Immunomodulation for Intestinal Transplantation by Allograft Irradiation, Adjunct Donor Bone Marrow Infusion, or Both1

Murase, Noriko; Ye, Qing; Nalesnik, Michael A.; Demetris, Anthony J.; Abu‐Elmagd, Kareem; Reyes, Jorge; Ichikawa, Naoya; Okuda, Toyokazu; Fung, John J.; Starzl, Thomas E.

doi:10.1097/00007890-200012150-00016

Cited by 63 publications

(37 citation statements)

References 35 publications

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“…The mean survival time was found to be three months with various FK506 treatments ( Table 1). [6][7][8][9] Other immunosuppressants or combination of drugs were tried but the results were contradictory. 13 Murase et al 8 performed OSBT from Brown Norway to Lewis rats underwent a short course of FK506 treatment (1mg/kg/day, POD0-13, 20, 27): all recipients survived over 150 days but CR was severe in the intestine.…”

Section: Discussionmentioning

confidence: 99%

“…[6][7][8][9] Other immunosuppressants or combination of drugs were tried but the results were contradictory. 13 Murase et al 8 performed OSBT from Brown Norway to Lewis rats underwent a short course of FK506 treatment (1mg/kg/day, POD0-13, 20, 27): all recipients survived over 150 days but CR was severe in the intestine. The BN-to-Lewis rat strain combination is strongly histoincompatible which led to severe rejection, while F344-to-LEW rat inbred strain combination showed less histoincompatible, so the doses of FK506 in our study should be lower.…”

Section: Discussionmentioning

confidence: 99%

“…Compared with HSBT, orthotopic small bowel transplantation (OSBT) is more similar to the clinical situation; however, OSBT has been performed by only a few researchers and without long-term survival. [5][6][7][8][9] Thus, the aim of this study was to establish a rat model in which chronic graft rejection of the orthotopic entire small intestine graft would develop in a long term and reproducible manner.…”

Section: List Of Abbreviationsmentioning

confidence: 99%

“…8 Donor and recipient surgeries were performed under anesthesia induced with 100 mg/kg ketamine, intraperitoneally. The entire small bowel from the ligament of Trietz to 1cm from the ileocecal valve was removed on a vascular pedicle consisting of the superior mesenteric artery, a portion of the inferior abdominal aorta, and the portal vein cut distal to the splenic vein, which was previously ligated.…”

Section: Surgical Proceduresmentioning

confidence: 99%

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FK506 treatment in a Long-term chronic rejection rat model of small bowel transplantation

Zhu¹,

Wei²,

Li³

2010

CIM

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Background: Although acute rejection (AR) can be significantly improved by effective immunosuppressants, such as FK506, chronic rejection (CR) remains a major hurdle to long-term allograft survival after small bowel transplantation, in part because the pathogenic mechanisms of CR are, as yet, unknown. The rat orthotopic small bowel transplantation (OSBT) model has been used by a few researchers, but without long-term survival. Methods: Rats were randomly divided into five groups: Group 1 (n=20), sham-operation rats; Group 2 (n=20), Lewis to Lewis; Group 3 (n=20), F344 to Lewis treated with FK506 (0.3 mg/kg/day); Group 4 (n=20), F344 to Lewis with FK506 (0.5 mg/kg/day); Group 5 (n=20), F344 to Lewis with FK506 (1.0 mg/kg/day). FK506 was administrated intramuscularly to recipients on postoperative days (POD) 0-13, 20 and 27. Body weight, survival rate and histology were measured. Results: Histopathological analysis revealed distinctive abnormalities of the allograft for all animals, including changes in villous architecture, interstitial fibrosis and intimal thickening; however, survival times were significantly increased with higher doses of FK506. Rats in Group 3 and Group 4 (low and moderate FK506 doses) survived 16-18 weeks, while recipients in Group 5 (high dose) survived 24-27 weeks.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: List Of Abbreviationsmentioning

confidence: 99%

Section: Surgical Proceduresmentioning

confidence: 99%

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FK506 treatment in a Long-term chronic rejection rat model of small bowel transplantation

