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A Human Fallopian Tube Model for Investigation of C. trachomatis Infections
Published on: August 11, 2012
Enhanced upper genital tract pathologies by blocking Tim-3 and PD-L1 signaling pathways in mice intravaginally
Bo Peng1, Chunxue Lu, Lingli Tang
1Department of Microbiology and Immunology, University of Texas Health Science Center at San Antonio, San Antonio, TX 78229, USA.
Background:
Although Tim-3 & PD-L1 signaling pathways play important roles in negatively regulating immune responses, their roles in chlamydial infection have not been evaluated.
Methods:
Neutralization antibodies targeting Tim-3 and PD-L1 were used to treat mice. Following an intravaginal infection with C. muridarum organisms, mice with or without the dual antibody treatment were compared for live chlamydial organism shedding from the lower genital tract and inflammatory pathology in the upper genital tract.
Results:
Mice treated with anti-Tim-3 and anti-PD-L1 antibodies displayed a time course of live organism shedding similar to that of mice treated with equivalent amounts of isotype-matched IgG molecules. The combined antibody blocking failed to alter either the lower genital tract cytokine or systemic humoral and cellular adaptive responses to C. muridarum infection. However, the antibody blocking significantly enhanced C. muridarum-induced pathologies in the upper genital tract, including more significant hydrosalpinx and inflammatory infiltration in uterine horn and oviduct tissues.
Conclusions:
The Tim-3 and PD-L1-mediated signaling can significantly reduce pathologies in the upper genital tract without suppressing immunity against chlamydial infection, suggesting that Tim-3 and PD-L1-mediated negative regulation may be manipulated to attenuate tubal pathologies in women persistently infected with C. trachomatis organisms.
Insights
Blocking Tim-3 and PD-L1 immune checkpoints did not affect chlamydial shedding but worsened upper genital tract inflammation. This suggests these pathways may be targeted to reduce tubal damage in persistent chlamydial infections.
Area of Science:
- Immunology
- Microbiology
- Reproductive Health
Background:
- T-cell immunoglobulin and mucin-domain containing-3 (Tim-3) and programmed death-ligand 1 (PD-L1) are key negative regulators of immune responses.
- The specific roles of Tim-3 and PD-L1 in chlamydial infections remain largely uninvestigated.
Purpose of the Study:
- To evaluate the impact of blocking Tim-3 and PD-L1 signaling on the immune response and pathology during Chlamydia muridarum infection.
- To determine if targeting these pathways could influence chlamydial clearance or associated inflammation.
Main Methods:
- Mice were infected intravaginally with C. muridarum.
- Treatment involved administering neutralization antibodies against Tim-3 and PD-L1.
- Outcomes measured included live organism shedding, cytokine levels, adaptive immune responses, and upper genital tract inflammatory pathology.
Main Results:
- Dual antibody blockade of Tim-3 and PD-L1 did not alter the shedding of live chlamydial organisms.
- Blocking these pathways did not affect lower genital tract cytokine profiles or systemic adaptive immune responses.
- Significantly enhanced C. muridarum-induced pathologies, such as hydrosalpinx and inflammatory infiltration, were observed in the upper genital tract.
Conclusions:
- Tim-3 and PD-L1 signaling negatively regulate upper genital tract pathologies during chlamydial infection without compromising anti-chlamydial immunity.
- Targeting Tim-3 and PD-L1 pathways offers a potential therapeutic strategy to attenuate tubal pathologies in women with persistent C. trachomatis infections.
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