Efficacy of Immunosuppressive Drugs in Islet Xenotransplantation

Wennberg, Lars; Karlsson‐Parra, Alex; Sundberg, Berit; Rafael, Ehab; Liu, Jing; Zhu, Shuguang; Cg, Groth; Korsgren, Olle

doi:10.1097/00007890-199705150-00008

Cited by 41 publications

(3 citation statements)

References 21 publications

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“…Although no functional studies were carried out, the impressive weight gain demonstrates that porcine islets can sustain growth in such distantly related recipients. This is in marked contrast to previous reports, in which no weight gain was found (7, 20, 31–33) or even substantial weight loss was seen (31, 33).…”

Section: Discussioncontrasting

confidence: 99%

“…Although rejection of islets is mostly described as infiltration, suggesting mechanisms similar to those in organ graft rejection, it is not unlikely that mechanisms are operational like the ones described in the present study (32). One study explicitly mentions that no lymphoid cells were detected within such islets (29) and a second study reports a sharp border between the infiltrate and the porcine xenograft during the entire process of rejection (31).…”

Section: Discussionmentioning

confidence: 99%

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Transplantation of Long-term Cultured Porcine Islets in the Rat: Prolonged Graft Survival and Recipient Growth on Reduced Immunosuppression

et al. 2010

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To evaluate whether further improvement in porcine islet xenotransplantation is feasible, a number of questions were addressed. Earlier we showed significant improvement in the nude mouse of the porcine islets by selection through long-term culture. Now these islets were tested in the stringent pig-to-rat model. Islets were isolated from adult pigs, cultured for 1.5-3 weeks and transplanted to rats. Possible rejection mechanisms were assessed by interference of the cellular response with cyclosporine A (CsA), blocking macrophages with gadolinium chloride (GdCl), and suppressing the humoral response with cyclophosphamide. Modifications in graft size and condition were analyzed. Untreated control recipients showed primary nonfunction (PNF). CsA treatment could fully overcome PNF and resulted in graft survival from 10 to over 134 days. Rejection was the main cause of function loss. Although rejection could not be prevented by intensifying the induction therapy, increased maintenance immunosuppression effectively blocked rejection, albeit at the expense of toxicity. Blocking the humoral response was ineffective; all grafts showed PNF. In contrast, depletion of macrophages fully prevented PNF. Combination of GdCl and CsA gave no additional effect, and grafts were rejected between 57 and 162 days. Generally, graft survivals were similar to those reported in the literature; however, long-term cultured islets required much less maintenance immunosuppression. Cessation of graft function was not always due to rejection; in some cases "islet exhaustion" was found, possibly caused by discrepancy between the graft size and the rapidly growing recipient. Neither the presence of damaged islet tissue in the graft nor the size of the graft exerted any influence on graft survival. On rejection, no real infiltration of the graft was seen; destruction gradually processed from the outside. The good functional capability of the cultured islets was illustrated by disappearance of the clinical symptoms and increase in body weight, which almost doubled in the long-term survivors.

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Section: Discussioncontrasting

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Transplantation of Long-term Cultured Porcine Islets in the Rat: Prolonged Graft Survival and Recipient Growth on Reduced Immunosuppression

et al. 2010

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“…Our group has previously identified several immunosuppressive protocols with efficacy in the pig-to-rat islet transplantation model [24,26]. In the present study, the efficacy of two of these immunosuppressive protocols, 15-deoxyspergualin (DSG) combined with cyclosporin A (CyA) and tacrolimus (FK 506) as single therapy, are evaluated in the guinea pig-to-C6--rat heart transplantation model.…”

Section: Nt Rod Udionmentioning

confidence: 99%

Deoxyspergualin delays xenograft rejection in the guinea pig-to-C6-deficient rat heart transplantation model

Wu¹,

Korsgren²,

Wennberg³

et al. 1999

Transplant International

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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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Efficacy of Immunosuppressive Drugs in Islet Xenotransplantation

Abstract: LEF+CsA+MMF prevented rejection of porcine ICC xenografts in the rat for up to 24 days after transplantation.

Cited by 41 publications

References 21 publications

Transplantation of Long-term Cultured Porcine Islets in the Rat: Prolonged Graft Survival and Recipient Growth on Reduced Immunosuppression

Transplantation of Long-term Cultured Porcine Islets in the Rat: Prolonged Graft Survival and Recipient Growth on Reduced Immunosuppression

Deoxyspergualin delays xenograft rejection in the guinea pig-to-C6-deficient rat heart transplantation model

Organ TransplantDrugs

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