IFN-gamma mediates the rejection of haematopoietic stem cells in IFN-gamma R1-deficient hosts

Background Interferon-gamma receptor 1 (IFN-gamma R1) 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-gamma R1 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-Guerin (BCG) rejected HSCT. Like infected IFN-gamma R1-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-gamma R1-deficient mice, inhibiting the development of heterologous, IFN-gamma R1-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-gamma R1-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.