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


RESULTS
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.
Rottman
Martin
M
Laboratoire de Génétique Humaine des Maladies Infectieuses, INSERM, U550, Paris, France.
Soudais
Claire
C
Vogt
Guillaume
G
Renia
Laurent
L
Emile
Jean-François
JF
Decaluwe
Hélène
H
Gaillard
Jean-Louis
JL
Casanova
Jean-Laurent
JL
D000818:Animals; D000911:Antibodies, Monoclonal / Q000494:pharmacology; D016026:Bone Marrow Transplantation; D000229:Dependovirus / Q000235:genetics; D005260:Female; D020022:Genetic Predisposition to Disease; D005822:Genetic Vectors / Q000235:genetics; D006084:Graft Rejection / Q000097:blood / Q000209:etiology / Q000503:physiopathology*; D006412:Hematopoietic Stem Cells / Q000378:metabolism; D007371:Interferon-gamma / Q000097:blood / Q000172:deficiency / Q000235:genetics / Q000276:immunology / Q000502:physiology*; D018664:Interleukin-12 / Q000276:immunology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009163:Mycobacterium bovis / Q000472:pathogenicity; D011828:Radiation Chimera; D017471:Receptors, Interferon / Q000172:deficiency* / Q000235:genetics / Q000502:physiology; D011993:Recombinant Fusion Proteins / Q000502:physiology; D013047:Specific Pathogen-Free Organisms; D014376:Tuberculosis / Q000209:etiology / Q000382:microbiology; D000096743:Interferon gamma Receptor
D000911:Antibodies, Monoclonal; D007371:Interferon-gamma; D018664:Interleukin-12; D017471:Receptors, Interferon; D011993:Recombinant Fusion Proteins; D000096743:Interferon gamma Receptor