Portal donor-specific blood transfusion and mycophenolate mofetil allow steroid avoidance and tacrolimus dose reduction with sustained levels of chimerism in a pig model of intestinal transplantation.
BACKGROUND
In a pig model of intestinal transplantation, we previously showed that hepatic conditioning through portal donor-specific blood transfusion (pDSBT), high-dose tacrolimus (TAC), and steroids prevented rejection and increased survival Our current study tests a protocol of pDSBT, short-term mycophenolate mofetil (MMF), and low-dose TAC to eliminate the use of steroids, reduce TAC dosage, and increase the level of chimerism in the peripheral blood.


METHODS
Four groups of outbred, mixed lymphocyte culture (MLC)-reactive pigs underwent bowel transplants and pDSBT. Immunosuppression (group 1, high-dose TAC and steroids; group 2, low-dose TAC and MMF; group 3, low-dose TAC, MMF, and aminoguanidine; group 4, low-dose TAC, MMF, and arginine) was discontinued after 28 days. RNA was extracted from intestinal graft and native liver biopsies for cytokine measurements. Chimerism levels were determined using a Q-PCR analysis.


RESULTS
Pig survival and death rates due to rejection did not significantly differ between the four groups. Chimerism levels determined by Q-PCR analysis were not different until day 28. After discontinuation of immunosuppression, we noted a trend (P = 0.15) toward higher mean chimerism levels on day 60 for groups 2, 3, and 4 (9%) vs. group 1 (0.5%). Tissue cytokine and serum nitrate levels did not significantly differ between the four groups. Attempts to modify nitric oxide synthase activity offered no added benefit.


CONCLUSIONS
The combination of pDSBT, MMF, and low-dose TAC (vs. high-dose TAC and steroids) allowed sustained levels of mixed chimerism to develop after discontinuation of immunosuppression.
Gruessner
Rainer W G
RW
Department of Surgery, University of Minnesota, MMC 90, 420 Delaware St. SE, Minneapolis, MN 55455, USA. grues001@umn.edu
Levay-Young
Brett K
BK
Nakhleh
Raouf E
RE
Shearer
Jeffry D
JD
Dunning
Michele
M
Nelson
Curtis M
CM
Gruessner
Angelika C
AC
D000818:Animals; D001803:Blood Transfusion; D016207:Cytokines / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D004334:Drug Administration Schedule; D004359:Drug Therapy, Combination; D006084:Graft Rejection / Q000401:mortality; D006086:Graft vs Host Disease / Q000401:mortality; D007166:Immunosuppressive Agents / Q000008:administration & dosage*; D007239:Infections / Q000401:mortality; D007422:Intestines / Q000637:transplantation*; D008297:Male; D009173:Mycophenolic Acid / Q000008:administration & dosage* / Q000031:analogs & derivatives*; D009569:Nitric Oxide / Q000378:metabolism; D011168:Portal System; D013256:Steroids / Q000008:administration & dosage; D016019:Survival Analysis; D013552:Swine; D016559:Tacrolimus / Q000008:administration & dosage*; D014019:Tissue Donors; D018183:Transplantation Chimera
D016207:Cytokines; D007166:Immunosuppressive Agents; D013256:Steroids; D009569:Nitric Oxide; D009173:Mycophenolic Acid; D016559:Tacrolimus