Clinical trial NCT02403089: Ontogeny of MAIT Cells in Neonates and Hematopoietic Stem Cell Transplant Recipients
Official title: Ontogeny of MAIT Cells in Neonates and Hematopoietic Stem Cell Transplant Recipients
Study type: OBSERVATIONAL
Overall status: COMPLETED
Conditions: Term and Preterm Neonates (24-41 Weeks Gestational Age)
Hematopoietic Stem Cell Transplant Recipient Children
Keywords: MAIT (Mucosal-Associated Invariant T) cells
Gut microbiota
Preterm birth
Hematopoietic stem cell transplantation
Microbial infections
Lead sponsor: Assistance Publique - Hôpitaux de Paris
Sponsor class: OTHER
Collaborators: name: Institut National de la Santé Et de la Recherche Médicale, France
name: Institut National de Recherche pour l'Agriculture, l'Alimentation et l'Environnement
name: Institut Curie
First posted: 2015-03-31
Enrollment: 300
Sex: ALL
Minimum age (years): 1
Maximum age (years): 18
Standard ages: CHILD
ADULT
Accepts healthy volunteers: no
Observational model: OTHER
Time perspective: PROSPECTIVE
Sampling method: NON_PROBABILITY_SAMPLE
Study population: newborns hospitalized in the Neonatal Intensive Care Unit of the Hospital Robert Debré and grafted children hospitalized in the Hematology-Immunology Pediatric Service of the Hospital Robert Debré

Brief summary: The objective of this study is 1/ to determine the rate and kinetics of MAIT cell expansion and maturation in neonates in relation with gestational age, and in HSCT recipient children in relation with the source of donor stem cells, 2/ to correlate gut microbiota diversity and function with MAIT cell maturation and function in neonates and HSCT recipients; and 3/ to link MAIT cells and gut microbiota composition with microbial infections and severe intestinal inflammatory events in term and preterm neonates, and in HSCT recipients

Detailed description: The mucosa-associated invariant T (MAIT) cells are innate-like T cells with restricted T cell receptor (TCR) usage, which are preferentially localized in mucosal tissues and respond to microbial infection by rapidly producing cytokines and cytotoxic effectors. They recognize the non-classical related molecule (MR1). MAIT cells react against a newly identified class of antigens presented by MR1: Riboflavin (Rib) precursors, which are found in most bacteria and yeasts. Currently, very little is known about the ontogeny of MAIT cells in the human, because of the difficulty to follow longitudinally their development. Cross-sectional studies have identified only the initial (cord blood) and final (adult subjects) steps of human MAIT cell maturation program. Moreover, there are no data on relationships between human MAIT cell expansion and maturation, and gut microbiota development. Given the potential importance of MAIT cells in protection from microbial infections at epithelial surfaces, we will investigate the maturation dynamics of MAIT cells in relation with gut microbiota diversity and function in two clinical settings characterized by a high predisposition to severe microbial infections before the establishment of protective adaptive immunity, namely i/ the neonatal period and ii/ the early immune reconstitution period following allogeneic hematopoietic stem cell transplantation (HSCT) in children. Our study will combine multiparametric phenotypic and functional characterization of MAIT cells with the use of new molecular microbiota analytic methodology (high throughput sequencing, metagenomics, Rib microbiology) to determine how the presence or functionality of MAIT cells is influenced by the gut microbiota.

Our consortium is composed of three independent research teams, experts in innate immunity, microbial ecology and MAIT cell biology, three independent clinical teams providing exceptional resources to patient samples, and one team providing expertise for methodology and statistical analysis. Their synergistic interaction will offer the various complementary expertise that is necessary for this project.

This project will decipher how MAIT cell numbers or functions are influenced by the gut microbiota composition, and reciprocally, how MAIT cells regulate or control expansion of gut microbiota components competing with opportunistic or pathogenic bacteria or responsible for infections. Ultimately, this study will determine how and when gut microbiota and MAIT cell interactions are involved in the control of severe infectious or intestinal inflammatory events in high risk infants, an indispensable step to design predictive biomarkers and ultimately propose new therapeutic options.

Eligibility criteria: Inclusion Criteria:

* neonates 24-41 weeks gestational age
* hematopoietic stem cell transplant recipient children (\< 18 years old, donor source: cord blood or genoidentical donor)

Exclusion Criteria:

* neonates : chromosomal abnormalities detected before birth
* source of HSCT: phenol-identical donors

Primary outcomes:
measure: MAIT cell numbering neonates after birth
timeFrame: to 60days
Secondary outcomes:
measure: Absolute number of MAIT
timeFrame: to 60days
measure: Absolute number of other immune cell populations
timeFrame: to 60 days
Other outcomes:
Locations:
city: Paris
country: France
facility: Hôpital Robert Debré
Study officials:
affiliation: Assistance Publique - Hôpitaux de Paris
name: Biran Valérie, PHD
role: PRINCIPAL_INVESTIGATOR
References:
citation: Ben Youssef G, Tourret M, Salou M, Ghazarian L, Houdouin V, Mondot S, Mburu Y, Lambert M, Azarnoush S, Diana JS, Virlouvet AL, Peuchmaur M, Schmitz T, Dalle JH, Lantz O, Biran V, Caillat-Zucman S. Ontogeny of human mucosal-associated invariant T cells and related T cell subsets. J Exp Med. 2018 Feb 5;215(2):459-479. doi: 10.1084/jem.20171739. Epub 2018 Jan 16.
citation: Tourret M, Talvard-Balland N, Lambert M, Ben Youssef G, Chevalier MF, Bohineust A, Yvorra T, Morin F, Azarnoush S, Lantz O, Dalle JH, Caillat-Zucman S. Human MAIT cells are devoid of alloreactive potential: prompting their use as universal cells for adoptive immune therapy. J Immunother Cancer. 2021 Oct;9(10):e003123. doi: 10.1136/jitc-2021-003123.