Immunogenicity of Isogenic IgG in Aggregates and Immune Complexes

• Published in: PloS one 2017-01, Vol.12 (1), p.e0170556-e0170556
• Main Authors: St Clair, J Benjamin, Detanico, Thiago, Aviszus, Katja, Kirchenbaum, Greg A, Christie, Merry, Carpenter, John F, Wysocki, Lawrence J
• Format: Article
• Language: English
• Subjects: Adoptive Transfer; Aggregates; Animals; Antibodies, Anti-Idiotypic - immunology; Antibodies, Monoclonal - immunology; Antigen presentation; Antigen-Antibody Complex - immunology; Antigen-antibody complexes; Biology and Life Sciences; Biomedical research; Bone marrow; CD4 antigen; CD4-Positive T-Lymphocytes - immunology; Cell proliferation; Helper cells; Immune Tolerance; Immunogenetics; Immunogenicity; Immunoglobulin G; Immunoglobulin G - immunology; Immunoglobulins; Immunology; Immunophenotyping; Lymphatic system; Lymphocytes; Lymphocytes B; Lymphocytes T; Medical research; Medicine; Medicine and Health Sciences; Mice; Monoclonal antibodies; Nanoparticles; Peritoneum; Pharmaceutical sciences; Research and Analysis Methods; Researchers; Studies; T cell receptors; Trace levels
• ISSN: 1932-6203; 1932-6203
• DOI: 10.1371/journal.pone.0170556

A paradox in monoclonal antibody (mAb) therapy is that despite the well-documented tolerogenic properties of deaggregated IgG, most therapeutic IgG mAb induce anti-mAb responses. To analyze CD4 T cell reactions against IgG in various physical states, we developed an adoptive transfer model using CD4+ T cells specific for a Vκ region-derived peptide in the hapten-specific IgG mAb 36-71. We found that heat-aggregated or immune complexes (IC) of mAb 36-71 elicited anti-idiotypic (anti-Id) antibodies, while the deaggregated form was tolerogenic. All 3 forms of mAb 36-71 induced proliferation of cognate CD4+ T cells, but the aggregated and immune complex forms drove more division cycles and induced T follicular helper cells (TFH) development more effectively than did the deaggregated form. These responses occurred despite no adjuvant and no or only trace levels of endotoxin in the preparations. Physical analyses revealed large differences in micron- and nanometer-sized particles between the aggregated and IC forms. These differences may be functionally relevant, as CD4+ T cell proliferation to aggregated, but not IC mAb 36-71, was nearly ablated upon peritoneal injection of B cell-depleting antibody. Our results imply that, in addition to denatured aggregates, immune complexes formed in vivo between therapeutic mAb and their intended targets can be immunogenic.