Macrophage labeling by SPIO as an early marker of allograft chronic rejection in a rat model of kidney transplantation.
Anatomical and functional information (renography, perfusion) was obtained by MRI in a life-supporting transplantation model, in which Lewis rats received kidneys from Fisher 344 donors. Renography and perfusion analyses were carried out with Gd-DOTA and small particles of iron oxide (SPIO), respectively. Starting 12 weeks posttransplantation, images from grafts of untreated recipients exhibited distinctive signal attenuation in the cortex. Animals treated with cyclosporin (Sandimmune Neoral; Novartis Pharma, Basel, Switzerland) to prevent acute rejection showed a signal attenuation in the cortex at 33 weeks posttransplantation, while kidneys from rats treated additionally with everolimus (Certican; Novartis), a rapamycin derivative, had no changes in anatomical appearance. A significant negative correlation was found between the MRI cortical signal intensity and the histologically determined iron content in macrophages located in the cortex. Renography revealed a significantly reduced functionality of the kidneys of untreated controls 33 weeks after transplantation, while no significant changes in perfusion were observed in any group of rats. These results suggest the feasibility, by labeling macrophages with SPIO, of detecting signs of graft rejection significantly earlier than when changes in function occur. Monitoring early changes associated with chronic rejection can have an impact in preclinical studies by shortening the duration of the experimental period and by facilitating the investigation of novel immunomodulatory therapies for transplantation.
Beckmann
N
N
Central Technologies, Novartis Institutes for Biomedical Research, CH-4002 Basel, Switzerland. nicolau.beckmann@pharma.novartis.com
Cannet
C
C
Fringeli-Tanner
M
M
Baumann
D
D
Pally
C
C
Bruns
C
C
Zerwes
H-G
HG
Andriambeloson
E
E
Bigaud
M
M
D000818:Animals; D015415:Biomarkers; D016572:Cyclosporine / Q000627:therapeutic use; D000068338:Everolimus; D005240:Feasibility Studies; D005290:Ferric Compounds; D006084:Graft Rejection / Q000175:diagnosis* / Q000000981:diagnostic imaging / Q000517:prevention & control; D007166:Immunosuppressive Agents / Q000627:therapeutic use; D016030:Kidney Transplantation / Q000009:adverse effects / Q000276:immunology*; D008264:Macrophages; D008279:Magnetic Resonance Imaging / Q000379:methods*; D008297:Male; D023421:Models, Animal; D011866:Radioisotope Renography; D051381:Rats; D011916:Rats, Inbred F344; D011917:Rats, Inbred Lew; D020123:Sirolimus / Q000031:analogs & derivatives / Q000627:therapeutic use
D015415:Biomarkers; D005290:Ferric Compounds; D007166:Immunosuppressive Agents; C000499:ferric oxide; D016572:Cyclosporine; D000068338:Everolimus; D020123:Sirolimus