Orthotopic Heart Transplantation in a Transgenic Pig-to-Primate Model1

Schmoeckel, Michael; Bhatti, Farah; Zaidi, Afzal; Cozzi, Emanuele; Waterworth, Paul; Tolan, Michael; Goddard, Martin; Warner, R.G.; Langford, Gillian; Dunning, John; Wallwork, J.; White, David J.

doi:10.1097/00007890-199806270-00006

Cited by 197 publications

(106 citation statements)

References 21 publications

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“…In contrast, rejection of a kidney allograft in cynomolgus monkeys has been documented for subtherapeutic intramuscular dosages yielding 24-h trough levels between 40 and 200 ngiml [30]. In recent years, interest has turned to new aspects of transplantation, and cyclosporine formed a basic immunosuppressant in conditioning regimens to induce chimerism and tolerance in primates [12], and in pig-to-primate xenotransplantation [6,7,21,22,31,32]. To mimick a potential clinical application, the compound was administered in a part of these studies orally.…”

Section: Introductionmentioning

confidence: 99%

Pharmacokinetics of cyclosporine in monkeys after oral and intramuscular administration: relation to efficacy in kidney allografting

Mennninger¹,

Odeh²,

Slingerland³

et al. 2001

Transplant Int

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In cynomolgus and rhesus monkeys, the dose-normalized exposure of cyclosporine administered orally as microemulsion preconcentrate (Neoral) was lower than that upon intramuscular administration. For oral administration, mean values ( f SD) of C,,,, 24-h area-under-the curve (AUC) and 24-h trough level, all normalized for a 1 mg/kg dose, were 20 k 9 ng kgfmg ml, 210 k 70 ng h kg/mg ml and 2.6 * 0.9 ng kg/mg ml, respectively.For intramuscular administration, levels were about 5.5-fold, 9-fold and 22-fold higher. Based on pharmacokinetic data, the efficacy of oral cyclosporine treatment (without any other immunosuppressant) was evaluated in life-supporting cynomolgus monkey kidney allotransplantation. Rej ection-free kidney allograft survival could be achieved using oral cyclosporine monotherapy with average 24-h trough concentrations above 100 ng/ml during maintenance treatment. Typically, daily oral doses of 100 mg/ kg-150 mg/kg during the first two weeks post-transplantation, followed by daily 30 mgfkg-100 mg/kg dose levels during subsequent maintenance can result in long-term allograft survival, with 24-h average trough levels in individual animals during maintenance between 110 ngfml and 700 ngtml.

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Section: Introductionmentioning

confidence: 99%

Pharmacokinetics of cyclosporine in monkeys after oral and intramuscular administration: relation to efficacy in kidney allografting

Mennninger¹,

Odeh²,

Slingerland³

et al. 2001

Transplant Int

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“…1B). Histopathologically, the rejected hearts showed features of DXR typically seen in discordant combinations when hyperacute rejection is averted by depletion of complement (46,47), or by genetic modification of donor pig organs to express human complementregulating proteins (9,48,49).…”

Section: Discussionmentioning

confidence: 99%

“…Complement-dependent cytotoxicity (CDC) was measured by a hemolytic assay using modified techniques described previously (9). In brief, the hamster was bled into Alsevers solution (Sigma) (1/1; v/v).…”

Section: Complement-dependent Cytotoxicitymentioning

confidence: 99%

Long-Term Survival of Hamster Hearts in Presensitized Rats

Lin

Soares

Sato

et al. 2000

The Journal of Immunology

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We transplanted hamster hearts into rats that had been sensitized to hamster cardiac grafts 5 days earlier as a model for discordant xenotransplantation. Sensitized rats had high serum levels of elicited anti-donor IgM and IgG that caused hyperacute rejection. Transient complement inhibition with cobra venom factor (CVF) plus daily and continuing cyclosporin A (CyA) prevented hyperacute rejection. However, grafts underwent delayed xenograft rejection (DXR). DXR involved IgG and associated Ab-dependent cell-mediated rejection, because depletion of IgG or Ab-dependent cell-mediated rejection-associated effector cells prolonged graft survival and the serum-mediated Ab-dependent cell-mediated cytotoxicity in vitro. Blood exchange in combination with CVF/CyA treatment dramatically decreased the level of preexisting Abs, but DXR still occurred in association with the return of Abs. Splenectomy and cyclophosphamide acted synergistically to delay Ab return, and when combined with blood exchange/CVF/CyA facilitated long-term survival of grafts. These grafts survived in the presence of anti-donor IgM, IgG, and complement that precipitated rejection of naive hearts, indicating that accommodation (survival in the presence of anti-graft Abs and complement) had occurred. We attribute the long-term survival to the removal of preexisting anti-donor Abs and therapy that attenuated the rate of Ab return. Under such conditions, the surviving hearts showed expression in endothelial cells and smooth muscle cells of protective genes and an intragraft Th2 immune response. Th2 responses and protective genes are associated with resistance to IgM- and IgG-mediated, complement-dependent and -independent forms of rejection.

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“…161 In a pig-to-primate model and in the absence of immunosuppression, a cardiac xenograft derived from a human DAF-transgenic pig survived up to 5 days compared with about 2 from non-transgenic donors. 162 Furthermore, in another pig-to-primate model, hearts from double-transgenic pigs expressing human DAF and CD59 survived hyperacute complementmediated damage even when expressed at low levels. 163 Finally, competition of complement binding by a soluble complement receptor (CR1) suppressed the destruction of pig cells and prolonged pig xenograft survival.…”

Section: Xenotransplantationmentioning

confidence: 99%