Chlamydia trachomatis y levonorgestrel

Dendritic cell function and pathogen-specific T cell immunity are inhibited in mice administered levonorgestrel prior to intranasal Chlamydia trachomatis infection

Nirk E. Quispe Calla, Rodolfo D. Vicetti Miguel, Ao Mei, Shumin Fan, Jocelyn R. Gilmore & Thomas L. Cherpes

1. Department of Microbial infection &Immunity, The Ohio State University College of Medicine, Columbus, OH, 43210, USA.

2. Department of Obstetrics &Gynecology The Ohio State University College of Medicine, Columbus, OH, 43210, USA.

The growing popularity of levonorgestrel (LNG)-releasing intra-uterine systems for long-acting reversible contraception provides strong impetus to define immunomodulatory properties of this exogenous progestin. In initial in vitro studies herein, we found LNG significantly impaired activation of human dendritic cell (DCs) and their capacity to promote allogeneic T cell proliferation. In follow-up studies in a murine model of intranasal Chlamydia trachomatis infection, we analogously found that LNG treatment prior to infection dramatically reduced CD40 expression in DCs isolated from draining lymph nodes at 2 days post infection (dpi). At 12 dpi, we also detected significantly fewer CD4⁺ and CD8⁺ T cells in the lungs of LNG-treated mice. This inhibition of DC activation and T cell expansion in LNG-treated mice also delayed chlamydial clearance and the resolution of pulmonary inflammation. Conversely, administering agonist anti-CD40 monoclonal antibody to LNG-treated mice at 1 dpi restored lung T cell numbers and chlamydial burden at 12 dpi to levels seen in infected controls. Together, these studies reveal that LNG suppresses DC activation and function, and inhibits formation of pathogen-specific T cell immunity. They also highlight the need for studies that define in vivo effects of LNG use on human host response to microbial pathogens. 

Scientific Reports. 2016 Nov 28;6:37723. doi: 10.1038/srep37723.

https://www.nature.com/articles/srep37723

Md. Rodolfo D. Vicetti Miguel, Ex-Miembro del GII

Md. Nirk E. Quispe Calla, Past President del GII

Herpes Simplex Virus type2 and contraception

Medroxyprogesterone acetate and levonorgestrel increase genital mucosal permeability and enhance susceptibility to genital herpes simplex virus type 2 infection

N E Quispe Calla1, R D Vicetti Miguel1, P N Boyaka2, L Hall-Stoodley1, B Kaur3, W Trout4, S D Pavelko1 and T L Cherpes1,4

1. Department of Microbial Infection and Immunity, Columbus, Ohio, USA

2. Department of Veterinary Biosciences, The Ohio State University College of Veterinary Medicine, Columbus, Ohio, USA

3. Department of Neurological Surgery, James Comprehensive Cancer Center, The Ohio State University Medical Center, Columbus, Ohio, USA

4.Department of Obstetrics and Gynecology, The Ohio State University College of Medicine, Columbus, Ohio, USA

Depot-medroxyprogesterone acetate (DMPA) is a hormonal contraceptive especially popular in areas with high prevalence of HIV and other sexually transmitted infections (STI). Although observational studies identify DMPA as an important STI risk factor, mechanisms underlying this connection are undefined. Levonorgestrel (LNG) is another progestin used for hormonal contraception, but its effect on STI susceptibility is much less explored. Using a mouse model of genital herpes simplex virus type 2 (HSV-2) infection, we herein found that DMPA and LNG similarly reduced genital expression of the desmosomal cadherin desmoglein-1α (DSG1α), enhanced access of inflammatory cells to genital tissue by increasing mucosal epithelial permeability, and increased susceptibility to viral infection. Additional studies with uninfected mice revealed that DMPA-mediated increases in mucosal permeability promoted tissue inflammation by facilitating endogenous vaginal microbiota invasion. Conversely, concomitant treatment of mice with DMPA and intravaginal estrogen restored mucosal barrier function and prevented HSV-2 infection. Evaluating ectocervical biopsy tissue from women before and 1 month after initiating DMPA remarkably revealed that inflammation and barrier protection were altered by treatment identically to changes seen in progestin-treated mice. Together, our work reveals DMPA and LNG diminish the genital mucosal barrier; a first-line defense against all STI, but may offer foundation for new contraceptive strategies less compromising of barrier protection.

