Quadruple immunosuppression in a pig model of small bowel transplantation

Rainer W G Gruessner, Carlos Fasola, Jon Fryer, Raouf E. Nakhleh, Sung Kim, Angelika C Gruessner, David Beebe, Chul Moon, Christoph Troppmann, John S. Najarian

Research output: Contribution to journalArticle

11 Citations (Scopus)

Abstract

Rejection remains a major obstacle to successful small bowel transplantation in humans, irrespective of the immunosuppressants. Previous large animal studies have not used quadruple immunosuppression (with high- dose intravenous cyclosporine A [CSA]) for induction, followed by triple immunosuppression for maintenance therapy. Nor have immunosuppressive doses been comparable to clinical solid organ transplants. We studied, in 78 nonrelated outbred pigs, the effect of quadruple immunosuppression (including horse anti-pig thymocyte globulin [ATG] and high-dose intravenous CSA) on the incidence and severity of rejection in the early, critical posttransplant period. Group A (n = 19) pigs were nonimmunosuppressed. Group B (n = 20) received quadruple immunosuppression: pig ATG (10 mg/kg/day x 10 days), intravenous CSA (3.0 mg/kg/day), prednisolone (2 mg/kg/day), and azathioprine (2.5 mg/kg/day); prednisolone and azathioprine were each reduced by 50% on posttransplant Days 8 and 15. Trough CSA levels were ≥400 ng/ml for the first 7 days posttransplant, >200 ng/ml thereafter. Recipient pigs underwent resection of large and small bowel; orthotopic transplants (proximal duodenojejunostomy, distal ileostomy) were done with systemic vein drainage. We developed a scoring system (no, mild, moderate, severe rejection) to grade the extent of both interstitial and vascular rejection; biopsies were obtained daily from the ileostomy. Rejection-free graft survival at posttransplant Days 7, 10, and 14 was 32, 26, and 16% in the nonimmunosuppressed group versus 95, 90, and 85% in the immunosuppressed group (P < 0.0001). Rejection grades were significantly better over the whole observation period in immunosuppressed pigs: interstitial rejection was not present in up to 67% of all daily biopsy specimens. Rejection was present in all specimens of nonimmunosuppressed pigs. Vascular rejection was uncommon (incidence < 10%) in both groups. Isolated vascular rejection without interstitial rejection was not found. Graft-versus-host reaction was noted in both groups in the skin only; liver and native bowel were not involved. We conclude that quadruple immunosuppression with pig ATG and high-dose intravenous CSA for induction effectively prevents moderate and severe rejection in this model. Since clinical transplant complications (rejection, lymphomas) have persisted under FK 506 treatment, our immunosuppressive regimen should be considered an alternative for bowel transplantation in humans to prevent early rejection.

Original languageEnglish (US)
Pages (from-to)260-266
Number of pages7
JournalJournal of Surgical Research
Volume61
Issue number1
DOIs
StatePublished - Feb 15 1996
Externally publishedYes

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Immunosuppression
Swine
Transplantation
Cyclosporine
Antilymphocyte Serum
Immunosuppressive Agents
Blood Vessels
Ileostomy
Azathioprine
Prednisolone
Transplants
Biopsy
Incidence
Graft Rejection
Tacrolimus
Graft Survival
Horses
Drainage
Veins
Lymphoma

ASJC Scopus subject areas

  • Surgery

Cite this

Quadruple immunosuppression in a pig model of small bowel transplantation. / Gruessner, Rainer W G; Fasola, Carlos; Fryer, Jon; Nakhleh, Raouf E.; Kim, Sung; Gruessner, Angelika C; Beebe, David; Moon, Chul; Troppmann, Christoph; Najarian, John S.

In: Journal of Surgical Research, Vol. 61, No. 1, 15.02.1996, p. 260-266.

