humoral allograft rejection is a defined mechanism for cardiac and renal graft dysfunction; C4d deposition, a stable component of complement activation, inversely correlates with graft survival. With the recent recognition of humoral rejection in lung grafts, we examined C4d's role as a prognostic adjunct in lung allografts.


METHODS
Twenty-three lung recipients underwent biopsies for deterioration in clinical status or routine surveillance. Clinically unwell patients possessed acute rejection or bronchiolitis obliterans syndrome (BOS). Biopsies attributable to infection were excluded from the study. In addition to routine light microscopy, an attempt was made to correlate the clinical status and morphologic findings with the pattern of C4d deposition and also to compare these clinical and morphologic parameters with the other assessed immunoreactants. Panel reactive antibody testing was also carried out at various points in their post transplantation course whereby in 6 of the cases the samples were procured at exactly the same time as the tissue samples.


RESULTS
The patients were segregated into two groups: those patients with recurrent acute rejection and those with BOS. In those patients with symptomatic acute rejection, all biopsies showed light microscopic and immunofluorescent evidence of humoral allograft rejection. The level of C4d was positively correlated with the degree of parenchymal injury, the hallmark being one of septal capillary necrosis. In addition, high and intermediate levels of C4d correlated with a clinical diagnosis of acute rejection. C4d was the strongest predictor of parenchymal injury and of the clinical status (p <.0001) compared to other the immunoreactants C1q, C5b-9 and immunoglobulin. There was no specific correlation between C4d deposition and the presence of acute cellular rejection. In those patients fulfilling clinical criteria of BOS, deposits of C4d as well as other immunoreactants were found in the bronchial wall as opposed to the rarity of this finding in bon-BOS patients. However the only statistically significant predictor of BOS was bronchial wall deposition of C1q. In no case were panel reactive antibodies at significant levels discovered post transplantation.


CONCLUSIONS
In the context of acute rejection, C4d deposition correlates with clinical evidence of rejection and the degree of humoral rejection assessed pathologically; there is no association with the presence of histocompatibility related antibodies. It is a more specific predictor of allograft status compared to other immunoreactants. C4d deposition within the bronchial wall is a feature of BOS and hence may be used as a marker of chronic graft dysfunction. The antigenic target resulting in C4d deposition may not be histocompatibility related.
Magro
Cynthia M
CM
Department of Pathology, The Ohio State University, Columbus, OH, USA.
Pope Harman
Amy
A
Klinger
Dana
D
Orosz
Charles
C
Adams
Patrick
P
Waldman
James
J
Knight
Deborah
D
Kelsey
Moira
M
Ross
Patrick
P
D000328:Adult; D000368:Aged; D001706:Biopsy; D001989:Bronchiolitis Obliterans / Q000175:diagnosis*; D003181:Complement C4 / Q000032:analysis*; D015935:Complement C4b; D005434:Flow Cytometry; D006084:Graft Rejection / Q000175:diagnosis*; D006801:Humans; D007518:Isoantibodies / Q000097:blood; D016040:Lung Transplantation / Q000473:pathology*; D008875:Middle Aged; D010446:Peptide Fragments / Q000032:analysis*; D011379:Prognosis; D014184:Transplantation, Homologous / Q000473:pathology
D003181:Complement C4; D007518:Isoantibodies; D010446:Peptide Fragments; D015935:Complement C4b; C032261:complement C4d