Abstract
Autoreactive lymphocytes that escape central immune tolerance may be silenced via an endogenous peripheral tolerance mechanism known as anergy. Antigen-specific therapies capable of inducing anergy may restore patients with autoimmune diseases to a healthy phenotype while avoiding deleterious side effects associated with global immunosuppression. Inducing anergy in B cells may be a particularly potent intervention, as B cells can contribute to autoimmune diseases through multiple mechanisms and offer the potential for direct antigen-specific targeting through the B cell receptor (BCR). Our previous results suggested autoreactive B cells may be silenced by multivalent ‘soluble antigen arrays’ (SAgAs), which are polymer conjugates displaying multiple copies of autoantigen with or without a secondary peptide that blocks intracellular cell-adhesion molecule-1 (ICAM-1). Here, key therapeutic molecular properties of SAgAs were identified and linked to the immunological mechanism through comprehensive cellular and in vivo analyses. We determined non-hydrolyzable ‘cSAgAs’ displaying multivalent ‘click’-conjugated antigen more potently suppressed experimental autoimmune encephalomyelitis (EAE) compared to hydrolyzable SAgAs capable of releasing conjugated antigen. cSAgAs restored a healthy phenotype in disease-specific antigen presenting cells (APCs) by inducing an anergic response in B cells and a subset of B cells called autoimmune-associated B cells (ABCs) that act as potent APCs in autoimmune disease. Accompanied by a cytokine response skewed towards a Th2/regulatory phenotype, this generated an environment of autoantigenic tolerance. By identifying key therapeutic molecular properties and an immunological mechanism that drives SAgA efficacy, this work guides the design of antigen-specific immunotherapies capable of inducing anergy.
| Original language | English (US) |
|---|---|
| Pages (from-to) | 76-88 |
| Number of pages | 13 |
| Journal | Journal of Autoimmunity |
| Volume | 93 |
| DOIs | |
| State | Published - Sep 2018 |
| Externally published | Yes |
Bibliographical note
Funding Information:We gratefully acknowledge support from the National Institutes of Health Graduate Training Program in Dynamic Aspects of Chemical Biology Grant (T32 GM008545) from the National Institute of General Medical Sciences (C.J.P. and M.L.), the Madison and Lila Self Graduate Fellowship at the University of Kansas (B.L.H. and J.D.G.), and the Howard Rytting pre-doctoral fellowship from the Department of Pharmaceutical Chemistry at the University of Kansas (C.J.P.). We would like to thank Dr. Blake Peterson for graciously donating the Pennsylvania Green parent compound. Additionally, we thank the Macromolecule and Vaccine Stabilization Center, KU NMR Lab, Microscopy and Analytical Imaging Core Lab, and the Kansas Vaccine Institute at the University of Kansas for their collaboration and instrument use.
Funding Information:
We gratefully acknowledge support from the National Institutes of Health Graduate Training Program in Dynamic Aspects of Chemical Biology Grant ( T32 GM008545 ) from the National Institute of General Medical Sciences (C.J.P. and M.L.), the Madison and Lila Self Graduate Fellowship at the University of Kansas (B.L.H. and J.D.G.), and the Howard Rytting pre-doctoral fellowship from the Department of Pharmaceutical Chemistry at the University of Kansas (C.J.P.). We would like to thank Dr. Blake Peterson for graciously donating the Pennsylvania Green parent compound. Additionally, we thank the Macromolecule and Vaccine Stabilization Center, KU NMR Lab, Microscopy and Analytical Imaging Core Lab, and the Kansas Vaccine Institute at the University of Kansas for their collaboration and instrument use.
Publisher Copyright:
© 2018 Elsevier Ltd
Keywords
- Antigen-specific B cells
- Autoimmune-associated B cells
- Autoimmunity
- EAE
- Tolerance
