IFN-γ mediates the rejection of haematopoietic stem cells in IFN-γR1-deficient hosts

被引:66
作者
Rottman, Martin [1 ,2 ,3 ]
Soudais, Claire [1 ,2 ]
Vogt, Guillaume [1 ]
Renia, Laurent [4 ,5 ,6 ]
Emile, Jean-Francois [7 ]
Decaluwe, Helene [1 ,2 ]
Gaillard, Jean-Louis [3 ]
Casanova, Jean-Laurent [1 ,2 ,8 ]
机构
[1] INSERM, Lab Genet Humaine Malad Infect, U550, Paris, France
[2] Univ Paris 05, Fac Med Necker Enfants Malad, Paris, France
[3] Hop Raymond Poincare, Fac Med Paris Ile France Ouest, UPRES Sud, EA3647,Lab Microbiol, Garches, France
[4] INSERM, Inst Cochin, U567, Paris, France
[5] CNRS, UMR8104, Paris, France
[6] Univ Paris 05, Hop Cochin, Paris, France
[7] Hop Ambroise Pare, Lab Anatomopathol, Boulogne, France
[8] Hop Necker Enfants Malad, Unite Immunol & Hematol Pediat, Paris, France
来源
PLOS MEDICINE | 2008年 / 5卷 / 01期
关键词
D O I
10.1371/journal.pmed.0050026
中图分类号
R5 [内科学];
学科分类号
1002 ; 100201 ;
摘要
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.
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收藏
页码:152 / 163
页数:12
相关论文
共 57 条
  • [51] DISTRIBUTION OF INTERFERON-GAMMA RECEPTOR IN HUMAN TISSUES
    VALENTE, G
    OZMEN, L
    NOVELLI, F
    GEUNA, M
    PALESTRO, G
    FORNI, G
    GAROTTA, G
    [J]. EUROPEAN JOURNAL OF IMMUNOLOGY, 1992, 22 (09) : 2403 - 2412
  • [52] Gains of glycosylation comprise an unexpectedly large group of pathogenic mutations
    Vogt, G
    Chapgier, A
    Yang, K
    Chuzhanova, N
    Feinberg, J
    Fieschi, C
    Boisson-Dupuis, S
    Alcais, A
    Filipe-Santos, O
    Bustamante, J
    de Beaucoudrey, L
    Al-Mohsen, I
    Al-Hajjar, S
    Al-Ghonaium, A
    Adimi, P
    Mirsaeidi, M
    Khalilzadeh, S
    Rosenzweig, S
    Martin, OD
    Bauer, TR
    Puck, JM
    Ochs, HD
    Furthner, D
    Engelhorn, C
    Mansouri, D
    Holland, SM
    Schreiber, RD
    Abel, L
    Cooper, DN
    Soudais, C
    Casanova, JL
    [J]. NATURE GENETICS, 2005, 37 (07) : 692 - 700
  • [53] INTERLEUKIN-12 IS REQUIRED FOR INTERFERON-GAMMA PRODUCTION AND LETHALITY IN LIPOPOLYSACCHARIDE-INDUCED SHOCK IN MICE
    WYSOCKA, M
    KUBIN, M
    VIEIRA, LQ
    OZMEN, L
    GAROTTA, G
    SCOTT, P
    TRINCHIERI, G
    [J]. EUROPEAN JOURNAL OF IMMUNOLOGY, 1995, 25 (03) : 672 - 676
  • [54] Effector cells of both nonhemopoietic and hemopoietic origin are required for interferon (IFN)-γ- and tumor necrosis factor (TNF)-α-dependent host resistance to the intracellular pathogen, Toxoplasma gondii
    Yap, GS
    Sher, A
    [J]. JOURNAL OF EXPERIMENTAL MEDICINE, 1999, 189 (07) : 1083 - 1091
  • [55] Bone marrow and thymus expression of interferon-gamma results in severe B-cell lineage reduction, T-cell lineage alterations, and hematopoietic progenitor deficiencies
    Young, HA
    Klinman, DM
    Reynolds, DA
    Grzegorzewski, KJ
    Nii, A
    Ward, JM
    WinklerPickett, RT
    Ortaldo, JR
    Kenny, JJ
    Komschlies, KL
    [J]. BLOOD, 1997, 89 (02) : 583 - 595
  • [56] ZHAO YX, 1995, J IMMUNOL, V155, P5736
  • [57] ZOUMBOS NC, 1984, J IMMUNOL, V133, P769