Research output: Contribution to journalArticle

Gruessner, RWG, Fasola, C, Fryer, J, Nakhleh, RE, Kim, S, Gruessner, AC, Beebe, D, Moon, C, Troppmann, C & Najarian, JS 1996, 'Quadruple immunosuppression in a pig model of small bowel transplantation', Journal of Surgical Research, vol. 61, no. 1, pp. 260-266. https://doi.org/10.1006/jsre.1996.0114
Gruessner, Rainer W G ; Fasola, Carlos ; Fryer, Jon ; Nakhleh, Raouf E. ; Kim, Sung ; Gruessner, Angelika C ; Beebe, David ; Moon, Chul ; Troppmann, Christoph ; Najarian, John S. / Quadruple immunosuppression in a pig model of small bowel transplantation. In: Journal of Surgical Research. 1996 ; Vol. 61, No. 1. pp. 260-266.
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abstract = "Rejection remains a major obstacle to successful small bowel transplantation in humans, irrespective of the immunosuppressants. Previous large animal studies have not used quadruple immunosuppression (with high- dose intravenous cyclosporine A [CSA]) for induction, followed by triple immunosuppression for maintenance therapy. Nor have immunosuppressive doses been comparable to clinical solid organ transplants. We studied, in 78 nonrelated outbred pigs, the effect of quadruple immunosuppression (including horse anti-pig thymocyte globulin [ATG] and high-dose intravenous CSA) on the incidence and severity of rejection in the early, critical posttransplant period. Group A (n = 19) pigs were nonimmunosuppressed. Group B (n = 20) received quadruple immunosuppression: pig ATG (10 mg/kg/day x 10 days), intravenous CSA (3.0 mg/kg/day), prednisolone (2 mg/kg/day), and azathioprine (2.5 mg/kg/day); prednisolone and azathioprine were each reduced by 50{\%} on posttransplant Days 8 and 15. Trough CSA levels were ≥400 ng/ml for the first 7 days posttransplant, >200 ng/ml thereafter. Recipient pigs underwent resection of large and small bowel; orthotopic transplants (proximal duodenojejunostomy, distal ileostomy) were done with systemic vein drainage. We developed a scoring system (no, mild, moderate, severe rejection) to grade the extent of both interstitial and vascular rejection; biopsies were obtained daily from the ileostomy. Rejection-free graft survival at posttransplant Days 7, 10, and 14 was 32, 26, and 16{\%} in the nonimmunosuppressed group versus 95, 90, and 85{\%} in the immunosuppressed group (P < 0.0001). Rejection grades were significantly better over the whole observation period in immunosuppressed pigs: interstitial rejection was not present in up to 67{\%} of all daily biopsy specimens. Rejection was present in all specimens of nonimmunosuppressed pigs. Vascular rejection was uncommon (incidence < 10{\%}) in both groups. Isolated vascular rejection without interstitial rejection was not found. Graft-versus-host reaction was noted in both groups in the skin only; liver and native bowel were not involved. We conclude that quadruple immunosuppression with pig ATG and high-dose intravenous CSA for induction effectively prevents moderate and severe rejection in this model. Since clinical transplant complications (rejection, lymphomas) have persisted under FK 506 treatment, our immunosuppressive regimen should be considered an alternative for bowel transplantation in humans to prevent early rejection.",
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AU - Fasola, Carlos

AU - Fryer, Jon

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N2 - Rejection remains a major obstacle to successful small bowel transplantation in humans, irrespective of the immunosuppressants. Previous large animal studies have not used quadruple immunosuppression (with high- dose intravenous cyclosporine A [CSA]) for induction, followed by triple immunosuppression for maintenance therapy. Nor have immunosuppressive doses been comparable to clinical solid organ transplants. We studied, in 78 nonrelated outbred pigs, the effect of quadruple immunosuppression (including horse anti-pig thymocyte globulin [ATG] and high-dose intravenous CSA) on the incidence and severity of rejection in the early, critical posttransplant period. Group A (n = 19) pigs were nonimmunosuppressed. Group B (n = 20) received quadruple immunosuppression: pig ATG (10 mg/kg/day x 10 days), intravenous CSA (3.0 mg/kg/day), prednisolone (2 mg/kg/day), and azathioprine (2.5 mg/kg/day); prednisolone and azathioprine were each reduced by 50% on posttransplant Days 8 and 15. Trough CSA levels were ≥400 ng/ml for the first 7 days posttransplant, >200 ng/ml thereafter. Recipient pigs underwent resection of large and small bowel; orthotopic transplants (proximal duodenojejunostomy, distal ileostomy) were done with systemic vein drainage. We developed a scoring system (no, mild, moderate, severe rejection) to grade the extent of both interstitial and vascular rejection; biopsies were obtained daily from the ileostomy. Rejection-free graft survival at posttransplant Days 7, 10, and 14 was 32, 26, and 16% in the nonimmunosuppressed group versus 95, 90, and 85% in the immunosuppressed group (P < 0.0001). Rejection grades were significantly better over the whole observation period in immunosuppressed pigs: interstitial rejection was not present in up to 67% of all daily biopsy specimens. Rejection was present in all specimens of nonimmunosuppressed pigs. Vascular rejection was uncommon (incidence < 10%) in both groups. Isolated vascular rejection without interstitial rejection was not found. Graft-versus-host reaction was noted in both groups in the skin only; liver and native bowel were not involved. We conclude that quadruple immunosuppression with pig ATG and high-dose intravenous CSA for induction effectively prevents moderate and severe rejection in this model. Since clinical transplant complications (rejection, lymphomas) have persisted under FK 506 treatment, our immunosuppressive regimen should be considered an alternative for bowel transplantation in humans to prevent early rejection.

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