Characterization of allograft rejection in an experimental model of small intestinal transplantation.
Graft rejection continues to be a major barrier to the success of clinical small intestinal transplantation. The objective of this study was to characterize histopathologic and immune parameters of allograft rejection in an experimental model of small intestinal transplantation. Heterotopic intestinal transplants were performed in allogeneic and isogeneic rat strain combinations. An additional group of allogeneic recipients was treated with tacrolimus (1 mg/kg/day) for 7 days beginning on posttransplant day 1. Recipients of allografts and isografts were killed on days 1 to 7 following transplantation, and tacrolimus-treated allograft recipients were killed on days 4 and 7. Grafts and native intestines were examined for histopathology and cytokine gene expression. Very early rejection was observed on posttransplant day 3 and severe rejection was apparent by day 7. The key histopathologic features of acute graft rejection including apoptosis, crypt epithelial cell injury, and an inflammatory infiltrate were uniformly identifiable on day 4 and progressed in severity through day 7. Interleukin (IL)-2, IL-4, IL-5, IL-6, interferon-gamma (IFN-gamma), and tumor necrosis factor-alpha mRNA were readily detectable in allografts on days 1 to 7. However, only IFN-gamma mRNA showed a significant early and sustained increase in allografts as compared to isografts and native intestine. Treatment of allograft recipients with tacrolimus abrogated the major histopathologic features of rejection and markedly inhibited IFN-gamma gene expression. These results indicate that graft rejection in small intestinal transplantation is characterized by a local and specific immune response marked by IFN-gamma production that results in crypt epithelial cell injury and apoptosis. Tacrolimus abrogates the histopathologic features of rejection in association with a marked inhibition of IFN-gamma gene expression.
Hayashi
M
M
Department of Surgery, Transplant Immunobiology Laboratory and Lucile Packard Children's Hospital, Stanford University School of Medicine, Stanford, CA, USA.
Martinez
O M
OM
Krams
S M
SM
Burns
W
W
Esquivel
C O
CO
D000208:Acute Disease; D000818:Animals; D017209:Apoptosis; D004195:Disease Models, Animal; D004847:Epithelial Cells / Q000473:pathology; D005786:Gene Expression Regulation; D006084:Graft Rejection / Q000209:etiology* / Q000276:immunology / Q000473:pathology / Q000517:prevention & control; D007166:Immunosuppressive Agents / Q000627:therapeutic use; D007371:Interferon-gamma / Q000032:analysis / Q000187:drug effects / Q000235:genetics; D007376:Interleukin-2 / Q000032:analysis / Q000235:genetics; D015847:Interleukin-4 / Q000032:analysis / Q000235:genetics; D015848:Interleukin-5 / Q000032:analysis / Q000235:genetics; D015850:Interleukin-6 / Q000032:analysis / Q000235:genetics; D007413:Intestinal Mucosa / Q000473:pathology; D007421:Intestine, Small / Q000276:immunology / Q000473:pathology / Q000637:transplantation*; D008297:Male; D012333:RNA, Messenger / Q000032:analysis / Q000235:genetics; D051381:Rats; D011912:Rats, Inbred ACI; D011917:Rats, Inbred Lew; D016559:Tacrolimus / Q000627:therapeutic use; D016042:Transplantation, Heterotopic / Q000276:immunology / Q000473:pathology; D014184:Transplantation, Homologous; D014185:Transplantation, Isogeneic; D014409:Tumor Necrosis Factor-alpha / Q000032:analysis / Q000235:genetics
D007166:Immunosuppressive Agents; D007376:Interleukin-2; D015848:Interleukin-5; D015850:Interleukin-6; D012333:RNA, Messenger; D014409:Tumor Necrosis Factor-alpha; D015847:Interleukin-4; D007371:Interferon-gamma; D016559:Tacrolimus