- D1.537 - Immunopharmacogenomics as a Systems Medicine Framework for Precision Therapy in Allergic and Immune Mediated Diseases

Interindividual variability in drug efficacy and immune-mediated toxicity limits the success of immunotherapies, transplantation, allergy treatments, and vaccination strategies. Classical pharmacogenomics based solely on host genetics does not adequately capture the dynamic, antigen-driven nature of immune responses. Immunopharmacogenomics integrates HLA genetics with high-throughput T- and B-cell receptor (TCR/BCR) repertoire profiling to establish a systems medicine framework for studying drug–immune interactions.

We conducted a narrative synthesis of translational and clinical studies applying immune repertoire sequencing and immunogenomic profiling across cancer immunotherapy, graft-versus-host disease, solid organ transplantation, autoimmune diseases, food allergy, and vaccine and biologic drug development, with emphasis on longitudinal immune dynamics and clinical outcomes.

Across disease settings, antigen-driven clonal expansion and immune repertoire remodeling emerged as unifying signatures of immune activity. Responses to immune checkpoint inhibitors were associated with sustained oligoclonal expansion of CD8⁺ cell clones, while immune-related adverse events reflected activation of latent autoreactive repertoires. In graft-versus-host disease, early post-transplant oligoclonal TCR expansions preceded clinical manifestations and predicted disease severity. Solid organ rejection was characterized by dynamic reshaping of recipient TCR repertoires and convergent BCR signatures associated with antibody-mediated rejection, enabling non-invasive monitoring and therapeutic optimization. In autoimmune diseases, including Crohn’s disease, ankylosing spondylitis, systemic lupus erythematosus, and type 1 diabetes, disease severity and relapse were linked to selective expansion of HLA-restricted autoreactive clonotypes. In food allergy and oral immunotherapy, allergen-specific TCR and BCR profiling identified clonotypic signatures predictive of treatment response and tolerance. Systems vaccinology and biologic drug studies further demonstrated that HLA genetics and immune repertoire dynamics shape vaccine efficacy, immunogenicity, and adverse event risk.

Immunopharmacogenomics enables system-level integration of immune repertoire dynamics with host genetics and provides powerful biomarkers for predicting efficacy, toxicity, and durability of immune-based therapies, supporting the advancement of precision medicine.