IFN-gamma mediates the rejection of haematopoietic stem cells in IFN-gammaR1-deficient hosts.Reportar como inadecuado




IFN-gamma mediates the rejection of haematopoietic stem cells in IFN-gammaR1-deficient hosts. - Descarga este documento en PDF. Documentación en PDF para descargar gratis. Disponible también para leer online.

* Corresponding author 1 Génétique Humaine des Maladies Infectieuses 2 EPIM - Physiopathologie et diagnostic des infections microbiennes 3 IC - Institut Cochin 4 Service d-anatomie pathologique 5 Service d-immunologie, hématologie et rhumatologie pédiatriques

Abstract : BACKGROUND: Interferon-gamma receptor 1 IFN-gammaR1 deficiency is a life-threatening inherited disorder, conferring predisposition to mycobacterial diseases. Haematopoietic stem cell transplantation HSCT is the only curative treatment available, but is hampered by a very high rate of graft rejection, even with intra-familial HLA-identical transplants. This high rejection rate is not seen in any other congenital disorders and remains unexplained. We studied the underlying mechanism in a mouse model of HSCT for IFN-gammaR1 deficiency. METHODS AND FINDINGS: We demonstrated that HSCT with cells from a syngenic C57BL-6 Ifngr1+-+ donor engrafted well and restored anti-mycobacterial immunity in naive, non-infected C57BL-6 Ifngr1- recipients. However, Ifngr1- mice previously infected with Mycobacterium bovis bacillus Calmette-Guérin BCG rejected HSCT. Like infected IFN-gammaR1-deficient humans, infected Ifngr1- mice displayed very high serum IFN-gamma levels before HSCT. The administration of a recombinant IFN-gamma-expressing AAV vector to Ifngr1- naive recipients also resulted in HSCT graft rejection. Transplantation was successful in Ifngr1- x Ifng- double-mutant mice, even after BCG infection. Finally, efficient antibody-mediated IFN-gamma depletion in infected Ifngr1- mice in vivo allowed subsequent engraftment. CONCLUSIONS: High serum IFN-gamma concentration is both necessary and sufficient for graft rejection in IFN-gammaR1-deficient mice, inhibiting the development of heterologous, IFN-gammaR1-expressing, haematopoietic cell lineages. These results confirm that IFN-gamma is an anti-haematopoietic cytokine in vivo. They also pave the way for HSCT management in IFN-gammaR1-deficient patients through IFN-gamma depletion from the blood. They further raise the possibility that depleting IFN-gamma may improve engraftment in other settings, such as HSCT from a haplo-identical or unrelated donor.





Autor: Martin Rottman - Claire Soudais - Guillaume Vogt - Laurent Renia - Jean-François Emile - Hélène Decaluwe - Jean-Louis Gaillard

Fuente: https://hal.archives-ouvertes.fr/



DESCARGAR PDF




Documentos relacionados