A Novel Therapeutic Approach Targeting Articular Inflammation Using the Filarial Nematode-Derived Phosphorylcholine-Containing Glycoprotein ES-62

Understanding modulation of the host immune system by pathogens offers rich therapeutic potential. Parasitic filarial nematodes are often tolerated in human hosts for decades with little evidence of pathology and this appears to reflect parasite-induced suppression of host proinflammatory immune responses. Consistent with this, we have previously described a filarial nematode-derived, secreted phosphorylcholine-containing glycoprotein, ES-62, with immunomodulatory activities that are broadly anti-inflammatory in nature. We sought to evaluate the therapeutic potential of ES-62 in vitro and in vivo in an autoimmune disease model, namely, collagen-induced arthritis in DBA/1 mice. ES-62 given during collagen priming significantly reduced initiation of inflammatory arthritis. Crucially, ES-62 was also found to suppress collagen-induced arthritis severity and progression when administration was delayed until after clinically evident disease onset. Ex vivo analyses revealed that in both cases, the effects were associated with inhibition of collagen-specific pro-inflammatory/Th1 cytokine (TNF-α, IL-6, and IFN-γ) release. In parallel in vitro human tissue studies, ES-62 was found to significantly suppress macrophage activation via cognate interaction with activated T cells. Finally, ES-62 suppressed LPS-induced rheumatoid arthritis synovial TNF-α and IL-6 production. Evolutionary pressure has promoted the generation by pathogens of diverse mechanisms enabling host immune system evasion and induction of “tolerance.” ES-62 represents one such mechanism. We now provide proof of concept that parasite-derived immunomodulatory strategies offer a novel therapeutic opportunity in inflammatory arthritis.

[1]  M. Harnett,et al.  Hyporesponsiveness of murine B lymphocytes exposed to the filarial nematode secreted product ES‐62 in vivo , 2003, Immunology.

[2]  O. Byron,et al.  Structural/functional aspects of ES-62--a secreted immunomodulatory phosphorylcholine-containing filarial nematode glycoprotein. , 2003, Current protein & peptide science.

[3]  E. Reinke,et al.  Immunoregulation of CNS autoimmunity by helminth and mycobacterial infections. , 2002, Immunology letters.

[4]  S. Lebecque,et al.  Anatomic Localization of Immature and Mature Dendritic Cells in an Ectopic Lymphoid Organ: Correlation with Selective Chemokine Expression in Rheumatoid Synovium , 2002, The Journal of Immunology.

[5]  C. Benoist,et al.  Arthritogenic Monoclonal Antibodies from K/BxN Mice , 2002, The Journal of experimental medicine.

[6]  C. Benoist,et al.  How antibodies to a ubiquitous cytoplasmic enzyme may provoke joint-specific autoimmune disease , 2002, Nature Immunology.

[7]  M. Feldmann,et al.  Evidence that rheumatoid arthritis synovial T cells are similar to cytokine-activated T cells: involvement of phosphatidylinositol 3-kinase and nuclear factor kappaB pathways in tumor necrosis factor alpha production in rheumatoid arthritis. , 2002, Arthritis and rheumatism.

[8]  A. Hoerauf,et al.  Resistance and susceptibility in human onchocerciasis--beyond Th1 vs. Th2. , 2002, Trends in parasitology.

[9]  P. Taylor,et al.  Immunotherapy for rheumatoid arthritis. , 2001, Current opinion in immunology.

[10]  H. Goodridge,et al.  Modulation of Macrophage Cytokine Production by ES-62, a Secreted Product of the Filarial Nematode Acanthocheilonema viteae1 , 2001, The Journal of Immunology.

[11]  E. Devaney,et al.  Lymphatic filariasis: parallels between the immunology of infection in humans and mice , 2001, Parasite immunology.

[12]  M. Harnett,et al.  A Filarial Nematode-Secreted Phosphorylcholine-Containing Glycoprotein Uncouples the B Cell Antigen Receptor from Extracellular Signal-Regulated Kinase-Mitogen-Activated Protein Kinase by Promoting the Surface Ig-Mediated Recruitment of Src Homology 2 Domain-Containing Tyrosine Phosphatase-1 and Pac , 2001, The Journal of Immunology.

[13]  M. Harnett,et al.  Modulation of the host immune system by phosphorylcholine-containing glycoproteins secreted by parasitic filarial nematodes. , 2001, Biochimica et biophysica acta.

[14]  J. Edwards,et al.  Sustained improvement in rheumatoid arthritis following a protocol designed to deplete B lymphocytes. , 2001, Rheumatology.

[15]  M. Harnett,et al.  Immunomodulation by filarial nematode phosphorylcholine-containing glycoproteins. , 2001 .

[16]  R N Maini,et al.  Infliximab and methotrexate in the treatment of rheumatoid arthritis. Anti-Tumor Necrosis Factor Trial in Rheumatoid Arthritis with Concomitant Therapy Study Group. , 2000, The New England journal of medicine.

[17]  Richard W. Martin,et al.  A comparison of etanercept and methotrexate in patients with early rheumatoid arthritis. , 2000, The New England journal of medicine.

[18]  B. Diamond,et al.  Peptide Mimic of Phosphorylcholine, a Dominant Epitope Found on Streptococcus pneumoniae , 2000, Infection and Immunity.

[19]  M. Harnett,et al.  Presence of Phosphorylcholine on a Filarial Nematode Protein Influences Immunoglobulin G Subclass Response to the Molecule by an Interleukin-10-Dependent Mechanism , 2000, Infection and Immunity.

