Distinct trajectories distinguish antigen-specific T cells in peanut-allergic individuals undergoing oral immunotherapy - 05/07/23

Doi : 10.1016/j.jaci.2023.03.020

Justine Calise, PhD ^a, Hannah DeBerg, PhD ^b, Nahir Garabatos, PhD ^a, Sugandhika Khosa, MS ^a, Veronique Bajzik, MS ^a, Lorena Botero Calderon, MD ^a, Kelly Aldridge, MS ^a, Mario Rosasco, PhD ^b, Brian C. Ferslew, PharmD, PhD ^c, Tong Zhu, PhD ^c, Ronald Smulders, MD, PhD ^c, Lisa M. Wheatley, MD ^f, Tanya M. Laidlaw, MD ^g,^h, Tielin Qin, PhD ^g, Gurunadh R. Chichili, PhD ^c, Daniel C. Adelman, MD ^d, Mary Farrington, MD ^e, David Robinson, MD ^e, David Jeong, MD ^e, Stacie M. Jones, MD ⁱ, Srinath Sanda, MD ^j, David Larson, PhD ^g, William W. Kwok, PhD ^a, Carolyn Baloh, MD ^g,^h, Gerald T. Nepom, MD, PhD ^g, Erik Wambre, PhD ^a,^⁎
IMPACT
Edwin H. Kim, MD ^b, Kari C. Nadeau, MD, PhD ^c, Anna Nowak-Wegrzyn, MD ^d,^f, Robert A. Wood, MD ^e, Hugh A. Sampson, MD ^d, Amy M. Scurlock, MD ^a, Sharon Chinthrajah, MD ^c, Julie Wang, MD ^d, Robert D. Pesek, MD ^a, Sayantani B. Sindher, MD ^c, Mike Kulis, PhD ^b, Jacqueline Johnson, DrPH ^g, Katharine Spain, MS ^g, Denise C. Babineau, PhD ^g, Hyunsook Chin, MPH ^g, Joy Laurienzo-Panza, RN ^h, Rachel Yan, MS ⁱ, David Larson, PhD ^j, Tielin Qin, PhD ^j, Don Whitehouse, MS ⁱ, Michelle L. Sever, PhD ^g, Srinath Sanda, MD ⁱ, Marshall Plaut, MD ^h, Lisa M. Wheatley, MD, MPH ^h, A. Wesley Burks, MD ^b, Gina Marchesini ^k, Kavitha Gilroy ^k, Sylvia Posso ^k, Sabrina Skiba ^k, Thien-Son Nguyen ^k, Adam Wojno ^k, Tuan Nguyen ^k, Vivian Gersuk ^k, Quynh-Anh Nguyen ^k, Jessica Garber ^k, Kimberly O’Brien ^k, Brandon Larson ^k, C. Cousens-Jacobs ^k, Alex Hu ^k
^a Department of Pediatrics, University of Arkansas for Medical Sciences and Arkansas Children’s Hospital, Little Rock, Ark
^b Departments of Medicine and Pediatrics, University of North Carolina, Chapel Hill, NC
^c Department of Pediatrics and the Sean N. Parker Center for Allergy and Asthma Research, Stanford University, Palo Alto, Calif
^d Department of Pediatrics, Icahn School of Medicine at Mount Sinai, New York, NY
^e Department of Pediatrics, Johns Hopkins University School of Medicine, Baltimore, Md
^f Department of Pediatrics, New York University Langone Health, New York, NY
^g Rho Federal Systems Division, Durham, NC
^h National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD
ⁱ Immune Tolerance Network, San Francisco, Calif
^j Immune Tolerance Network, Bethesda, Md
^k Benaroya Research Institute at Virginia Mason, Seattle, Wash

^a Translational Immunology, Benaroya Research Institute at Virginia Mason, Seattle, Wash
^b Systems Immunology, Benaroya Research Institute at Virginia Mason, Seattle, Wash
^c Astellas Pharma Global Development Inc, Northbrook, Ill
^d Aimmune Therapeutics, Brisbane, Calif
^e Virginia Mason Medical Center, Seattle, Wash
^f National Institute of Allergy and Infectious Diseases, Bethesda, Md
^g Immune Tolerance Network, Benaroya Research Institute at Virginia Mason, Seattle, Wash
^h Department of Medicine, Harvard Medical School, Division of Allergy and Clinical Immunology, Brigham and Women’s Hospital, Boston, Mass
ⁱ Department of Pediatrics, University of Arkansas for Medical Sciences, Arkansas Children’s Hospital, Little Rock, Ark
^j Immune Tolerance Network, UCSF Diabetes Center & UCSF School of Medicine, San Francisco, Calif

^∗Corresponding author: Erik Wambre, PhD, 1201 Ninth Ave, Benaroya Research Institute, Seattle, WA 98101.Benaroya Research Institute1201 Ninth AveSeattleWA98101

Graphical abstract

Le texte complet de cet article est disponible en PDF.

