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PI3Kγ inhibition blocks glomerulonephritis and extends lifespan in a mouse model of systemic lupus

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Abstract

Systemic lupus erythematosus (SLE) is a chronic inflammatory disease generated by deregulation of T cell–mediated B-cell activation, which results in glomerulonephritis and renal failure. Disease is treated with immunosuppressants and cytostatic agents that have numerous side effects. Here we examine the use of inhibitors of phosphoinositide 3-kinase (PI3K) γ, a lipid kinase that regulates inflammation, in the MRL-lpr mouse model of SLE. Treatment reduced glomerulonephritis and prolonged lifespan, suggesting that P13Kγ may be a useful target in the treatment of chronic inflammation.

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Figure 1: p110γ inhibition reduces hypercellularity and PI3K-PKB pathway activity in MRL-lpr mice.
Figure 2: p110γ inhibition reduces renal disease and memory T-cell numbers in MRL-lpr mice.

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Acknowledgements

We thank M.C. Moreno-Ortíz for cytofluorometry studies, P. Pallares, J. Martín and L. Gómez for animal work, A. Quadropani and the Serono team for technical advice and C. Mark for editorial assistance. D.F.B. has a Ramón y Cajal contract from the Spanish Ministry of Education and Science. This work was supported by grants from the Ramon Areces Fundation, European Union (QLRT2001-02171), the Community of Madrid (8.3/0030/2000) and the Spanish Dirección General de Ciencia y Desarrollo Tecnológico (SAF2001.2278). The Department of Immunology and Oncology was founded and is supported by the Spanish Council for Scientific Research and by Pfizer.

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Authors and Affiliations

  1. Department of Immunology and Oncology, and Animal Facility, Centro Nacional de Biotecnología/CSIC, Universidad Autónoma de Madrid, Cantoblanco, Madrid, E-28049, Spain

    Domingo F Barber, Almira Bartolomé, Carmen Hernandez, Cristina Fernandez-Arias, Santiago Rodríguez, Carlos Martinez-A, Dimitrios Balomenos & Ana C Carrera

  2. Department of Animal Medicine and Surgery, Veterinary School, Universidad Complutense de Madrid, Madrid, E-28040, Spain

    Juana M Flores

  3. Hospital Ramón y Cajal, Carretera de Colmenar Viejo Km 9, Madrid, E-28034, Spain

    Clara Redondo

  4. Serono Pharmaceutical Research Institute, Serono International S.A., Geneva, CH-1211, Switzerland

    Montserrat Camps, Thomas Rückle, Matthias K Schwarz & Christian Rommel

Authors
  1. Domingo F Barber
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  2. Almira Bartolomé
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  3. Carmen Hernandez
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  4. Juana M Flores
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  5. Clara Redondo
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  6. Cristina Fernandez-Arias
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  7. Montserrat Camps
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  8. Thomas Rückle
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  9. Matthias K Schwarz
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  10. Santiago Rodríguez
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  11. Carlos Martinez-A
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  12. Dimitrios Balomenos
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  13. Christian Rommel
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  14. Ana C Carrera
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Corresponding author

Correspondence to Ana C Carrera.

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The authors declare no competing financial interests.

Supplementary information

Supplementary Fig. 1

Different cell types in splenocytes from Control, Dexamethasone- and AS605240-treated MRL-lpr mice. (PDF 412 kb)

Supplementary Fig. 2

Proportion and absolute numbers of memory cells in splenocytes from Control, Dexamethasone- and AS605240-treated MRL-lpr mice. (PDF 352 kb)

Supplementary Table 1

SLE-like disease in AS605240-treated MRL-lpr mice. (PDF 51 kb)

Supplementary Methods (PDF 88 kb)

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Barber, D., Bartolomé, A., Hernandez, C. et al. PI3Kγ inhibition blocks glomerulonephritis and extends lifespan in a mouse model of systemic lupus. Nat Med 11, 933–935 (2005). https://doi.org/10.1038/nm1291

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  • DOI: https://doi.org/10.1038/nm1291

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