AUTHOR=Kanchan Kanika , Shankar Gautam , Huffaker Michelle F. , Bahnson Henry T. , Chinthrajah R Sharon , Sanda Srinath , Manohar Monali , Ling Hua , Paschall Justin E. , Toit George Du , Ruczinski Ingo , Togias Alkis , Lack Gideon , Nadeau Kari C. , Jones Stacie M. , Nepom Gerald T. , Mathias Rasika A. 

TITLE=HLA-associated outcomes in peanut oral immunotherapy trials identify mechanistic and clinical determinants of therapeutic success

JOURNAL=Frontiers in Immunology

VOLUME=Volume 13 - 2022

YEAR=2022

URL=https://www.frontiersin.org/journals/immunology/articles/10.3389/fimmu.2022.941839

DOI=10.3389/fimmu.2022.941839

ISSN=1664-3224

ABSTRACT=Rationale: Previous studies identified an interaction between HLA and oral peanut exposure. HLA-DQA1*01:02 had a protective role with the induction of Ara h 2 epitope-specific IgG4 associated with peanut consumption during the LEAP clinical trial for the prevention of peanut allergy, while it was a risk allele for peanut allergy in the peanut avoidance group. We have now evaluated this gene-environment interaction in two subsequent peanut oral immunotherapy (OIT) trials - IMPACT and POISED - to better understand the potential for the HLA-DQA1*01:02 allele as an indicator of the higher likelihood of desensitization, sustained unresponsiveness, and peanut allergy remission.

Methods: We determined HLA-DQA1*01:02 carrier status using genome sequencing from POISED (N=118, age: 7-55yr) and IMPACT (N=126, age: 12-<48mo). We tested for association with remission, sustained unresponsiveness (SU), and desensitization in the OIT groups, as well as peanut component-specific IgG4 (psIgG4) using generalized linear models and adjusting for relevant covariates and ancestry.

Results: While not quite statistically significant, a higher proportion of HLA-DQA1*01:02 carriers receiving OIT in IMPACT were desensitized (93%) compared to non-carriers (78%); odds ratio (OR)=5.74 (p=0.06). In this sample, we also observed that a higher proportion of carriers achieved remission (35%) compared to non-carriers (22%); OR=1.26 (p=0.80). In POISED, carriers more frequently attained continued desensitization (80% versus 61% among non-carriers; OR=1.28, p=0.86) and achieved SU (52% versus 31%; OR=2.32, p=0.19). psIgG4 associations with HLA-DQA1*01:02 in the OIT arm of IMPACT which included younger study subjects recapitulated patterns noted in LEAP, but no associations of note were observed in the older POISED study subjects.

Conclusions: Findings across three clinical trials show a pattern of gene-environment interaction between HLA and oral peanut exposure. Age and prior sensitization contribute additional determinants of outcomes, consistent with a mechanism of restricted antigen recognition fundamental to driving protective immune responses to OIT.