Anti-IL-23 therapy inhibits multiple inflammatory pathways and ameliorates autoimmune encephalomyelitis.

IL-23 is a member of the IL-12 cytokine family that drives a highly pathogenic T cell population involved in the initiation of autoimmune diseases. We have shown that IL-23-dependent, pathogenic T cells produced IL-17 A, IL-17 F, IL-6, and TNF but not IFN-gamma or IL-4. We now show that T-bet and STAT1 transcription factors are not required for the initial production of IL-17. However, optimal IL-17 production in response to IL-23 stimulation appears to require the presence of T-bet. To explore the clinical efficacy of targeting the IL-23 immune pathway, we generated anti-IL-23p19-specific antibodies and tested to determine whether blocking IL-23 function can inhibit EAE, a preclinical animal model of human multiple sclerosis. Anti-IL-23p19 treatment reduced the serum level of IL-17 as well as CNS expression of IFN-gamma, IP-10, IL-17, IL-6, and TNF mRNA. In addition, therapeutic treatment with anti-IL-23p19 during active disease inhibited proteolipid protein (PLP) epitope spreading and prevented subsequent disease relapse. Thus, therapeutic targeting of IL-23 effectively inhibited multiple inflammatory pathways that are critical for driving CNS autoimmune inflammation.

[1]  T. Mcclanahan,et al.  IL-23 is essential for T cell-mediated colitis and promotes inflammation via IL-17 and IL-6. , 2006, The Journal of clinical investigation.

[2]  R. Kastelein,et al.  Understanding the IL-23-IL-17 immune pathway. , 2006, Trends in immunology.

[3]  Ying Wang,et al.  A distinct lineage of CD4 T cells regulates tissue inflammation by producing interleukin 17 , 2005, Nature Immunology.

[4]  R. D. Hatton,et al.  Interleukin 17–producing CD4+ effector T cells develop via a lineage distinct from the T helper type 1 and 2 lineages , 2005, Nature Immunology.

[5]  S. Khader,et al.  IL-23 Compensates for the Absence of IL-12p70 and Is Essential for the IL-17 Response during Tuberculosis but Is Dispensable for Protection and Antigen-Specific IFN-γ Responses if IL-12p70 Is Available1 , 2005, The Journal of Immunology.

[6]  T. Olsson,et al.  Expression of T cell immunoglobulin- and mucin-domain-containing molecules-1 and -3 (TIM-1 and -3) in the rat nervous and immune systems , 2005, Journal of Neuroimmunology.

[7]  S. Miller,et al.  Epitope spreading initiates in the CNS in two mouse models of multiple sclerosis , 2005, Nature Medicine.

[8]  K. Ley,et al.  Phagocytosis of apoptotic neutrophils regulates granulopoiesis via IL-23 and IL-17. , 2005, Immunity.

[9]  Pamela L. Schwartzberg,et al.  T Helper Cell Fate Specified by Kinase-Mediated Interaction of T-bet with GATA-3 , 2005, Science.

[10]  T. Mcclanahan,et al.  IL-23 drives a pathogenic T cell population that induces autoimmune inflammation , 2005, The Journal of experimental medicine.

[11]  V. Kuchroo,et al.  IL-12– and IL-23–induced T helper cell subsets , 2005, The Journal of experimental medicine.

[12]  P. Vermersch,et al.  New insights into cell responses involved in experimental autoimmune encephalomyelitis and multiple sclerosis. , 2005, Immunology Letters.

[13]  A. Gottlieb,et al.  A phase I study evaluating the safety, pharmacokinetics, and clinical response of a human IL-12 p40 antibody in subjects with plaque psoriasis. , 2004, The Journal of investigative dermatology.

[14]  R. de Waal Malefyt,et al.  IL‐12 and IL‐23: master regulators of innate and adaptive immunity , 2004, Immunological reviews.

[15]  M. Neurath,et al.  Anti-interleukin-12 antibody for active Crohn's disease. , 2004, The New England journal of medicine.

[16]  A. Lovett-racke,et al.  Silencing T-bet defines a critical role in the differentiation of autoreactive T lymphocytes. , 2004, Immunity.

[17]  R. Kastelein,et al.  IL-23 Provides a Limited Mechanism of Resistance to Acute Toxoplasmosis in the Absence of IL-121 , 2004, The Journal of Immunology.

[18]  S. Szabo,et al.  Loss of T-bet, But Not STAT1, Prevents the Development of Experimental Autoimmune Encephalomyelitis , 2004, The Journal of experimental medicine.

[19]  A. Amadori,et al.  The IL-12Rβ2 gene functions as a tumor suppressor in human B cell malignancies , 2004 .

[20]  T. Mcclanahan,et al.  Divergent Pro- and Antiinflammatory Roles for IL-23 and IL-12 in Joint Autoimmune Inflammation , 2003, The Journal of experimental medicine.

[21]  H. Mühl,et al.  Anti-inflammatory properties of pro-inflammatory interferon-gamma. , 2003, International immunopharmacology.

[22]  L. Glimcher,et al.  T-bet is required for optimal production of IFN-γ and antigen-specific T cell activation by dendritic cells , 2003, Proceedings of the National Academy of Sciences of the United States of America.

