Strategies for preventing porcine xenograft rejection: recent progress and future developments

Dorling, Anthony

doi:10.1517/13543776.7.11.1307

Cited by 4 publications

(3 citation statements)

References 72 publications

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“…All these advances may result in specific therapies to prevent DXR or promote accommodation [9], and these may emerge in the next few years. Alternatively, it may be possible to induce a kind of "tolerance" to DXR, following the example of Lin et al This article will review the biology of T cell xenoresponses and speculate, using available experimental data, on the nature of the in vivo human antipig xenoresponse.…”

Section: Introductionmentioning

confidence: 99%

T cell‐mediated xenograft rejection: Specific tolerance is probably required for long term xenograft survival

Dorling

Lechler

1998

Xenotransplantation

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T cell-mediated mechanisms of xenograft rejection appear resistant to standard immunosuppression protocols used to prevent allograft rejection and, consequently, higher doses of immunosuppressive drugs are required to promote xenograft compared to allograft survival. Evidence from recent studies suggests that porcine xenografts may be especially immunogenic in humans because of a prominent and vigorous indirect xenoresponse and because of the ability of porcine endothelium to activate human T cells. This has led to an anxiety that systemic immunosuppressives, used as the mainstay of therapy for clinical xenotransplantation, may not allow the long-term survival of porcine organs transplanted into human recipients. This article will review the biology of T cell xenoresponses, present the case for the development of novel graft-specific immunosuppressive regimes in clinical xenotransplantation, and review recent experimental progress in this area.

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Section: Introductionmentioning

confidence: 99%

T cell‐mediated xenograft rejection: Specific tolerance is probably required for long term xenograft survival

Dorling

Lechler

1998

Xenotransplantation

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“…Indeed, xenogeneic immune responses mediated by preexisting, naturally occurring antibodies and complement lead to hyperacute and acute rejection of vascularized organ grafts. These issues have been investigated in the pig to non-human primate model of heart xenotransplantation, where the presence of monkey xenoreactive natural antibodies to pig antigens and their attachment to the vascular endothelium of pig organs stimulated the classical pathway of complement activation and led to the irreversible loss of the heart because of hyperacute rejection . On the basis of genetic engineering, significant progress has been made to avert hyperacute rejection as demonstrated in monkey transplantation studies with pig transgenic hearts expressing human decay accelerating factor (DAF), a species-specific inhibitor of complement activation .…”

Section: Introductionmentioning

confidence: 99%

“…These issues have been investigated in the pig to non-human primate model of heart xenotransplantation, where the presence of monkey xenoreactive natural antibodies to pig antigens and their attachment to the vascular endothelium of pig organs stimulated the classical pathway of complement activation and led to the irreversible loss of the heart because of hyperacute rejection. 4 On the basis of genetic engineering, significant progress has been made to avert hyperacute rejection as demonstrated in monkey transplantation studies with pig transgenic hearts expressing human decay accelerating factor (DAF), a species-specific inhibitor of complement activation. 5 However, if complement activation is blocked in the absence of immunosuppression and the xenografts survive hyperacute rejection, the graft is still lost due to acute vascular rejection since excessive Ab production is induced by the transplanted xenograft.…”

Section: Introductionmentioning

confidence: 99%

Pyrazole Bioisosteres of Leflunomide as B-Cell Immunosuppressants for Xenotransplantation and Chronic Rejection: Scope and Limitations

et al. 1998

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T-cell immunosuppressant-based therapies efficiently control early graft rejection in allotransplantation settings. They fail, however, to prevent those rejection events which are mediated by transplant-induced antibody (Ab) responses such as those involved in xenograft and chronic allograft rejection. This is mainly due to their inability to block T-cell-independent Ab production against the transplanted organs. The bioactive metabolite 2(Z) of leflunomide (1) inhibits the formation of such Ab, but the drug has pharmacokinetic properties and a therapeutic window incompatible with transplantation indications. Pyrazole 3, a constrained analogue of 2(Z), was designed and shown to be conformationally and biologically similar to 2(Z). Further investigations with derivatives of 3 demonstrated that the pyrazoles had very tight structure-activity relationships, the only equipotent compound being 3o. However, in contrast to 2(Z), both 3 and 3o were inactive in vivo due to short half-life and drug concentrations lower than the in vitro obtained IC50 values. Compound 3o inhibits T-cell-independent Ab production by a different biochemical mechanism from that of 2(Z) and 3 and may therefore represent a valuable tool for the identification of new targets for B-cell inhibition.

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The Role of Complement in Transplantation

Kirschfink

Mollnes

The Complement System

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Strategies for preventing porcine xenograft rejection: recent progress and future developments

Cited by 4 publications

References 72 publications

T cell‐mediated xenograft rejection: Specific tolerance is probably required for long term xenograft survival

T cell‐mediated xenograft rejection: Specific tolerance is probably required for long term xenograft survival

Pyrazole Bioisosteres of Leflunomide as B-Cell Immunosuppressants for Xenotransplantation and Chronic Rejection: Scope and Limitations

The Role of Complement in Transplantation

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