Abstract

Background

Despite similar clinical symptoms, peanut-allergic (PA) individuals may respond quite differently to the same therapeutic interventions.

Objective

This study aimed to determine whether inherent qualities of cell response at baseline could influence response to peanut oral immunotherapy (PnOIT).

Methods

We first performed ex vivo T-cell profiling on peanut-reactive CD154⁺CD137⁺ T (pTeff) cells from 90 challenge-confirmed PA individuals. We developed a gating strategy for unbiased assessment of the phenotypic distribution of rare pTeff cells across different memory CD4⁺ T-cell subsets to define patient immunotype. In longitudinal samples of 29 PA participants enrolled onto the IMPACT trial of PnOIT, we determined whether patient immunotype at baseline could influence response to PnOIT.

Results

Our data emphasize the heterogeneity of pTeff cell responses in PA participants with 2 mutually exclusive phenotypic entities (CCR6⁻CRT_H2⁺ and CCR6⁺CRT_H2⁻). Our findings lead us to propose that peanut allergy can be classified broadly into at least 2 discrete subtypes, termed immunotypes, with distinct immunologic and clinical characteristics that are based on the proportion of T_H2A pTeff cells. PnOIT induced elimination of T_H2A pTeff cells in the context of the IMPACT clinical trial. Only 1 PA patient with a low level of T_H2A pTeff cells at baseline experienced long-lasting benefit of remission after PnOIT discontinuation.

Conclusion

Dividing PA patients according to their individual peanut-specific T-cell profile may facilitate patient stratification in clinical settings by identifying which immunotypes might respond best to different therapies.

Le texte complet de cet article est disponible en PDF.

Key words : CD4⁺ T cells, oral immunotherapy, immunotype, peanut allergy, T_H2A cells, IMPACT trial

Abbreviations used : CRT_H2, DBPCFC, PA, PBMC, PnOIT, ps, pTeff, RNA-Seq, SPT, TCR, Tfh, T_H2A, T_H2conv

Plan

Methods

Study design

PA study participants

IMPACT trial design and participants

Ex vivo peanut-reactive T-cell assay

Intracellular cytokine analysis

Analysis of allergen-elicited T-helper response

RNA-Seq library preparation and analysis

T-cell receptor clonality analysis

Statistical analysis

Results

Peanut-reactive CCR6⁺ T cells display distinct effector and homing properties from T_H2A cells

Markers of T_H2A inflammation are absent in a specific subset of PA individuals

T_H2A-high and -low immunotypes are associated with distinct gene expression signatures

Immunotype trajectories associated with PnOIT

Characteristic gene transcript alterations during PnOIT reflect each immunotype profile

Discussion

This research was performed as a project of the Immune Tolerance Network and was supported by the US National Institutes of Health (NIH), National Institute of Allergy and Infectious Diseases (awards UM1AI109565 and U19 AI135817 E.W. and W.W.K.). The Seattle Food Allergy Consortium (SeaFAC) and the Food Allergy Research and Education (FARE) contributed supplemental support to the Wambre laboratory. Astellas Pharma provided support to the Benaroya Research Institute for experiments on samples from Astellas’s clinical trial. The content is solely the responsibility of the authors and does not necessarily represent the official views of the NIH.

Disclosure of potential conflict of interest: E. Wambre receives grant support from the National Institute of Allergy and Infectious Diseases, the National Cancer Institute, FARE, and the Immune Tolerance Network, as well as research sponsorship from Regeneron Pharmaceuticals, Astellas Pharma, COUR Pharma, and Aimmune Therapeutics. B. C. Ferslew, T. Zhu, R. Smulders, and G. R. Chichili are full-time employees of Astellas and hold stock or stock options. D. C. Adelman is a former employee of Aimmune Therapeutics and currently chairs the company’s scientific advisory board. The rest of the authors declare that they have no relevant conflicts of interest.

Export

Vol 152 - N° 1

P. 155 - juillet 2023 Retour au numéro

Article précédent

Impact of using less objective symptoms to define tolerated dose during food challenges: A data-driven approach
Paul J. Turner, Nandinee Patel, Katharina Blumchen, Stefanie Berkes, Hugh A. Sampson, Kirsten Beyer

| Article suivant

Lung-resident CD69⁺ST2⁺ T_H2 cells mediate long-term type 2 memory to inhaled antigen in mice
Takao Kobayashi, Koji Iijima, Koji Matsumoto, Jyoti K. Lama, Hirohito Kita

Bienvenue sur EM-consulte, la référence des professionnels de santé.
L’accès au texte intégral de cet article nécessite un abonnement.

Déjà abonné à cette revue ?

connectez-vous ou créez un compte

Distinct trajectories distinguish antigen-specific T cells in peanut-allergic individuals undergoing oral immunotherapy - 05/07/23

Graphical abstract

Abstract

Background

Objective

Methods

Results

Conclusion

Plan

Export citations

Fichier

Contenu

Accès rapides

Mon compte

Aide & support

Plateformes Elsevier Masson

Déclaration CNIL