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

Rottman M, Soudais C, Vogt G, Renia L, Emile JF, Decaluwe H, Gaillard JL, Casanova JL - PLoS Med. (2008)

Bottom Line: Transplantation was successful in Ifngr1-/- x Ifng-/- double-mutant mice, even after BCG infection.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.

View Article: PubMed Central - PubMed

Affiliation: 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.

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Ifngr1−/− Mice Are Susceptible to BCG Infection(A) Ifngr1−/− mice were infected with between 102 and 106 CFU of BCG, and animal survival (five animals per group) was monitored thereafter.(B) Splenic mycobacterial loads were determined on days 4, 15, 45, and 90 in infected Ifngr1−/− and Ifngr+/+ mice; means of five animals per point are shown.
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pmed-0050026-g001: Ifngr1−/− Mice Are Susceptible to BCG Infection(A) Ifngr1−/− mice were infected with between 102 and 106 CFU of BCG, and animal survival (five animals per group) was monitored thereafter.(B) Splenic mycobacterial loads were determined on days 4, 15, 45, and 90 in infected Ifngr1−/− and Ifngr+/+ mice; means of five animals per point are shown.

Mentions: C57BL/6 Ifngr1−/− mice were unable to control BCG infection following intravenous injection with ≥ 102 CFU (Figure 1A). Deficient animals survived 29 ± 2 weeks (mean ± SD) following challenge with 102 CFU, whereas no mortality was observed in wild-type C57BL/6 control mice (Ifngr1+/+) during 12 mo of follow-up, even after infection with the highest counts of CFU. The survival of deficient animals was inversely proportional to the size of the inoculum (Figure 1A), with mortality ranging from 29 wk with 102 CFU to 12 wk with 106 CFU. Ifngr1−/− mice challenged i.v. with 106 CFU of BCG were unable to control the infection: the bacterial load in the spleen increased to 7.4 ± 0.3 (Log10 CFU) by 45 d after infection and exceeded 8 Log10 CFU in dying animals (Figure 1B). In Ifngr1+/+ mice, the BCG burden was controlled, with a decrease in CFU observed by day 45, and CFU numbers falling to 5 Log10 by day 90. Granuloma formation was altered in BCG-infected Ifngr1−/− mice. Two weeks after infection, Ifngr1−/− mice had fewer and smaller granulomas in both the spleen and the liver than infected Ifngr1+/+ control mice. Granulomas were mostly lymphoid, with no recruitment of epithelioid cells, whereas the granulomas observed in Ifngr1+/+ BCG-infected mice contained mostly epithelioid cells and a few lymphocytes (unpublished data). By day 90 post-infection, Ifngr1−/− mice presented massive mycobacterial dissemination associated with large necrotising granulomas. In contrast, a very small number of small, well-delimited granulomas were observed in infected Ifngr1+/+ control mice (unpublished data). These data are consistent with the absence of mature granulomas observed in patients entirely lacking IFN-γR1 [11]. Our results confirm that Ifngr1−/− mice are highly susceptible to M. bovis BCG infection, consistent with previous reports [27], and validate this model for the study of IFN-γR1 deficiency in humans.


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

Rottman M, Soudais C, Vogt G, Renia L, Emile JF, Decaluwe H, Gaillard JL, Casanova JL - PLoS Med. (2008)

Ifngr1−/− Mice Are Susceptible to BCG Infection(A) Ifngr1−/− mice were infected with between 102 and 106 CFU of BCG, and animal survival (five animals per group) was monitored thereafter.(B) Splenic mycobacterial loads were determined on days 4, 15, 45, and 90 in infected Ifngr1−/− and Ifngr+/+ mice; means of five animals per point are shown.
© Copyright Policy
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC2214797&req=5

pmed-0050026-g001: Ifngr1−/− Mice Are Susceptible to BCG Infection(A) Ifngr1−/− mice were infected with between 102 and 106 CFU of BCG, and animal survival (five animals per group) was monitored thereafter.(B) Splenic mycobacterial loads were determined on days 4, 15, 45, and 90 in infected Ifngr1−/− and Ifngr+/+ mice; means of five animals per point are shown.
Mentions: C57BL/6 Ifngr1−/− mice were unable to control BCG infection following intravenous injection with ≥ 102 CFU (Figure 1A). Deficient animals survived 29 ± 2 weeks (mean ± SD) following challenge with 102 CFU, whereas no mortality was observed in wild-type C57BL/6 control mice (Ifngr1+/+) during 12 mo of follow-up, even after infection with the highest counts of CFU. The survival of deficient animals was inversely proportional to the size of the inoculum (Figure 1A), with mortality ranging from 29 wk with 102 CFU to 12 wk with 106 CFU. Ifngr1−/− mice challenged i.v. with 106 CFU of BCG were unable to control the infection: the bacterial load in the spleen increased to 7.4 ± 0.3 (Log10 CFU) by 45 d after infection and exceeded 8 Log10 CFU in dying animals (Figure 1B). In Ifngr1+/+ mice, the BCG burden was controlled, with a decrease in CFU observed by day 45, and CFU numbers falling to 5 Log10 by day 90. Granuloma formation was altered in BCG-infected Ifngr1−/− mice. Two weeks after infection, Ifngr1−/− mice had fewer and smaller granulomas in both the spleen and the liver than infected Ifngr1+/+ control mice. Granulomas were mostly lymphoid, with no recruitment of epithelioid cells, whereas the granulomas observed in Ifngr1+/+ BCG-infected mice contained mostly epithelioid cells and a few lymphocytes (unpublished data). By day 90 post-infection, Ifngr1−/− mice presented massive mycobacterial dissemination associated with large necrotising granulomas. In contrast, a very small number of small, well-delimited granulomas were observed in infected Ifngr1+/+ control mice (unpublished data). These data are consistent with the absence of mature granulomas observed in patients entirely lacking IFN-γR1 [11]. Our results confirm that Ifngr1−/− mice are highly susceptible to M. bovis BCG infection, consistent with previous reports [27], and validate this model for the study of IFN-γR1 deficiency in humans.

Bottom Line: Transplantation was successful in Ifngr1-/- x Ifng-/- double-mutant mice, even after BCG infection.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.

View Article: PubMed Central - PubMed

Affiliation: 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.

Show MeSH
Related in: MedlinePlus