Reversal of diabetes in non‐immunosuppressed rhesus macaques by intraportal porcine islet xenografts precedes acute cellular rejection

Abstract

Pig-to-primate intraportal islet xenografts reverse diabetes and the majority of intraportally transplanted xenogeneic islets are not subject to hyperacute rejection. They undergo acute cellular rejection mediated by CD4+- and CD8+ T cells and macrophages.

Immunological Challenges and Therapies in Xenotransplantation

“…Xenogeneic activation also prompts neutrophils to secrete proinflammatory cytokines, such as IL-1a/b, IL-6, and IL-8, involved in cellular and humoral adaptive immune responses and platelet activation, crucial players in the rejection process. As shown in some studies, polymorphonuclear neutrophils appear to (Kirchhof et al 2004;Hisashi et al 2008;Ezzelarab et al 2009;Shimizu et al 2012). As shown in the majority of reports, however, this infiltration appears to be replaced by T cells and macrophages (Kirchhof et al 2004;Hisashi et al 2008;Ezzelarab et al 2009;Shimizu et al 2012 Sommaggio et al 2012).…”

“…As shown in some studies, polymorphonuclear neutrophils appear to (Kirchhof et al 2004;Hisashi et al 2008;Ezzelarab et al 2009;Shimizu et al 2012). As shown in the majority of reports, however, this infiltration appears to be replaced by T cells and macrophages (Kirchhof et al 2004;Hisashi et al 2008;Ezzelarab et al 2009;Shimizu et al 2012 Sommaggio et al 2012). The direct cytotoxic activity of NK cells, which is inhibited primarily by human MHC class I molecules through inhibitory NK receptors, is not blocked by SLA class I products.…”

“…It has also been shown that islets from neonatal (Cardona et al 2006) or adult pigs (Kirchhof et al 2004) infused intraportally in nonimmunosuppressed primates and engrafted in the liver are destroyed within 3-5 d with a marked infiltration of CD4 þ and CD8 þ cells and macrophages (Kirchhof et al 2004;Cardona et al 2006).…”

Les xénogreffes finiront-elles par être acceptées ?

“…Des études ont également montré que des greffes orthotopiques de coeur et de poumons permettaient la survie de primates tant que ces organes n'étaient pas rejetés [9][10][11]. Chez le macaque rendu diabétique par administration de streptozotocine, des îlots pancréatiques porcins injectés par voie intraportale sont capables de restaurer la normoglycémie tant qu'un rejet de type cellulaire ne les détruit pas [12]. La greffe de neuroblastes foetaux porcins a également été testée chez des patients parkinsoniens ou atteints de maladie de Huntington, dans un essai clinique de phase I. Un an après la transplantation, une amélioration modérée du score clinique d'éva-luation avait été notée chez les patients parkinsoniens, mais pas chez ceux atteints de maladie de Huntington.…”

Cellular Therapies for Type 1 Diabetes

“…Nonetheless, it is possible that the current immunosuppressive strategies still have negative effects on islet graft function or are unable to completely control reactivity. Thus new strategies to reverse autoimmunity and induce longterm tolerance, including those that target co-stimulatory and adhesion molecules as well as growth factors, are being explored in mouse and non-human primate models [41][42][43][44][45][46][47][48].…”