Development of Tolerance to Class Ii-Mismatched Renal Transplants After a Short Course of Cyclosporine Therapy in Miniature Swine

Fishbein, Jonathan M.; Rosengard, Bruce R.; Gianello, Pierre; Nickeleit, Volker; Guzzetta, Philip C.; Smith, Craig V.; Nakajima, Kiyokazu; Vitiello, Danielle; Hill, George C.; Sachs, David H.

doi:10.1097/00007890-199405150-00002

Cited by 30 publications

(13 citation statements)

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“…One possible explanation is that absorption of CsA might be more variable than sirolimus in a pancreatectomized pig that is on cotazyme. In some cases, we encountered unexpected high levels of CsA, which might have contributed to operational tolerance because it has been shown that tolerance to renal and liver allografts can be achieved with high-dose calcineurin inhibitor induction in pigs (33)(34)(35). Even though no immunosuppression was given to some of our recipients, histological examination showed remarkable preservation of the islets without infiltrating lymphocytes in four of the seven pigs.…”

Section: Discussionmentioning

confidence: 96%

Reversal of Diabetes in Pancreatectomized Pigs After Transplantation of Neonatal Porcine Islets

et al. 2005

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Neonatal porcine islets (NPIs) are able to grow and to reverse hyperglycemia after transplantation in immunoincompetent mice. The aim of this study was to demonstrate the feasibility of allogeneic NPI grafts to achieve normoglycemia in a pancreatectomized diabetic pig. NPIs were isolated from pancreases of 1-to 3-dayold pigs, cultured, and then transplanted via the portal vein into the liver of totally pancreatectomized pigs (mean body weight, 20.8 kg). Each pig received NPIs consisting of 3.1 ؎ 0.3 ؋ 10 6 ␤-cells/kg (12,476 ؎ 1,146 islet equivalent/kg). The six pigs that were given cyclosporine and sirolimus achieved normoglycemia by day 14 without insulin therapy. Three pigs died of surgical complications shortly after transplantation, whereas the other three remained insulin independent up to day 69. Of seven nonimmunosuppressed recipients, four pigs became normoglycemic by day 14 without insulin treatment, with two of the animals remaining normoglycemic long term. Well-preserved insulin-positive cells were found in the graft at the end of follow-up with a significant increase in insulin content in long-term survivors of both groups. This study demonstrates for the first time that allogeneic NPIs can reverse hyperglycemia in totally pancreatectomized diabetic pigs.

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Section: Discussionmentioning

confidence: 96%

Reversal of Diabetes in Pancreatectomized Pigs After Transplantation of Neonatal Porcine Islets

et al. 2005

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“…CyA (7.5–15 mg/kg body weight) was given twice per day to maintain a trough level of 400 to 600 ng/mL for 7 consecutive days, followed by a 7-day tapering dose. This level of immunosuppression was chosen based on our experience with therapeutic levels of CyA and steroids used to induce tolerance to renal transplants in miniature swine (14, 15). Immunosuppressive treatments were administered beginning 1 day before pUTC injections.…”

Section: Methodsmentioning

confidence: 99%

Approaches to Avoid Immune Responses Induced by Repeated Subcutaneous Injections of Allogeneic Umbilical Cord Tissue-Derived Cells

et al. 2010

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Background Cellular treatments for repairing diseased tissues represent a promising clinical strategy. Umbilical cord tissue-derived cells (UTC) are a unique source of cells with a low immunogenic profile and potential for tissue repair. By using UTC from miniature swine, we previously demonstrated that despite their low immunogenic phenotype, UTC could induce an immune response under certain inflammatory conditions and after multiple subcutaneous (SC) injections. Given that repeat dosing of cells may be necessary to achieve a lasting therapeutic benefit, in this study, we examined approaches to avoid an immune response to multiple SC injections of UTC. Methods By using in vitro and in vivo measures of sensitization to SC cellular injections, we assessed the effects of varying the location of administration site, prolongation of timing between injections, and use of immunosuppressive treatments on repeated cellular injections in Massachusetts General Hospital major histocompatibility complex-defined miniature swine. Results Although under normal conditions, a single SC injection of major histocompatibility complex-mismatched UTC did not induce a detectable immune response, multiple SC injections of UTC demonstrated rapid humoral and cell-mediated immune responses. Avoidance of an immune response to repeat SC injection was achieved by concurrent immunosuppression with each dose of UTC. Conclusions UTC and other similar cell types believed to be nonimmunogenic have the potential to induce immune responses under certain conditions. These studies provide important considerations and guidelines for preclinical studies investigating allogeneic cellular therapies.

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“…We have previously hypothesized a competition between alloreactive and regulatory cells as responsible for the outcome in this model, and have demonstrated how, in the presence of adequate T cell help, tolerance succumbs to rejection (16). Consistent with this hypothesis, cyclosporine early posttransplant may blunt an alloaggressive response while permitting a down-regulatory response to persist, resulting in tolerance (1).…”

Section: Discussionmentioning

confidence: 99%

Evidence for a Gene Controlling the Induction of Transplantation Tolerance

Lee

Hanekamp

Villani

et al. 2014

American Journal of Transplantation

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Class I mismatched kidney transplantation in Massachusetts General Hospital MHC-defined miniature swine has been studied extensively as a model for induction of systemic allograft tolerance. In a large series of juvenile swine, long-term graft acceptance has been observed consistently following a 12-day course of cyclosporine. It was therefore surprising when three of five recipients in one of our studies rejected their grafts. Examination of the origins of the rejecting animals revealed that they were derived from a subline of the SLAdd miniature swine herd that was intentionally being inbred toward full homozygosity and had been inbred for eight generations prior to these experiments. A blinded study of additional class I mismatched renal transplants into animals from this subline confirmed the genetic basis of this rejection. We present here preliminary evidence suggesting that a likely explanation for this phenomenon is that the rejectors in this subline are homozygous for a recessive mutant allele of a gene normally involved in the induction of tolerance. Subsequent studies will be directed toward identification and characterization of the gene(s) involved, since existence of a similar genetic locus in humans might have implications for assessing an individual's likelihood of graft rejection versus tolerance induction prior to organ transplantation.

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Development of Tolerance to Class Ii-Mismatched Renal Transplants After a Short Course of Cyclosporine Therapy in Miniature Swine

Cited by 30 publications

References 0 publications

Reversal of Diabetes in Pancreatectomized Pigs After Transplantation of Neonatal Porcine Islets

Reversal of Diabetes in Pancreatectomized Pigs After Transplantation of Neonatal Porcine Islets

Approaches to Avoid Immune Responses Induced by Repeated Subcutaneous Injections of Allogeneic Umbilical Cord Tissue-Derived Cells

Evidence for a Gene Controlling the Induction of Transplantation Tolerance

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