Development of the Intestinal Transplantation Model With Major Histocompatibility Complex Inbred CLAWN Miniature Swine.
BACKGROUND
Clinical intestinal transplantation (Int-Tx) is associated with some problems such as rejection, infection, graft-versus-host disease, and ischemia-reperfusion injury (IRI). To determine mechanisms of rejection as well as to develop treatment strategies for Int-Tx, this study was designed to establish both heterotopic and orthotropic Int-Tx models using major histocompatibility antigen complex (MHC) inbred CLAWN miniature swine.


METHODS
Eleven CLAWN miniature swine received MHC matched but minor antigen mismatched allogenic intestinal grafts. Four animals received intestinal grafts heterotopically and kept host intestine intact. The remaining 7 animals received intestinal grafts orthotopically and resected host small intestine. Continuous infusion of tacrolimus was given from day 0 for 12 days.


RESULTS
Heterotopically transplanted small intestine were well perfused after revascularization; however, grafts easily underwent ischemic changes during or soon after abdomen closure due to oppression of the grafts in the limited abdominal space. In contrast, all of 7 orthotopically transplanted intestinal grafts in which recipients' small intestine was removed from the jejunum to the ileum had no signs of severe ischemia associated with compartment syndrome. Elevation of the serum concentration of inflammatory cytokines and the progression of lethal acidosis seen in recipients of heterotipic transplantation were markedly less in the case of orthotopic transplantation. Two recipients survived more than 30 days, and 1 long-term survivor showed no evidence of rejection at day 90 despite the fact that tacrolimus was stopped at day 12.


CONCLUSIONS
In this study, we demonstrated the establishment of a clinically relevant orthotopic Int-Tx model with long survival in MHC inbred CLAWN miniature swine. We believe that this unique MHC inbred swine Int-Tx model is useful for developing treatment strategies for clinical Int-Tx.
Division of Organ Replacement and Xenotransplantation Surgery, Kagoshima University, Kagoshima, Japan; Division of Digestive and General Surgery, Niigata University Graduate School of Medical and Dental Sciences, Niigata, Japan.
K
K
Miura
Division of Organ Replacement and Xenotransplantation Surgery, Kagoshima University, Kagoshima, Japan.
H
H
Sahara
Division of Organ Replacement and Xenotransplantation Surgery, Kagoshima University, Kagoshima, Japan.
S
S
Waki
Division of Organ Replacement and Xenotransplantation Surgery, Kagoshima University, Kagoshima, Japan.
A
A
Kawai
Division of Organ Replacement and Xenotransplantation Surgery, Kagoshima University, Kagoshima, Japan.
M
M
Sekijima
Division of Digestive and General Surgery, Niigata University Graduate School of Medical and Dental Sciences, Niigata, Japan.
T
T
Kobayashi
Division of Digestive and General Surgery, Niigata University Graduate School of Medical and Dental Sciences, Niigata, Japan.
Z
Z
Zhang
Division of Digestive and General Surgery, Niigata University Graduate School of Medical and Dental Sciences, Niigata, Japan.
T
T
Wakai
Division of Organ Replacement and Xenotransplantation Surgery, Kagoshima University, Kagoshima, Japan.
A
A
Shimizu
Division of Organ Replacement and Xenotransplantation Surgery, Kagoshima University, Kagoshima, Japan. Electronic address: kyyamada@m2.kufm.kagoshima-u.ac.jp.
K
K
Yamada
D000818:Animals; D004195:Disease Models, Animal; D006084:Graft Rejection / Q000517:prevention & control; D006086:Graft vs Host Disease / Q000517:prevention & control; D007082:Ileum / Q000601:surgery; D007166:Immunosuppressive Agents / Q000008:administration & dosage / Q000494:pharmacology; D007262:Infusions, Intravenous; D007421:Intestine, Small / Q000637:transplantation*; D007583:Jejunum / Q000601:surgery; D008285:Major Histocompatibility Complex / Q000502:physiology; D015427:Reperfusion Injury / Q000517:prevention & control; D013552:Swine; D013556:Swine, Miniature; D016559:Tacrolimus / Q000008:administration & dosage; D016042:Transplantation, Heterotopic / Q000379:methods; D014184:Transplantation, Homologous / Q000379:methods
D007166:Immunosuppressive Agents; D016559:Tacrolimus