Tolerance and long-lasting peripheral chimerism after allogeneic intestinal transplantation in MGH miniature swine.
OBJECTIVE
Clinical intestinal transplantation (Int-Tx) is limited by high rates of rejection, infection, and graft versus host disease. To improve clinical outcomes and eliminate the comorbidities associated with chronic immunosuppression, the induction of donor-specific tolerance to intestinal grafts is desirable, especially in the pediatric population. This study determined the ability of intestinal grafts to facilitate tolerance induction in major histocompatibility complex (MHC)-inbred miniature swine.


METHODS
Seven MGH-miniature swine received heterotopic intestinal grafts, two across MHC-matched, minor-antigen disparities, three across a class I MHC disparity with 12 days of cyclosporine A, and two across a class I MHC disparity without an immunosuppressant. Chimerism was assessed by FACS analysis and immunohistochemistry. Cell-mediated lympholysis assays were used to assess antidonor responses.


RESULTS
Two animals receiving intestinal grafts without an immunosuppressant developed antidonor IgG in 14 days and rejected these completely. All other grafts were accepted with 12 days of cyclosporine A across both MHC-matched and MHC class I barriers. Cell-mediated lympholysis assays showed donor-specific unresponsiveness by day 30 across MHC class I barriers. Greater than 15% peripheral donor cell chimerism persisted for more than 60 days after MHC-matched Int-Tx. Although less than 1.5% peripheral donor cell chimerism was seen during the maintenance period after class I-mismatched Int-Tx, 5% to 10% myeloid chimerism was found in the peripheral blood 14 to 90 days after Int-Tx. FACS analysis demonstrated that 1% to 2% of lymphocytes in the graft mesenteric lymph nodes were CD4/CD25(HIGH+)/Foxp3(+) cells.


CONCLUSIONS
To our knowledge, this is the first demonstration of tolerance induction and persistence of chimerism in a large animal intestinal transplant model.
Ishikawa
Yoshinori
Y
Transplantation Biology Research Center, Massachusetts General Hospital, Boston, MA, USA.
Hirakata
Atsushi
A
Griesemer
Adam D
AD
Etter
Justin
J
Moran
Shannon
S
Weiner
Joshua
J
Shimizu
Akira
A
Yamada
Kazuhiko
K
D000818:Animals; D001012:Aorta, Abdominal / Q000601:surgery; D002405:Catheterization, Central Venous; D002445:Celiac Artery / Q000601:surgery; D004386:Duodenum / Q000637:transplantation; D006084:Graft Rejection / Q000473:pathology; D006085:Graft Survival; D006086:Graft vs Host Disease / Q000473:pathology; D006680:HLA Antigens / Q000276:immunology; D015395:Histocompatibility Antigens Class I / Q000276:immunology; D006650:Histocompatibility Testing / Q000379:methods; D007082:Ileum / Q000637:transplantation; D007178:Inbreeding; D007422:Intestines / Q000637:transplantation*; D008214:Lymphocytes / Q000276:immunology; D008285:Major Histocompatibility Complex / Q000276:immunology; D013552:Swine; D013556:Swine, Miniature; D018183:Transplantation Chimera; D023001:Transplantation Tolerance; D014184:Transplantation, Homologous / Q000276:immunology / Q000379:methods / Q000473:pathology
D006680:HLA Antigens; D015395:Histocompatibility Antigens Class I