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PLoS Med. 2008 Jan 29;5(1):e26. doi: 10.1371/journal.pmed.0050026.

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

Author information

1
Laboratoire de Génétique Humaine des Maladies Infectieuses, INSERM, U550, Paris, France.

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.

PMID:
18232731
PMCID:
PMC2214797
DOI:
10.1371/journal.pmed.0050026
[Indexed for MEDLINE]
Free PMC Article

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