The use of technetium Tc 99m annexin V for in vivo imaging of apoptosis during cardiac allograft rejection.
OBJECTIVE
Apoptosis, or programmed cell death, has been suggested as a mechanism of immunologic injury during cardiac allograft rejection. We tested the hypothesis that technetium Tc 99m annexin V, a novel radiopharmaceutical used to detect apoptosis, can be used to detect cardiac allograft rejection by nuclear imaging.


METHODS
Untreated ACI rats served as recipients of allogeneic PVG rat (n = 66) or syngeneic ACI rat (n = 30) cardiac grafts. Untreated recipient animals underwent 99mTc-annexin V imaging daily for 7 days. Region of interest analysis was used to quantify the uptake of 99mTc-annexin V. Immediately after imaging grafts were procured for histopathologic analysis and terminal deoxynucleotidyltransferase-mediated deoxyuridine triphosphate-biotin nick-end labeling of apoptotic nuclei. One group was treated with 10 mg/kg/d cyclosporine (INN: ciclosporin) commencing on day 4 after transplantation (n = 6).


RESULTS
Untreated allografts showed histologic signs of rejection 4 days after transplantation. Apoptotic nuclei could be demonstrated in myocytes, endothelial cells, and graft-infiltrating cells of all rejecting allografts. Nuclear imaging revealed a significantly greater uptake of 99mTc-annexin V in rejecting allogeneic grafts than in syngeneic grafts on day 4 (P = .05), day 5 (P < .001), day 6 (P < .001), and day 7 (P = .013) after transplantation. A correlation between the histologic grade of acute rejection and uptake of 99mTc-annexin V was observed (r2 = 0.87). After treatment of rejection with cyclosporine, no apoptotic nuclei could be identified in allografts and uptake of 99mTc-annexin V decreased to baseline.


CONCLUSIONS
Apoptosis occurs during acute cardiac allograft rejection and disappears after treatment of rejection. 99mTc-annexin V can be used to detect and monitor cardiac allograft rejection.
Vriens
P W
PW
Department of Cardiothoracic Surgery, Stanford University Medical Center, Calif 94305-5407, USA.
Blankenberg
F G
FG
Stoot
J H
JH
Ohtsuki
K
K
Berry
G J
GJ
Tait
J F
JF
Strauss
H W
HW
Robbins
R C
RC
D000818:Animals; D017304:Annexin A5; D017209:Apoptosis / Q000187:drug effects / Q000502:physiology*; D016572:Cyclosporine / Q000494:pharmacology; D006084:Graft Rejection / Q000000981:diagnostic imaging* / Q000473:pathology; D016027:Heart Transplantation / Q000276:immunology* / Q000473:pathology; D007166:Immunosuppressive Agents / Q000494:pharmacology; D020287:In Situ Nick-End Labeling; D008297:Male; D009206:Myocardium / Q000276:immunology / Q000473:pathology; D011877:Radionuclide Imaging; D051381:Rats; D011912:Rats, Inbred ACI; D011919:Rats, Inbred Strains; D012680:Sensitivity and Specificity; D013667:Technetium; D014184:Transplantation, Homologous
D017304:Annexin A5; D007166:Immunosuppressive Agents; D013667:Technetium; D016572:Cyclosporine