Engineering autoreactive T and B cell responses toward active immunotherapy for inflammatory diseases

Abstract

Antiinflammatory therapeutics are commonly used to combat a vast array of chronic inflammatory and autoimmune diseases, including rheumatoid arthritis, inflammatory bowel disease, psoriasis, and Crohn’s disease (1). These chronic inflammatory diseases affect ∼5 to 7% of the population, creating a significant socioeconomic burden and impact on patients’ quality of life (2). Current therapies have revolved around the use of anti-tumor necrosis factor (TNF) antibodies, aiming to block the activity of TNF-α and cytokines such as interleukin (IL)-1, IL-6, and granulocytemacrophage colony-stimulating factor that make up its downstream proinflammatory cascade (3). Although these anti-TNF therapeutics have shown efficacy over the past two decades, there are several drawbacks to this approach, including the need for repeated injections, patient compliance issues, tolerability, and the development of antidrug antibodies, which could lead to reduction of drug efficacy and adverse side effects such as increased risk of infections and hypersensitivity (4, 5). In PNAS, Hainline et al. (6) developed an alternative active immunotherapy approach that incorporates an engineered fragment of complement protein C3dg and peptide epitopes derived from the soluble form of TNF into a self-assembled supramolecular nanofiber. Administration of these nanofibers as an immunomodulatory vaccine successfully lowered inflammatory signatures in models of TNF-driven septic shock and psoriasis. Despite the simplicity of the components, these nanofibers are shown by the authors to act in multiple complementary ways to modulate the immune system (Fig. 1). First, C3dg acts as a molecular adjuvant to promote B cell activation and costimulation of the complement receptor 2 (CD21) (7), helping to break tolerance against TNF and raise endogenous antibodies against the cytokine. Second, antibodies are directly raised against C3dg, with the potential to limit complement effector functions. Finally, autoreactive helper T cells specific for peptides derived from C3dg are primed. Intriguingly, this last mechanism appears to play an important role in both of the inflammatory models tested here. Studies have shown that linking C3dg or C3d (a fragment of C3dg) to vaccine immunogens can enhance humoral responses against the antigen, and this is further enhanced through multivalent display of C3dg. Most C3d-adjuvanted vaccine platforms rely on cross-linking C3d to the target antigen to achieve multivalent display, but this approach is random in nature and difficult to control. Alternatively, genetic assembly and expression of recombinant proteins that include C3dg coexpressed with the antigens have also been previously demonstrated, but this approach is often limited in the degree of C3 multimerization that can be achieved (8–11). Hainline et al. (6) elegantly address this problem by incorporating a βtail-tagged C3dg protein and B and T cell peptide epitopes into a supramolecular self-assembly nanofiber platform able to codisplay different proteins in a controlled and modular manner. To highlight the benefits of multivalent display of C3dg-incorparated nanofibers, the authors show increased B cell activation in vitro following treatment with βtail–C3dg nanofibers in a dosedependent manner, compared to soluble C3dg. This enhanced B cell activation response correlated with stronger antigen-specific antibody titers when mice were immunized with either βtail–C3dg coassembled nanofibers carrying OVAQ (self-assembling ovalbumin peptide epitopes) or βtail–C3dg coassembled nanofibers with TNFQ and PADREQ (B cell epitope peptide and T cell epitope peptide, respectively). Interestingly, these immunizations also induced substantial autoreactive anti-C3dg antibodies, indicating