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ITIM ‐dependent negative signaling pathways for the control of cell‐mediated xenogeneic immune responses

ITIM ‐dependent negative signaling pathways for the control of cell‐mediated xenogeneic immune... Xenotransplantation is an innovative field of research with the potential to provide us with an alternative source of organs to face the severe shortage of human organ donors. For several reasons, pigs have been chosen as the most suitable source of organs and tissues for transplantation in humans. However, porcine xenografts undergo cellular immune responses representing a major barrier to their acceptance and normal functioning. Innate and adaptive xenogeneic immunity is mediated by both the recognition of xenogeneic tissue antigens and the lack of inhibition due to molecular cross‐species incompatibilities of regulatory pathways. Therefore, the delivery of immunoreceptor tyrosine‐based inhibitory motif (ITIM)‐dependent and related negative signals to control innate (NK cells, macrophages) and adaptive T and B cells might overcome cell‐mediated xenogeneic immunity. The proof of this concept has already been achieved in vitro by the transgenic overexpression of human ligands of several inhibitory receptors in porcine cells resulting in their resistance against xenoreactivity. Consequently, several transgenic pigs expressing tissue‐specific human ligands of inhibitory coreceptors (HLA‐E, CD47) or soluble competitors of costimulation (belatacept) have already been generated. The development of these robust and innovative approaches to modulate human anti‐pig cellular immune responses, complementary to conventional immunosuppression, will help to achieve long‐term xenograft survival. In this review, we will focus on the current strategies to enhance negative signaling pathways for the regulation of undesirable cell‐mediated xenoreactive immune responses. http://www.deepdyve.com/assets/images/DeepDyve-Logo-lg.png Xenotransplantation Wiley

ITIM ‐dependent negative signaling pathways for the control of cell‐mediated xenogeneic immune responses

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References (83)

Publisher
Wiley
Copyright
© 2013 John Wiley & Sons A/S
ISSN
0908-665X
eISSN
1399-3089
DOI
10.1111/xen.12049
pmid
23968542
Publisher site
See Article on Publisher Site

Abstract

Xenotransplantation is an innovative field of research with the potential to provide us with an alternative source of organs to face the severe shortage of human organ donors. For several reasons, pigs have been chosen as the most suitable source of organs and tissues for transplantation in humans. However, porcine xenografts undergo cellular immune responses representing a major barrier to their acceptance and normal functioning. Innate and adaptive xenogeneic immunity is mediated by both the recognition of xenogeneic tissue antigens and the lack of inhibition due to molecular cross‐species incompatibilities of regulatory pathways. Therefore, the delivery of immunoreceptor tyrosine‐based inhibitory motif (ITIM)‐dependent and related negative signals to control innate (NK cells, macrophages) and adaptive T and B cells might overcome cell‐mediated xenogeneic immunity. The proof of this concept has already been achieved in vitro by the transgenic overexpression of human ligands of several inhibitory receptors in porcine cells resulting in their resistance against xenoreactivity. Consequently, several transgenic pigs expressing tissue‐specific human ligands of inhibitory coreceptors (HLA‐E, CD47) or soluble competitors of costimulation (belatacept) have already been generated. The development of these robust and innovative approaches to modulate human anti‐pig cellular immune responses, complementary to conventional immunosuppression, will help to achieve long‐term xenograft survival. In this review, we will focus on the current strategies to enhance negative signaling pathways for the regulation of undesirable cell‐mediated xenoreactive immune responses.

Journal

Xenotransplantation – Wiley

Published: Nov 1, 2013

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