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Dendritic cell activation and memory cell development are impaired among mice administered medroxyprogesterone acetate prior to mucosal herpes simplex virus type 1 infection.

ABSTRACT: Epidemiological studies indicate that the exogenous sex steroid medroxyprogesterone acetate (MPA) can impair cell-mediated immunity, but mechanisms responsible for this observation are not well defined. In this study, MPA administered to mice 1 wk prior to HSV type 1 (HSV-1) infection of their corneal mucosa impaired initial expansion of viral-specific effector and memory precursor T cells and reduced the number of viral-specific memory T cells found in latently infected mice. MPA treatment also dampened expression of the costimulatory molecules CD40, CD70, and CD80 by dendritic cells (DC) in lymph nodes draining acute infection, whereas coculture of such DC with T cells from uninfected mice dramatically impaired ex vivo T cell proliferation compared with the use of DC from mice that did not receive MPA prior to HSV-1 infection. In addition, T cell expansion was comparable to that seen in untreated controls if MPA-treated mice were administered recombinant soluble CD154 (CD40L) concomitant with their mucosal infection. In contrast, the immunomodulatory effects of MPA were infection site dependent, because MPA-treated mice exhibited normal expansion of virus-specific T cells when infection was systemic rather than mucosal. Taken together, our results reveal that the administration of MPA prior to viral infection of mucosal tissue impairs DC activation, virus-specific T cell expansion, and development of virus-specific immunological memory.

SUBMITTER: Vicetti Miguel RD

PROVIDER: S-EPMC3448807 | biostudies-literature | 2012 Oct

REPOSITORIES: biostudies-literature

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Dendritic cell activation and memory cell development are impaired among mice administered medroxyprogesterone acetate prior to mucosal herpes simplex virus type 1 infection.

Vicetti Miguel Rodolfo D RD Hendricks Robert L RL Aguirre Alfredo J AJ Melan Melissa A MA Harvey Stephen A K SA Terry-Allison Tracy T St Leger Anthony J AJ Thomson Angus W AW Cherpes Thomas L TL

Journal of immunology (Baltimore, Md. : 1950) 20120831 7

Epidemiological studies indicate that the exogenous sex steroid medroxyprogesterone acetate (MPA) can impair cell-mediated immunity, but mechanisms responsible for this observation are not well defined. In this study, MPA administered to mice 1 wk prior to HSV type 1 (HSV-1) infection of their corneal mucosa impaired initial expansion of viral-specific effector and memory precursor T cells and reduced the number of viral-specific memory T cells found in latently infected mice. MPA treatment also ...[more]

PMID: 22942424

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Project description:Does medroxyprogesterone acetate (MPA) impair human dendritic cell (DC) activation and function?In vitro MPA treatment suppressed expression of CD40 and CD80 by human primary DCs responding to Toll-like receptor 3 (TLR3) agonist stimulation (i.e. DC activation). Moreover, this MPA-mediated decrease in CD40 expression impaired DC capacity to stimulate T cell proliferation (i.e. DC function).MPA is the active molecule in Depo-Provera(®) (DMPA), a commonly used injectable hormonal contraceptive (HC). Although DMPA treatment of mice prior to viral mucosal tissue infection impaired the capacity of DCs to up-regulate CD40 and CD80 and prime virus-specific T cell proliferation, neither DC activation marker expression nor the ability of DCs to promote T cell proliferation were affected by in vitro progesterone treatment of human DCs generated from peripheral blood monocytes.This cross-sectional study examined MPA-mediated effects on the activation and function of human primary untouched peripheral blood DCs.Human DCs isolated from peripheral blood mononuclear cells by negative immunomagnetic selection were incubated for 24 h with various concentrations of MPA. After an additional 24 h incubation with the TLR3 agonist polyinosinic:polycytidylic acid (poly I:C), flow cytometry was used to evaluate DC phenotype (i.e. expression of CD40, CD80, CD86, and HLA-DR). In separate experiments, primary untouched human DCs were sequentially MPA-treated, poly I:C-activated, and incubated for 7 days with fluorescently labeled naïve allogeneic T cells. Flow cytometry was then used to quantify allogeneic T cell proliferation.Several pharmacologically relevant concentrations of MPA dramatically reduced CD40 and CD80 expression in human primary DCs responding to the immunostimulant poly I:C. In addition, MPA-treated DCs displayed a reduced capacity to promote allogeneic CD4(+) and CD8(+) T cell proliferation. In other DC: T cell co-cultures, the addition of antibody blocking the CD40-CD154 (CD40L) interaction mirrored the decreased T cell proliferation produced by MPA treatment, while addition of recombinant soluble CD154 restored the capacity of MPA-treated DCs to induce T cell proliferation to levels produced by non-MPA-treated controls.While our results newly reveal that pharmacologically relevant MPA concentrations suppress human DC function in vitro, additional research is needed to learn if DMPA similarly inhibits DC maturation and function in the human female genital tract.Identification of a mechanism by which MPA impairs human DC activation and function increases the biological plausibility for the relationships currently suspected between DMPA use and enhanced susceptibility to genital tract infection.Funding provided by the NIH (grant R01HD072663) and The Ohio State University College of Medicine. The authors have no con?icts of interest to declare.

Project description:ObjectivesEvidence on contraceptive self-injection from the United States and similar settings is promising, and the practice may increase access. There are no published studies on the feasibility of contraceptive self-injection in sub-Saharan Africa to date. The purpose of this study was to assess feasibility of subcutaneous depot medroxyprogesterone acetate self-injection in Uganda, with specific objectives to (a) measure the proportion of participants who self-injected competently, (b) measure the proportion who self-injected on time 3 months after training (defined conservatively as within 7 days of their reinjection date) and (c) assess acceptability.Study designIn this prospective cohort study, 380 18-45-year-old participants completed self-injection training by licensed study nurses, guided by a client instruction booklet, and practiced injection on prosthetics until achieving competence. Nurses supervised participants' self-injection and evaluated injection technique using an observation checklist. Those judged competent were given a Sayana® Press unit, instruction booklet and reinjection calendar for self-injection at home 3 months later. Participants completed an interview before and after self-injection. Nurses visited participants at home following reinjection dates; during the follow-up visit, participants demonstrated self-injection on a prosthetic, injection technique was reevaluated, and a postreinjection interview was completed.ResultsOf 368 participants followed up 3 months posttraining, 88% [95% confidence interval (CI)=84-91] demonstrated injection competence, and 95% (95% CI=92-97) reinjected on time, while 87% (95% CI=84-90) were both on time and competent. Nearly all (98%) expressed a desire to continue.ConclusionsSelf-injection is feasible and highly acceptable among most study participants in Uganda.ImplicationsThe first research results on contraceptive self-injection in sub-Saharan Africa indicate initial feasibility and acceptability of the practice 3 months after women received one-on-one training and a highly visual training and memory aid. Results can inform self-injection programs which aim to increase women's autonomy and access to injectable contraception.

Dataset Information

Dendritic cell activation and memory cell development are impaired among mice administered medroxyprogesterone acetate prior to mucosal herpes simplex virus type 1 infection.

Publications

Dendritic cell activation and memory cell development are impaired among mice administered medroxyprogesterone acetate prior to mucosal herpes simplex virus type 1 infection.

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