Mucosal Immunology (2016) 9, 1571–1583; doi:10.1038/mi.2016.22

https://www.nature.com/mi/journal/v9/n6/full/mi201622a.html

Md. Rodolfo D. Vicetti Miguel, Ex-Miembro del GII

Md. Nirk E. Quispe Calla, Past President del GII

EGFR y Cancer de Cabeza y Cuello

Anti-EGFR Targeted Monoclonal Antibody Isotype Influences Antitumor Cellular Immunity in Head and Neck Cancer Patients.

Trivedi S1, Srivastava RM1, Concha-Benavente F2, Ferrone S3, Garcia-Bates TM4, Li J5, Ferris RL6,7,8.

1. Department of Otolaryngology, University of Pittsburgh, Pittsburgh, Pennsylvania.

2. Department of Immunology, University of Pittsburgh, Pittsburgh, Pennsylvania.

3. Department of Surgery, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts.

4. Department of Infectious Diseases and Microbiology, University of Pittsburgh, Pittsburgh, Pennsylvania.

5. Department of Pharmacology and Pharmaceutical Sciences, School of Medicine, Tsinghua University, Beijing, China.

6. Department of Otolaryngology, University of Pittsburgh, Pittsburgh, Pennsylvania. ferrrl@upmc.edu.

7. University of Pittsburgh Cancer Institute, Pittsburgh, Pennsylvania.

8. Cancer Immunology Program, University of Pittsburgh Cancer Institute, Pittsburgh, Pennsylvania.

Abstract

PURPOSE:

EGF receptor (EGFR) is highly overexpressed on several cancers and two targeted anti-EGFR antibodies which differ by isotype are FDA-approved for clinical use. Cetuximab (IgG1 isotype) inhibits downstream signaling of EGFR and activates antitumor, cellular immune mechanisms. As panitumumab (IgG2 isotype) may inhibit downstream EGFR signaling similar to cetuximab, it might also induce adaptive immunity.

EXPERIMENTAL DESIGN:

We measured in vitro activation of cellular components of the innate and adaptive immune systems. We also studied the in vivo activation of components of the adaptive immune system in patient specimens from two recent clinical trials using cetuximab or panitumumab.

RESULTS:

Both monoclonal antibodies (mAb) primarily activate natural killer (NK) cells, although cetuximab is significantly more potent than panitumumab. Cetuximab-activated neutrophils mediate antibody-dependent cellular cytotoxicity (ADCC) against head and neck squamous cell carcinomas (HNSCC) tumor cells, and interestingly, this effect was FcγRIIa- and FcγRIIIa genotype-dependent. Panitumumab may activate monocytes through CD32 (FcγRIIa); however, monocytes activated by either mAb are not able to mediate ADCC. Cetuximab enhanced dendritic cell (DC) maturation to a greater extent than panitumumab, which was associated with improved tumor antigen cross-presentation by cetuximab compared with panitumumab. This correlated with increased EGFR-specific cytotoxic CD8+ T cells in patients treated with cetuximab compared with those treated with panitumumab.

CONCLUSIONS:

Although panitumumab effectively inhibits EGFR signaling to a similar extent as cetuximab, it is less effective at triggering antitumor, cellular immune mechanisms which may be crucial for effective therapy of HNSCC. Clin Cancer Res; 22(21); 5229-37. ©2016 AACR.

Clin Cancer Res. 2016 Nov 1;22(21):5229-5237. Epub 2016 May 23.

http://clincancerres.aacrjournals.org/content/22/21/5229.long

Md. PhD. Fernando Concha. Ex-miembro del GII