[20]  I. McInnes,et al.  Cell-cell interactions in synovitis: Interactions between T lymphocytes and synovial cells , 2000, Arthritis research.

[21]  M. Harnett,et al.  A Filarial Nematode-Secreted Product Signals Dendritic Cells to Acquire a Phenotype That Drives Development of Th2 Cells1 , 2000, The Journal of Immunology.

[22]  H. Huhtala,et al.  Antineutrophil cytoplasmic antibodies in patients with early rheumatoid arthritis: an early marker of progressive erosive disease. , 2000, Arthritis and rheumatism.

[23]  H. Schumacher,et al.  Rheumatoid arthritis associated autoantibodies in patients with synovitis of recent onset , 2000, Arthritis research.

[24]  T. Ochi.  The human endoplasmic reticulum molecular chaperone bip is an autoantigen for rheumatoid arthritis and prevents the induction of experimental arthritis , 2000 .

[25]  G. Feng,et al.  Extracellular signal-related kinase (ERK) and p38 mitogen-activated protein (MAP) kinases differentially regulate the lipopolysaccharide-mediated induction of inducible nitric oxide synthase and IL-12 in macrophages: Leishmania phosphoglycans subvert macrophage IL-12 production by targeting ERK MAP , 1999, Journal of immunology.

[26]  I. McInnes,et al.  A proinflammatory role for IL-18 in rheumatoid arthritis. , 1999, The Journal of clinical investigation.

[27]  W. Harnett,et al.  Molecular and immunodiagnosis of human filarial nematode infections , 1999, Parasitology.

[28]  J. Dayer,et al.  Cytokines and direct cell contact in synovitis: relevance to therapeutic intervention , 1999, Arthritis research.

[29]  Elson,et al.  Onchocerciasis modulates the immune response to mycobacterial antigens , 1999, Clinical and experimental immunology.

[30]  Ranjeny Thomas,et al.  Dendritic cells and the pathogenesis of rheumatoid arthritis , 1999, Journal of leukocyte biology.

[31]  P. Miossec,et al.  Human interleukin-17: A T cell-derived proinflammatory cytokine produced by the rheumatoid synovium. , 1999, Arthritis and rheumatism.

[32]  K. Rajewsky,et al.  From systemic T cell self-reactivity to organ-specific autoimmune disease via immunoglobulins. , 1999, Immunity.

[33]  M. Harnett,et al.  Phosphorylcholine: friend or foe of the immune system? , 1999, Immunology today.

[34]  B. Combe,et al.  Anti-Sa antibody is an accurate diagnostic and prognostic marker in adult rheumatoid arthritis. , 1999, The Journal of rheumatology.

[35]  Harnett,et al.  MAPkinase: a second site of G‐protein regulation of B‐cell activation via the antigen receptors , 1998, Immunology.

[36]  M. Odeh,et al.  Role of cytokines in rheumatoid arthritis. , 1998, Drug news & perspectives.

[37]  C. Mackay,et al.  The chemokine receptors CXCR3 and CCR5 mark subsets of T cells associated with certain inflammatory reactions. , 1998, The Journal of clinical investigation.

[38]  M. Baggiolini,et al.  CCR5 is characteristic of Th1 lymphocytes , 1998, Nature.

[39]  S. Reid,et al.  A phosphorylcholine-containing filarial nematode-secreted product disrupts B lymphocyte activation by targeting key proliferative signaling pathways. , 1997, Journal of immunology.

[40]  L. Klareskog,et al.  Production of T-cell cytokines at the single-cell level in patients with inflammatory arthritides: enhanced activity in synovial fluid compared to blood. , 1998, British journal of rheumatology.

[41]  J. Dayer,et al.  Direct contact with stimulated T cells induces the expression of IL-1beta and IL-1 receptor antagonist in human monocytes. Involvement of serine/threonine phosphatases in differential regulation. , 1997, Cytokine.

[42]  G. Panayi.  T-cell-dependent pathways in rheumatoid arthritis. , 1997, Current opinion in rheumatology.

[43]  C. Specker,et al.  Rheumatoid arthritis: autoreactive T cells recognising a novel 68k autoantigen , 1997, Annals of the rheumatic diseases.

[44]  D. Fox,et al.  The role of T cells in the immunopathogenesis of rheumatoid arthritis: new perspectives. , 1997, Arthritis and rheumatism.

[45]  L. Joosten,et al.  Role of interleukin-4 and interleukin-10 in murine collagen-induced arthritis. Protective effect of interleukin-4 and interleukin-10 treatment on cartilage destruction. , 1997, Arthritis and rheumatism.

[46]  I. McInnes,et al.  Interleukin-15 mediates T cell-dependent regulation of tumor necrosis factor-α production in rheumatoid arthritis , 1997, Nature Medicine.

[47]  J. Dayer,et al.  Expression and cleavage of tumor necrosis factor‐α and tumor necrosis factor receptors by human monocytic cell lines upon direct contact with stimulated T cells , 1996, European journal of immunology.

[48]  M. Harnett,et al.  Inhibition of murine B cell proliferation and down-regulation of protein kinase C levels by a phosphorylcholine-containing filarial excretory-secretory product. , 1993, Journal of immunology.

[49]  M. Feldmann,et al.  Anti-tumor necrosis factor ameliorates joint disease in murine collagen-induced arthritis. , 1992, Proceedings of the National Academy of Sciences of the United States of America.

[50]  H. Valkenburg,et al.  Rheumatoid arthritis in a rural South African Negro population. , 1975, Annals of the rheumatic diseases.