Document Detail

Dectin immunoadhesins and pneumocystis pneumonia.
MedLine Citation:
PMID:  23836814     Owner:  NLM     Status:  MEDLINE    
The opportunistic pathogen Pneumocystis jirovecii is a significant cause of disease in HIV-infected patients and others with immunosuppressive conditions. Pneumocystis can also cause complications in treatment following antiretroviral therapy or reversal of immunosuppressive therapy, as the newly reconstituted immune system can develop a pathological inflammatory response to remaining antigens or a previously undetected infection. To target β-(1,3)-glucan, a structural component of the Pneumocystis cell wall with immune-stimulating properties, we have developed immunoadhesins consisting of the carbohydrate binding domain of Dectin-1 fused to the Fc regions of the 4 subtypes of murine IgG (mIgG). These immunoadhesins bind β-glucan with high affinity, and precoating the surface of zymosan with Dectin-1:Fc can reduce cytokine production by macrophages in an in vitro stimulation assay. All Dectin-1:Fc variants showed specificity of binding to the asci of Pneumocystis murina, but effector activity of the fusion molecules varied depending on Fc subtype. Dectin-1:mIgG2a Fc was able to reduce the viability of P. murina in culture through a complement-dependent mechanism, whereas previous studies have shown the mIgG1 Fc fusion to increase macrophage-dependent killing. In an in vivo challenge model, systemic expression of Dectin-1:mIgG1 Fc significantly reduced ascus burden in the lung. When administered postinfection in a model of immune reconstitution inflammatory syndrome (IRIS), both Dectin-1:mIgG1 and Dectin-1:mIgG2a Fc reduced hypoxemia despite minimal effects on fungal burden in the lung. Taken together, these data indicate that molecules targeting β-glucan may provide a mechanism for treatment of fungal infection and for modulation of the inflammatory response to Pneumocystis and other pathogens.
David M Ricks; Kong Chen; Mingquan Zheng; Chad Steele; Jay K Kolls
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Publication Detail:
Type:  Journal Article     Date:  2013-07-08
Journal Detail:
Title:  Infection and immunity     Volume:  81     ISSN:  1098-5522     ISO Abbreviation:  Infect. Immun.     Publication Date:  2013 Sep 
Date Detail:
Created Date:  2013-08-14     Completed Date:  2014-02-20     Revised Date:  2014-03-19    
Medline Journal Info:
Nlm Unique ID:  0246127     Medline TA:  Infect Immun     Country:  United States    
Other Details:
Languages:  eng     Pagination:  3451-62     Citation Subset:  IM    
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MeSH Terms
Antibodies, Monoclonal / immunology*
B-Lymphocytes / immunology
Cell Wall / immunology
Cytokines / immunology
Immune Reconstitution Inflammatory Syndrome / immunology
Immunoglobulin G / immunology
Inflammation / immunology
Lectins, C-Type / immunology*
Lung / immunology
Macrophages / immunology
Mice, Inbred C57BL
Pneumonia, Pneumocystis / immunology*
T-Lymphocytes / immunology
Zymosan / immunology
beta-Glucans / immunology
Grant Support
Reg. No./Substance:
0/Antibodies, Monoclonal; 0/Cytokines; 0/Immunoglobulin G; 0/Lectins, C-Type; 0/beta-Glucans; 0/dectin 1; 9010-72-4/Zymosan

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