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Neutralization of endogenous granulocyte-macrophage colony-stimulating factor subverts the protective immune response
G S Deepe1, R Gibbons, E Woodward
1Division of Infectious Diseases, Department of Medicine, University of Cincinnati College of Medicine, OH 45267, USA. george.deepe@uc.edu
Abstract:
We examined the influence of endogenous GM-CSF on the course of primary and secondary pulmonary histoplasmosis. A high proportion (>/=75%) of C57BL/6 mice given mAb to GM-CSF did not survive primary infection, whereas 88-94% of infected controls survived. Analysis of leukocytes revealed significantly fewer CD4+ and CD8+ cells in lungs, but not airways, of anti-GM-CSF-treated mice as compared with infected controls. However, the histopathology was similar between the two groups. Lungs of mice given mAb to GM-CSF manifested depressed levels of TNF-alpha, IFN-gamma, and reactive nitrogen intermediates and elevated levels of IL-4 and IL-10. Administration of mAb to IL-4, to IL-10, or both restored protective immunity in GM-CSF-neutralized mice. In secondary infection, administration of mAb to GM-CSF exacerbated infection but did not alter survival over 30 days. The character of the inflammatory response was similar, and no differences were detected in Th1 or Th2 cytokine production between the two groups. Thus, endogenous GM-CSF is essential for survival in primary but not secondary infection, and blockade perturbs protective immunity. These findings reveal a new mechanism whereby GM-CSF contributes to host protection and demonstrate differences in control of primary and secondary histoplasmosis.
Insights
Endogenous granulocyte-macrophage colony-stimulating factor (GM-CSF) is crucial for survival during primary pulmonary histoplasmosis by modulating immune cell counts and cytokine profiles. However, its role diminishes in secondary infections.
Area of Science:
- Immunology
- Infectious Diseases
- Pulmonary Medicine
Background:
- Pulmonary histoplasmosis is a significant fungal infection affecting the lungs.
- The role of endogenous granulocyte-macrophage colony-stimulating factor (GM-CSF) in histoplasmosis pathogenesis is not fully understood.
- Understanding immune responses is critical for developing effective treatments.
Purpose of the Study:
- To investigate the influence of endogenous GM-CSF on primary and secondary pulmonary histoplasmosis.
- To elucidate the mechanisms by which GM-CSF affects immune cell populations and cytokine production.
- To compare the control of primary versus secondary histoplasmosis infections.
Main Methods:
- C57BL/6 mice were infected with Histoplasma and treated with monoclonal antibodies (mAbs) against GM-CSF.
- Leukocyte analysis, histopathology, and cytokine profiling (TNF-alpha, IFN-gamma, IL-4, IL-10) were performed.
- Secondary infections were induced, and the effects of GM-CSF blockade were assessed.
Main Results:
- GM-CSF blockade significantly reduced survival in primary infection, associated with decreased CD4+ and CD8+ cells and altered cytokine levels (decreased Th1, increased Th2).
- Neutralizing IL-4, IL-10, or both restored protective immunity in GM-CSF-neutralized mice during primary infection.
- GM-CSF blockade exacerbated secondary infection but did not significantly alter survival, with similar inflammatory responses and cytokine profiles.
Conclusions:
- Endogenous GM-CSF is essential for host survival during primary pulmonary histoplasmosis.
- GM-CSF blockade impairs protective immunity by altering immune cell infiltration and cytokine balance.
- Control mechanisms differ between primary and secondary histoplasmosis infections, with GM-CSF playing a critical role primarily in the initial response.