Peanut oral immunotherapy transiently expands circulating Ara h 2–specific B cells with a homologous repertoire in unrelated subjects - 03/07/15
, Adebola O. Ogunniyi, PhD c, Agustin Calatroni, MA, MS d, Vasisht R. Tadigotla, PhD e, Bert Ruiter, PhD a, b, Alex Ma, BS a, James Moon, PhD a, J. Christopher Love, PhD c, f, Wayne G. Shreffler, MD, PhD a, bAbstract |
Background |
Peanut oral immunotherapy (PNOIT) induces persistent tolerance to peanut in a subset of patients and induces specific antibodies that might play a role in clinical protection. However, the contribution of induced antibody clones to clinical tolerance in PNOIT is unknown.
Objective |
We hypothesized that PNOIT induces a clonal, allergen-specific B-cell response that could serve as a surrogate for clinical outcomes.
Methods |
We used a fluorescent Ara h 2 multimer for affinity selection of Ara h 2–specific B cells and subsequent single-cell immunoglobulin amplification. The diversity of related clones was evaluated by means of next-generation sequencing of immunoglobulin heavy chains from circulating memory B cells with 2x250 paired-end sequencing on the Illumina MiSeq platform.
Results |
Expression of class-switched antibodies from Ara h 2–positive cells confirms enrichment for Ara h 2 specificity. PNOIT induces an early and transient expansion of circulating Ara h 2–specific memory B cells that peaks at week 7. Ara h 2–specific sequences from memory cells have rates of nonsilent mutations consistent with affinity maturation. The repertoire of Ara h 2–specific antibodies is oligoclonal. Next-generation sequencing–based repertoire analysis of circulating memory B cells reveals evidence for convergent selection of related sequences in 3 unrelated subjects, suggesting the presence of similar Ara h 2–specific B-cell clones.
Conclusions |
Using a novel affinity selection approach to identify antigen-specific B cells, we demonstrate that the early PNOIT-induced Ara h 2–specific B-cell receptor repertoire is oligoclonal and somatically hypermutated and shares similar clonal groups among unrelated subjects consistent with convergent selection.
Le texte complet de cet article est disponible en PDF.Key words : Immunotherapy, antigen-specific B cells, peanut allergy, food allergy, antibody repertoire
Abbreviations used : APC, BCR, CDR, NGS, OIT, PNOIT
Plan
| Supported by contracts with the National Institute of Allergy and Infectious Diseases (NIAID U19 AI087881 and NIAID U19 AI095261), National Institutes of Health grant 1S10RR023440-01A1, and in part by Koch Institute Support (core) grant P30-CA14051. Research was also supported by the Keck Foundation and the Bill and Melinda Gates Foundation. S.U.P. is supported by NIAID F32 AI104182and 2013 AAAAI/Food Allergy Research & Education Howard Gittis Memorial Research Award. J.C.L is a Camile Dreyfus Teacher-Scholar. Clinical studies were supported in part by the Harvard Clinical and Translational Science Center (National Center for Research Resources and the National Center for Advancing Translational Sciences, National Institutes of Health Award UL1 TR001102), and financial contributions from Harvard University and its affiliated academic health care centers. |
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| Disclosure of potential conflict of interest: S. U. Patil has received research support from Sanofi, the National Institutes of Health (NIH)/National Institute of Allergy and Infectious Diseases (NIAID), and the American Academy of Allergy, Asthma & Immunology (AAAAI)/Food Allergy Research and Education (FARE); has received royalties from UpToDate; and has received travel support from Buhlmann Laboratories. J. Moon has received research support from the NIH and Sanofi. J. C. Love has received research support from the NIH and Sanofi and has received consultancy fees from and has stock/stock options in Enumeral Biomedical. W. G. Shreffler has been supported by the NIAID/NIH, Sanofi, the Gerber Foundation, and private donations; has received consultancy fees from GLG (Gerson Lehrman Group) and Sanofi; is employed by Massachusetts General Hospital; has received royalties from UpToDate; and has received travel support from the European Academy of Allergy and Clinical Immunology, the Allergy Society of South Africa, and the Australasian Society of Clinical Immunology and Allergy. The rest of the authors declare that they have no relevant conflicts of interest. |
Vol 136 - N° 1
P. 125 - juillet 2015 Retour au numéro
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