B cell tolerance and xenotransplantation

Bardwell, Philip D.; Ohdan, Hideki; Sykes, Megan

doi:10.1097/01.mot.0000175544.97974.92

Cited by 3 publications

(2 citation statements)

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“…While the early anergy was reversible by transfer of anti‐αGal‐forming cells to a non‐αGal‐containing environment, the later deletional tolerance, as expected, could not be reversed by removal of B cells from the αGal‐containing environment . Further mechanistic studies of the early tolerance induction in this model revealed a role for complement receptors (CR1/2) expressed on non‐hematopoietic cells in promoting both anti‐αGal Nab formation following immunization and tolerance induction via mixed chimerism, possibly implicating follicular dendritic cells . Unpublished studies (P. Bardwell, I. Shimizu, V. Levesque, H.‐W.…”

Section: Lessons From Mixed Chimerism Induction In Rodent and Humanizmentioning

confidence: 62%

IXA Honorary Member Lecture, 2017: The long and winding road to tolerance

Sykes

2018

Xenotransplantation

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The last 15 years or so have seen exciting progress in xenotransplantation, with porcine organ grafts surviving months or even years in non-human primates. These advances reflect the application of new scientific knowledge, improved immunosuppressive agents, and genetic engineering. The field has recently enjoyed a renaissance of interest and hope, largely due to the exponential increase in our capacity to genetically engineer porcine source animals. However, immune responses to xenografts are very powerful and widespread clinical application of xenotransplantation will depend on the ability to suppress these immune responses while preserving the capacity to protect both the recipient and the graft from infectious microorganisms. Our work over the last three decades has aimed to engineer the immune system of the recipient in a manner that achieves specific tolerance to the xenogeneic donor while preserving otherwise normal immune function. Important proofs of principle have been obtained, first in rodents, and later in human immune systems in "humanized mice" and finally in non-human primates, demonstrating the capacity and potential synergy of mixed xenogeneic chimerism and xenogeneic thymic transplantation in tolerizing multiple arms of the immune system. Considering the fact that clinical tolerance has recently been achieved for allografts and the even greater importance of avoiding excessive immunosuppression for xenografts, it is my belief that it is both possible and imperative that we likewise achieve xenograft tolerance. I expect this to be accomplished through the availability of targeted approaches to recipient immune conditioning, understanding of immunological mechanisms of tolerance, advanced knowledge of physiological incompatibilities, and the availability of inbred miniature swine with optimized use of genetic engineering.

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Section: Lessons From Mixed Chimerism Induction In Rodent and Humanizmentioning

confidence: 62%

IXA Honorary Member Lecture, 2017: The long and winding road to tolerance

Sykes

2018

Xenotransplantation

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“…Once engraftment of xenogeneic HCs is achieved, pre-existing natural IgM antibodies against the donor disappear in mixed xenogeneic chimeras (reviewed in 91 ). Using GalTdeficient mice, the loss of anti-donor Nabs in mixed chimeras was shown to be due to specific B cell tolerance induction, initially via anergy and later by a deletional mechanism (reviewed in 92 ).…”

Section: B Tolerancementioning

confidence: 99%

Transplanting organs from pigs to humans

2019

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The success of organ transplantation is limited by the complications of immunosuppression, by chronic rejection, and by the insufficient organ supply, and thousands of patients die every year while waiting for a transplant. With recent progress in xenotransplantation permitting porcine organ graft survival of months or even years in nonhuman primates, there is renewed interest in its potential to alleviate the organ shortage. Many of these advances are the result of our heightened capacity to modify pigs genetically, particularly with the development of CRISPR-Cas9–based gene editing methodologies. Although this approach allows the engineering of pig organs that are less prone to rejection, the clinical application of xenotransplantation will require the ability to avoid the ravages of a multifaceted attack on the immune system while preserving the capacity to protect both the recipient and the graft from infectious microorganisms. In this review, we will discuss the potential and limitations of these modifications and how the engineering of the graft can be leveraged to alter the host immune response so that all types of immune attack are avoided.

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Progress in xenotransplantation: overcoming immune barriers

Sykes

Sachs

2022

Nat Rev Nephrol

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B cell tolerance and xenotransplantation

Cited by 3 publications

References 69 publications

IXA Honorary Member Lecture, 2017: The long and winding road to tolerance

IXA Honorary Member Lecture, 2017: The long and winding road to tolerance

Transplanting organs from pigs to humans

Progress in xenotransplantation: overcoming immune barriers

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