Zhu¹,

Wei²,

Li³

2010

CIM

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“…OSBT was performed using standard microvascular techniques [10]. Donor and recipient surgery were performed under anesthesia induced with 100mg/kg ketamine intraperitoneally.…”

Section: Methodsmentioning

confidence: 99%

Increased NPC1L1 and serum cholesterol in a chronic rejection rat

Zhu

Zhou²

2011

CIM

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Increased NPC1L1 and serum cholesterol in a chronic rejection rat Abstract Purpose: To measure serum cholesterol and triglyceride levels and NPC1L1 mRNA and protein as an index of cholesterol absorption during the development of chronic rejection (CR) in a rat model of intestinal transplantation.Methods: Rats were randomly divided into two groups: Group 1 (n=20) underwent syngenic Lewis-to-Lewis transplantation and Group 2 (n=20) underwent allogenic F344-toLewis transplantation as well as treatment with FK506. Blood samples and intestinal tissue were procured on the 190th day a er operation. Histological changes were analyzed and the semiquantitative scores of histological parameters were compared. e serum levels of cholesterol and triglyceride were determined. e expression of Niemann-Pick C1 Like 1(NPC1L1) mRNA and protein were analyzed by Reverse Transcriptase Polymerase Chain Reaction (RT-PCR) and immunohistochemistry, respectively.Results: All the animals survived for the 190 days. e appearance and histology of isogra s were almost normal whereas the allogra s displayed thickened bowel wall and mesenteric brosis, concentric intimal thickening and interstitial brosis and in ammatory in ltration. e histology scores displayed a signi cant di erence between the allogra s and isogra s (P<0.001). No di erences were observed for triglycerides for the two groups.e serum cholesterol levels increased signi cantly in the allogenic group in comparison with the syngenic group (P=0.034), while no di erence was observed for triglyceride levels between groups. RT-PCR showed that the expression of NPC1L1 of allogra s increased signi cantly (P=0.004). Immunohistochemistry con rmed RT-PCR ndings.Conclusions: Neointima formation and mesenteric brosis were the dominant pathological features. e increased expression of NPC1L1 might contribute to hypercholesterolemia, which may be involved in the pathogenesis of transplant arteriosclerosis.ORIGINAL RESEARCH

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Organ TransplantDrugs

Kundu

2003

Burger's Medicinal Chemistry and Drug Discovery

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In recent years several new immunosuppressive agents for organ transplantation have been introduced for clinical usage. They have greater efficacy and fewer side effects than those of the classical therapies involving corticosteroids, azathioprine, and cyclosporine. The new maintenance immunosuppressive drugs are either immunophilin‐binding drugs or are inhibitors of de novo synthesis of nucleotides (purines or pyrimidines) that inhibit signal transduction in lymphocytes. The immunophilin‐binding drugs are cyclosporine, tacrolimus, and rapamycin, whereas inhibitors of de novo nucleotide synthesis include mycophenolate mofetil, mizoribine, brequinar, and leflunomide. Gusperimus (deoxyspergualin), which inhibits IL‐1 synthesis, was useful in reversing early and late acute rejection in clinical trials. FTY‐720, another promising drug, prolonged the survival of allografts and synergized with cyclosporin and sirolimus in experimental models. Antibody preparations such as OKT3, as well as the newer recombinant products, which specifically bind to the IL‐2 receptor, basiliximab, and daclizumab, not only reduced acute rejection but were associated with few adverse effects. Antisense oligonucleotides that interfere with the intercellular adhesion molecules involved in rejection gave encouraging results in primate renal allografts. Use of stem cells, donor bone marrow, and xenotransplantation are some of the alternatives that are likely to find application in organ transplantation in the near future.

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Immunomodulation for Intestinal Transplantation by Allograft Irradiation, Adjunct Donor Bone Marrow Infusion, or Both1

Cited by 63 publications

References 35 publications

FK506 treatment in a Long-term chronic rejection rat model of small bowel transplantation

FK506 treatment in a Long-term chronic rejection rat model of small bowel transplantation

Increased NPC1L1 and serum cholesterol in a chronic rejection rat

Organ TransplantDrugs

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