Abstracts
1997 Digestive Disease Week

Studies of intestinal allograft rejection using a murine paratopic model.

KA Newell, G He, J Hart, JR Thistlethwaite Jr. University of Chicago, Chicago, IL.

Allograft rejection is the major factor limiting the wider application of intestinal transplantation in humans. The study of intestine rejection has been limited by the lack of a genetically well-defined model. In this study the immune response of C57BL/6 (H-2^b) recipients to fully allogeneic B6C3F₁ (H-2^b/k) intestine grafts was examined. The entire small bowel of donor mice was harvested with its vasculature and transplanted in a paratopic position into C57BL/6 recipients. An end-to-side anastomosis was performed between the donor and recipient aortas followed by an end-to-side anastomosis between the donor portal vein and the recipient inferior vena cava. The jejunum of the donor intestine was brought through the abdominal wall as a stoma and the ileum was anastomosed to the side of the recipient jejunum. Four experimental groups were studied: 1) a syngeneic control (C57BL/6 donor and recipient), 2) untreated allogeneic grafts (B6C3F₁ donors into C57BL/6 recipients), 3) allografts (B6C3F₁ donors) transplanted into C57BL/6 recipients treated with FK506 (1 mg/kg i.p. for 7 days posttransplant), 4) allografts (B6C3F₁ donors) transplanted into alpha-ß T cell deficient C57BL/6 recipients (T cell receptor (Tcr) ß chain knock out mice). Rejection was scored by a blinded pathologist (scale 0 to 3, no rejection to severe rejection). The technical success rate during the study period was 88%. Between 8 and 28 days following transplantation no intestinal allografts from the syngeneic group (n = 14) or allogeneic grafts transplanted into alpha-ß Tcr deficient mice (n = 12) developed rejection (rejection score all animals = 0).

     Recipient       Rej Score        Rej Score        P value
      Group          Day 10           Day 14
 Syngeneic           0 (n=4)          0 (n=3)
 Untreated Allo      2.2±1.2 (n=5)    2.5±0.9 (n=4)    p < 0.01 vs Syn
 Tcr alpha-ß Neg     0 (n=3)          0 (n=3)          p < 0.01 vs untx
 FK506 treated       0.5±0.5 (n=4)    0.6±0.5 (n=5)    p < 0.05 vs untx

This study demonstrates the utility of the murine, paratopic intestinal transplant model. The data show that syngeneic grafts have prolonged survival without evidence of damage. Allografts were rejected promptly and consistently by recipients using a T cell-dependent mechanism. Furthermore, clinically effective anti-T cell immunosuppressants such as FK506 can significantly blunt allograft rejection. Given the broader availability of reagents and genetically modified mice, these findings suggest that the murine paratopic model may provide unique opportunities for the study of intestine allograft rejection.