Soluble antigen arrays disarm antigen-specific B cells to promote lasting immune tolerance in experimental autoimmune encephalomyelitis

被引:30
作者
Hartwell, Brittany L. [1 ]
Pickens, Chad J. [2 ]
Leon, Martin [3 ]
Northrup, Laura [2 ]
Christopher, Matthew A. [2 ]
Griffin, J. Daniel [1 ]
Martinez-Becerra, Francisco [4 ]
Berkland, Cory [1 ,2 ,5 ]
机构
[1] Univ Kansas, Bioengn Grad Program, 1520 West 15th St, Lawrence, KS 66045 USA
[2] Univ Kansas, Dept Pharmaceut Chem, 2095 Constant Ave, Lawrence, KS 66047 USA
[3] Univ Kansas, Dept Chem, 1251 Wescoe Hall Dr, Lawrence, KS 66045 USA
[4] Univ Kansas, Immunol Core Lab, Kansas Vaccine Inst, 2030 Becker Dr, Lawrence, KS 66047 USA
[5] Univ Kansas, Dept Chem & Petr Engn, 1530 West 15th St, Lawrence, KS 66045 USA
基金
美国国家卫生研究院;
关键词
Tolerance; Autoimmunity; Autoimmune-associated B cells; Antigen-specific B cells; EAE; AUTOANTIBODY PRODUCTION; MULTIPLE-SCLEROSIS; PRESENTING CELLS; RECEPTOR; LYMPHOCYTES; ANERGY; IMMUNOTHERAPY; ACCUMULATION; DETERMINES; INDUCTION;
D O I
10.1016/j.jaut.2018.06.006
中图分类号
R392 [医学免疫学]; Q939.91 [免疫学];
学科分类号
100102 ;
摘要
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 auto immune 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.
引用
收藏
页码:76 / 88
页数:13
相关论文
共 56 条
  • [1] B-cell anergy: from transgenic models to naturally occurring anergic B cells?
    Cambier, John C.
    Gauld, Stephen B.
    Merrell, Kevin T.
    Vilen, Barbara J.
    [J]. NATURE REVIEWS IMMUNOLOGY, 2007, 7 (08) : 633 - 643
  • [2] Interleukin-10 produced by B cells is crucial for the suppression of Th17/Th1 responses, induction of T regulatory type 1 cells and reduction of collagen-induced arthritis
    Carter, Natalie A.
    Rosser, Elizabeth C.
    Mauri, Claudia
    [J]. ARTHRITIS RESEARCH & THERAPY, 2012, 14 (01)
  • [3] B Cells Are Multifunctional Players in Multiple Sclerosis Pathogenesis: Insights from Therapeutic Interventions
    Claes, Nele
    Fraussen, Judith
    Stinissen, Piet
    Hupperts, Raymond
    Somers, Veerle
    [J]. FRONTIERS IN IMMUNOLOGY, 2015, 6
  • [4] Design of effective immunotherapy for human autoimmunity
    Feldmann, M
    Steinman, L
    [J]. NATURE, 2005, 435 (7042) : 612 - 619
  • [5] Statistical analysis of data from studies on experimental autoimmune encephalomyelitis
    Fleming, KK
    Bovaird, JA
    Mosier, MC
    Emerson, MR
    LeVine, SM
    Marquis, JG
    [J]. JOURNAL OF NEUROIMMUNOLOGY, 2005, 170 (1-2) : 71 - 84
  • [6] T cells in multiple sclerosis and experimental autoimmune encephalomyelitis
    Fletcher, J. M.
    Lalor, S. J.
    Sweeney, C. M.
    Tubridy, N.
    Mills, K. H. G.
    [J]. CLINICAL AND EXPERIMENTAL IMMUNOLOGY, 2010, 162 (01) : 1 - 11
  • [7] Targeting B cells in treatment of autoimmunity
    Franks, S. Elizabeth
    Getahun, Andrew
    Hogarth, P. Mark
    Cambier, John C.
    [J]. CURRENT OPINION IN IMMUNOLOGY, 2016, 43 : 39 - 45
  • [8] Maintenance of B cell anergy requires constant antigen receptor occupancy and signaling
    Gauld, SB
    Benschop, RJ
    Merrell, KT
    Cambier, JC
    [J]. NATURE IMMUNOLOGY, 2005, 6 (11) : 1160 - 1167
  • [9] Silencing of autoreactive B cells by anergy: a fresh perspective
    Gauld, Stephen B.
    Merrell, Kevin T.
    Cambier, John C.
    [J]. CURRENT OPINION IN IMMUNOLOGY, 2006, 18 (03) : 292 - 297
  • [10] Establishing Anergy as a Bona Fide In Vivo Mechanism of B Cell Tolerance
    Getahun, Andrew
    O'Neill, Shannon K.
    Cambier, John C.
    [J]. JOURNAL OF IMMUNOLOGY, 2009, 183 (09) : 5439 - 5441