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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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Rejection of the HSCT Graft in Ifngr1−/− Mice Previously Infected with BCG(A) Chimerism was determined by assessing the surface expression of Ly5.1 (donor cells) on lymphocytes, in Ifngr1−/− and Ifngr+/+ mice treated by HSCT with bone marrow from Ifngr+/+ mice, nine weeks post HSCT. Ifngr1−/− and Ifngr+/+ mice were infected with BCG either before or after HSCT (five animals per group).(B) Bacterial loads were determined after the treatment of Ifngr1−/− and Ifngr+/+ mice previously infected with BCG (three animals per group), by HSCT with bone marrow from Ifngr+/+ mice.
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pmed-0050026-g003: Rejection of the HSCT Graft in Ifngr1−/− Mice Previously Infected with BCG(A) Chimerism was determined by assessing the surface expression of Ly5.1 (donor cells) on lymphocytes, in Ifngr1−/− and Ifngr+/+ mice treated by HSCT with bone marrow from Ifngr+/+ mice, nine weeks post HSCT. Ifngr1−/− and Ifngr+/+ mice were infected with BCG either before or after HSCT (five animals per group).(B) Bacterial loads were determined after the treatment of Ifngr1−/− and Ifngr+/+ mice previously infected with BCG (three animals per group), by HSCT with bone marrow from Ifngr+/+ mice.

Mentions: All the IFN-γR1-deficient patients undergoing HSCT had a history of mycobacterial disease, as HSCT has not yet been attempted in an asymptomatic child [12–15]. We thus infected animals with BCG before HSCT. Ifngr1−/− and Ifngr1+/+ mice were infected intravenously with 106 CFU BCG and subjected to HSCT 40 d later, with sex- and age-matched syngenic Ifngr1+/+ donors. Following intense irradiation (1,200 rads), both Ifngr1−/− and Ifngr1+/+ BCG-infected mice displayed successful immune reconstitution with Ifngr1+/+ bone marrow (unpublished data). However, with a milder conditioning regimen (550 rads) more closely mimicking the situation in human transplant patients in terms of the chimerism post HSCT [12–15], Ifngr1−/− mice infected with BCG before HSCT rejected the graft, with Ly5.1 lymphocytes from the donor phenotype accounting for less than 2% of the circulating cells, whereas about 50% chimerism was observed in the absence of BCG infection (Figure 3A). Serving as a control, Ifngr1+/+ mice infected with BCG and subjected to HSCT with Ifngr1+/+ donor marrow, under the same milder conditioning regimen, displayed successful engraftment and reconstitution. Bacterial loads, determined 11 wk after infection, reached 8.4 Log10 CFU per spleen in the Ifngr1−/− cohort, versus only 4.5 Log10 CFU in Ifngr1+/+ mice (Figure 3B). Histological observations confirmed dissemination in the Ifngr1−/− cohort, contrasting with small, well-delimited granulomas in Ifngr1+/+ animals (unpublished data). Thus, Ifngr1−/− mice infected with BCG reject HSCT, with features mimicking the graft rejection observed in IFN-γR1-deficient patients.


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)

Rejection of the HSCT Graft in Ifngr1−/− Mice Previously Infected with BCG(A) Chimerism was determined by assessing the surface expression of Ly5.1 (donor cells) on lymphocytes, in Ifngr1−/− and Ifngr+/+ mice treated by HSCT with bone marrow from Ifngr+/+ mice, nine weeks post HSCT. Ifngr1−/− and Ifngr+/+ mice were infected with BCG either before or after HSCT (five animals per group).(B) Bacterial loads were determined after the treatment of Ifngr1−/− and Ifngr+/+ mice previously infected with BCG (three animals per group), by HSCT with bone marrow from Ifngr+/+ mice.
© Copyright Policy
Related In: Results  -  Collection

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

pmed-0050026-g003: Rejection of the HSCT Graft in Ifngr1−/− Mice Previously Infected with BCG(A) Chimerism was determined by assessing the surface expression of Ly5.1 (donor cells) on lymphocytes, in Ifngr1−/− and Ifngr+/+ mice treated by HSCT with bone marrow from Ifngr+/+ mice, nine weeks post HSCT. Ifngr1−/− and Ifngr+/+ mice were infected with BCG either before or after HSCT (five animals per group).(B) Bacterial loads were determined after the treatment of Ifngr1−/− and Ifngr+/+ mice previously infected with BCG (three animals per group), by HSCT with bone marrow from Ifngr+/+ mice.
Mentions: All the IFN-γR1-deficient patients undergoing HSCT had a history of mycobacterial disease, as HSCT has not yet been attempted in an asymptomatic child [12–15]. We thus infected animals with BCG before HSCT. Ifngr1−/− and Ifngr1+/+ mice were infected intravenously with 106 CFU BCG and subjected to HSCT 40 d later, with sex- and age-matched syngenic Ifngr1+/+ donors. Following intense irradiation (1,200 rads), both Ifngr1−/− and Ifngr1+/+ BCG-infected mice displayed successful immune reconstitution with Ifngr1+/+ bone marrow (unpublished data). However, with a milder conditioning regimen (550 rads) more closely mimicking the situation in human transplant patients in terms of the chimerism post HSCT [12–15], Ifngr1−/− mice infected with BCG before HSCT rejected the graft, with Ly5.1 lymphocytes from the donor phenotype accounting for less than 2% of the circulating cells, whereas about 50% chimerism was observed in the absence of BCG infection (Figure 3A). Serving as a control, Ifngr1+/+ mice infected with BCG and subjected to HSCT with Ifngr1+/+ donor marrow, under the same milder conditioning regimen, displayed successful engraftment and reconstitution. Bacterial loads, determined 11 wk after infection, reached 8.4 Log10 CFU per spleen in the Ifngr1−/− cohort, versus only 4.5 Log10 CFU in Ifngr1+/+ mice (Figure 3B). Histological observations confirmed dissemination in the Ifngr1−/− cohort, contrasting with small, well-delimited granulomas in Ifngr1+/+ animals (unpublished data). Thus, Ifngr1−/− mice infected with BCG reject HSCT, with features mimicking the graft rejection observed in IFN-γR1-deficient patients.

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