Impact of Gender and Pubertal Status on Human Plasmacytoid Dendritic Cells. PLASMACYTOKID

Impact of Gender and Pubertal Status on Human Plasmacytoid Dendritic Cells - PLASMACYTOKID Study

Differences in pDCs function related to gender have been demonstrated in adults but have never been addressed in children. Yet, differences in immune responses related to gender also exist in children, both in responses to pathogens and susceptibility to autoimmune diseases. The investigators suppose that these differences are partly linked to difference in pDCs functions. This study aim is to compare pDCs functions in children based on gender and pubertal status. This study will be performed in healthy children, boys with Klinefelter syndrome and girls with Turner syndrome.

Study Overview

• Status: Terminated
• Conditions: Innate Immune Responses
• Intervention / Treatment: Biological: Blood Plasmacytoid dendritic cells (pDCs) absolute number

Detailed Description

There are differences in immune responses according to gender. Women have stronger responses against pathogens, especially viruses but are also more susceptible to develop autoimmune diseases. These points reflect more robust innate and adaptive responses in women. Plasmacytoid dendritic cells (pDCs) are key actor of innate immune responses through their ability to produce large amounts of type 1 Interferons (IFN1) secondary to stimulation of their toll like receptors (TLR) 7 and 9 by nucleic acids. Thus, pDCs play a major beneficial role in antiviral responses. In autoimmune diseases like Systemic Erythematous Lupus, pDCs also play a role, mostly deleterious, through inappropriate production of IFN1 upon stimulation of their TLR's by self nucleic acids. In these diseases, pDCs from women have been demonstrated to produce more IFN1 as compared to men, a phenomenon that can be linked to both hormonal and genetic factors. Indeed, the investigators research team demonstrated that IFN1 production by human pDCs can be increased by oestradiol through a specific receptor present in pDCs. Regarding genetics, some studies recently shown in a humanized mouse model, that pDCs developing from female hematopoietic precursor cells have an enhanced TLR 7 mediated IFN1 response as compared to male ones. These results indicate that X chromosome dosage could contribute independently to the enhanced TLR 7 mediated response of pDCs from women. Although some genes implicated in IFN1 production are on the X chromosome, including TLR 7, the mechanism underlying this observation are presently unknown.

• Study Type: Interventional
• Enrollment (Actual): 78
• Phase: Not Applicable

Contacts and Locations

Study Locations

• France
  • Toulouse, France
    • CHU Toulouse, Hôpital des Enfants

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: No older than 14 years (Child, Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

1. Pediatric patients (0-18 years old):

   • Group 1 : Age<8 years old
   • Group 2 : Age>12 years old
2. Body weight >10kgs
3. Pubescent (group 2) or non-pubescent (group 1)
4. Written consent of parents

Exclusion Criteria:

1. Active infectious disease
2. Known perturbations of immune and/or inflammatory systems
3. Oral or subcutaneous contraception in pubescent girls

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Screening
• Allocation: Non-Randomized
• Interventional Model: Parallel Assignment
• Masking: None (Open Label)

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Group 1: non-pubescent children; 70 non-pubescent children (25 healthy boys, 25 healthy girls, 10 boys with Klinefelter syndrome and 10 girls with Turner syndrome) Two 7 ml tubes of blood will be taken to perform the functional assays as well as the quantification of Blood Plasmacytoid dendritic cells (pDCs) absolute number in this 70 non-pubescent children.	Biological: Blood Plasmacytoid dendritic cells (pDCs) absolute number; Two 7 ml tubes will be necessary to perform the functional assays as well as the quantification of blood pDCs absolute number. Functional assays will be performed on isolated PBMC by Ficoll procedure. Quantification of blood pDCs absolute number will be performed on whole blood. After written parental consent, blood sample will be performed on children participating to the study.
Experimental: Group 2: pubescent healthy children; 50 pubescent healthy children (25 boys and 25 girls) Two 7 ml tubes of blood will be taken to perform the functional assays as well as the quantification of Blood Plasmacytoid dendritic cells (pDCs) absolute number in this 50 pubescent healthy children.	Biological: Blood Plasmacytoid dendritic cells (pDCs) absolute number; Two 7 ml tubes will be necessary to perform the functional assays as well as the quantification of blood pDCs absolute number. Functional assays will be performed on isolated PBMC by Ficoll procedure. Quantification of blood pDCs absolute number will be performed on whole blood. After written parental consent, blood sample will be performed on children participating to the study.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
percentage of IFN1 producing pDCs	Assessment of the percentage of IFN1 producing pDCs after ex vivo stimulation with TLR 7, 9 and 8 ligands.	1 day

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Percentage of IFN1 producing tumor necrosis factor(TNF)-alpha	Innate immune functions of pDCs present in the circulating blood of healthy children will be assessed by the percentage of pDCs producing TNF-alpha.	1 day
IFN1 concentration in the peripheral blood mononuclear cells circulating (PBMC) culture supernatant.	The innate immune functions of pDCs present in the circulating blood of healthy children will also be assessed by measuring the concentration IFN1 present in the culture supernatant of PBMC stimulated with TLR 7 or TLR 9 ligands.	1 day
percentage of cells producing TNF alpha and Interleukin(IL)-12p40	Innate immune functions of conventional dendritic cells (cDC) and monocytes present in the circulating blood of healthy children will be assessed by the percentage of cells producing TNF alpha and IL-12p40.	1 day
percentage of pDc, cDC and monocytes in circulating blood	Innate immune functions of pDCs, cDC and Monocytes present in the circulating blood of boys with Klinefelter syndrome or girls with Turner syndrome will be evaluated identically to healthy children.	1 day
Number of DC (cDC and pDC) by milliliter of blood	The number of DCs (pDCs CDC) / ml of blood flowing will be quantified and expressed in blood and percentage of PBMCs.	1 day

Collaborators and Investigators

• Sponsor: University Hospital, Toulouse
• Investigators: Principal Investigator: Arnaud Garnier, MD, CHU Toulouse, Hôpital des Enfants

Study record dates

Study Major Dates

• Study Start (Actual): June 21, 2017
• Primary Completion (Actual): December 31, 2018
• Study Completion (Actual): December 31, 2018

Study Registration Dates

• First Submitted: November 3, 2016
• First Submitted That Met QC Criteria: November 4, 2016
• First Posted (Estimate): November 6, 2016

Study Record Updates

• Last Update Posted (Actual): July 15, 2019
• Last Update Submitted That Met QC Criteria: July 11, 2019
• Last Verified: July 1, 2019

More Information

Terms related to this study

• Keywords: children; gender; sex difference; type 1 interferons; pubertal status
• Other Study ID Numbers: RC31/16/8251; AOL 2016 (Other Grant/Funding Number: University Hospital Toulouse)

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: No

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No