Pig–to–Non-human Primate Heart Transplantation: Immunologic Progress Over 20 Years

Zhu, Xiaoping; Dor, Frank J. M. F.; Cooper, David K.C.

doi:10.1016/j.healun.2006.12.005

Cited by 15 publications

(13 citation statements)

References 67 publications

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“…Therefore, one must examine the requirements for T-cell-dependent xenograft rejection using defined tissues/organs of interest and particular inter-species transplant combinations. It is now possible to genetically manipulate porcine donors such that they become less vulnerable to hyperacute rejection by naturally occurring anti-porcine antibodies and complement [36–38]. As such, the problem of T-cell-dependent xenograft immunity has become a more pressing obstacle to overcome.…”

Section: Discussionmentioning

confidence: 99%

CD4 T cells mediate cardiac xenograft rejection via host MHC Class II

Plenter¹,

Grazia²,

Doan³

et al. 2012

The Journal of Heart and Lung Transplantation

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Background Previous studies indicate that acute CD4 T-cell-mediated cardiac allograft rejection requires donor MHC class II expression and can be independent of ‘indirect’ antigen presentation. However, other studies suggest that indirect antigen presentation to CD4 T-cells may play a primary role in cellular xenograft immunity. Thus, the relative roles of direct/indirect CD4 T-cell reactivity against cardiac xenografts is unclear. We set out to determine the role for indirect CD4 T-cell reactivity in cardiac xenograft rejection. Methods Rat hearts were transplanted heterotopically into wild-type and immuno-deficient mice. Recipients were untreated, treated with depleting antibodies or reconstituted with wild-type cells. Results Antibody depletion confirmed that rat heart xenograft rejection in C57Bl/6 mice was CD4 T-cell-dependent. Also, heart xenografts survived long-term in B6 MHC class II (C2D) deficient mice. Graft acceptance in C2D mice was not secondary to CD4 T-cell deficiency alone, because transferred B6 CD4 T-cells failed to trigger rejection in C2D hosts. Furthermore, purified CD4 T-cells were sufficient for acute rejection of rat heart xenografts in immune-deficient B6rag1−/− recipients. Importantly, CD4 T-cells did not reject rat hearts in C2Drag1−/− hosts, contrasting results using cardiac allografts. ‘Direct’ xenoreactive CD4 T-cells were not sufficient to mediate rejection despite vigorous reactivity to rat stimulator cells in vitro. Conclusion Taken together, results show that CD4 T-cells are both necessary and sufficient for acute cardiac xenograft rejection and host MHC class II is critical in this process.

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Section: Discussionmentioning

confidence: 99%

CD4 T cells mediate cardiac xenograft rejection via host MHC Class II

Plenter¹,

Grazia²,

Doan³

et al. 2012

The Journal of Heart and Lung Transplantation

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“…Survival after heterotopic heart transplantation now extends to 8 months (86,87) and after life-supporting kidney transplantation to almost 3 months (88,89). However, this is not yet to the extent that clinical trials can be contemplated.…”

Section: Approaches To Exogenous Immunomodulatory Therapymentioning

confidence: 99%

New Concepts of Immune Modulation in Xenotransplantation

et al. 2013

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The shortage of human organs for transplantation has focused research on the possibility of transplanting pig organs into humans. Many factors contribute to the failure of a pig organ graft in a primate. A rapid innate immune response (natural anti-pig antibody, complement activation, and an innate cellular response, e.g., neutrophils, monocytes, macrophages, NK cells) is followed by an adaptive immune response, although T cell infiltration of the graft has rarely been reported. Other factors (e.g., coagulation dysregulation, inflammation) appear to play a significantly greater role than in allotransplantation. The immune responses to a pig xenograft cannot therefore be controlled simply by suppression of T cell activity. Before xenotransplantation can be introduced successfully into the clinic, the problems of the innate, coagulopathic, and inflammatory responses will have to be overcome, most likely by the transplantation of organs from genetically-engineered pigs. Many of the genetic manipulations aimed at protecting against these responses also reduce the adaptive response. The T cell and elicited antibody responses can be prevented by the biologic and/or pharmacologic agents currently available, in particular, by costimulation blockade-based regimens. The exogenous immunosuppressive regimen may be significantly reduced by the presence of a graft from a pig transgenic for a mutant (human) class II transactivator gene, resulting in downregulation of SLA class II expression, or from a pig with ‘local’ vascular endothelial cell expression of an immunosuppressive gene, e.g., CTLA4-Ig. The immunomodulatory efficacy of regulatory T cells or mesenchymal stromal cells has been demonstrated in vitro, but not yet in vivo.

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“…Progress during the past 20 years or so can be illustrated by the prolongation of survival of pig hearts transplanted heterotopically into baboons using wild-type or genetically modified pigs and various immunosuppressive protocols (Figure 2) [72]. …”

Section: Genetically Engineered Pigsmentioning

confidence: 99%

“…The role of T cells in the development of thrombotic microangiopathy is uncertain and controversial. Reproduced with permission from [72]. …”

Section: Figuresmentioning

confidence: 99%