[23]  J. Lötvall,et al.  Endogenous IL-17 as a Mediator of Neutrophil Recruitment Caused by Endotoxin Exposure in Mouse Airways1 , 2003, The Journal of Immunology.

[24]  J. Shellito,et al.  Cutting Edge: Roles of Toll-Like Receptor 4 and IL-23 in IL-17 Expression in Response to Klebsiella pneumoniae Infection1 , 2003, The Journal of Immunology.

[25]  M. Kamoun,et al.  Induction of Experimental Autoimmune Encephalomyelitis in IL-12 Receptor-β2-Deficient Mice: IL-12 Responsiveness Is Not Required in the Pathogenesis of Inflammatory Demyelination in the Central Nervous System1 , 2003, The Journal of Immunology.

[26]  R. Kastelein,et al.  Interleukin-23 rather than interleukin-12 is the critical cytokine for autoimmune inflammation of the brain , 2003, Nature.

[27]  M. Kamoun,et al.  IL-12p35-Deficient Mice Are Susceptible to Experimental Autoimmune Encephalomyelitis: Evidence for Redundancy in the IL-12 System in the Induction of Central Nervous System Autoimmune Demyelination1 , 2002, The Journal of Immunology.

[28]  B. '. ’t Hart,et al.  Prevention of Experimental Autoimmune Encephalomyelitis in Common Marmosets Using an Anti-IL-12p40 Monoclonal Antibody1 , 2002, Journal of Immunology.

[29]  B. Becher,et al.  Experimental autoimmune encephalitis and inflammation in the absence of interleukin-12. , 2002, The Journal of clinical investigation.

[30]  J. Renauld,et al.  IL-23 and IL-12 Have Overlapping, but Distinct, Effects on Murine Dendritic Cells1 , 2002, The Journal of Immunology.

[31]  T. Mcclanahan,et al.  A Receptor for the Heterodimeric Cytokine IL-23 Is Composed of IL-12Rβ1 and a Novel Cytokine Receptor Subunit, IL-23R1 , 2002, The Journal of Immunology.

[32]  Tatyana Chernova,et al.  Th1-specific cell surface protein Tim-3 regulates macrophage activation and severity of an autoimmune disease , 2002, Nature.

[33]  Jianfei Yang,et al.  T-bet is a STAT1-induced regulator of IL-12R expression in naïve CD4+ T cells , 2002, Nature Immunology.

[34]  S. Khoury,et al.  Effect of targeted disruption of STAT4 and STAT6 on the induction of experimental autoimmune encephalomyelitis. , 2001, The Journal of clinical investigation.

[35]  J. Shellito,et al.  Requirement of Interleukin 17 Receptor Signaling for Lung Cxc Chemokine and Granulocyte Colony-Stimulating Factor Expression, Neutrophil Recruitment, and Host Defense , 2001, The Journal of experimental medicine.

[36]  C. Samuel,et al.  The role of gamma interferon in antimicrobial immunity. , 2001, Current opinion in microbiology.

[37]  A. O’Garra,et al.  The molecular basis of T helper 1 and T helper 2 cell differentiation. , 2000, Trends in cell biology.

[38]  J Wagner,et al.  Novel p19 protein engages IL-12p40 to form a cytokine, IL-23, with biological activities similar as well as distinct from IL-12. , 2000, Immunity.

[39]  A. Komiyama,et al.  Anti-IL-12 antibody prevents the development and progression of multiple sclerosis-like relapsing–remitting demyelinating disease in NOD mice induced with myelin oligodendrocyte glycoprotein peptide , 2000, Journal of Neuroimmunology.

[40]  H. Hartung,et al.  Immunopathogenesis of multiple sclerosis: the role of T cells. , 1999, Current opinion in neurology.

[41]  G. Trinchieri,et al.  Antibodies against IL-12 prevent superantigen-induced and spontaneous relapses of experimental autoimmune encephalomyelitis. , 1998, Journal of immunology.

[42]  Brennan,et al.  Blockade of IL‐12 during the induction of collagen‐induced arthritis (CIA) markedly attenuates the severity of the arthritis , 1998, Clinical and experimental immunology.

[43]  G. Forni,et al.  Expression and role in apoptosis of the alpha- and beta-chains of the IFN-gamma receptor on human Th1 and Th2 clones. , 1997, Journal of immunology.

[44]  K. McIntyre,et al.  Reduced incidence and severity of collagen‐induced arthritis in interleukin‐12‐deficient mice , 1996, European journal of immunology.

[45]  W. Cowden,et al.  IFN-gamma plays a critical down-regulatory role in the induction and effector phase of myelin oligodendrocyte glycoprotein-induced autoimmune encephalomyelitis. , 1996, Journal of immunology.

[46]  J. Leonard,et al.  Regulation of Experimental Autoimmune Encephalomyelitis by Interleukin‐12 , 1996, Annals of the New York Academy of Sciences.

[47]  L. Steinman,et al.  Mice with a disrupted IFN-gamma gene are susceptible to the induction of experimental autoimmune encephalomyelitis (EAE). , 1996, Journal of immunology.

[48]  L. Adorini,et al.  Manipulation of the Th1/Th2 cell balance: an approach to treat human autoimmune diseases? , 1996, Autoimmunity.

[49]  L. Adorini,et al.  The role of IL-12 in the induction of organ-specific autoimmune diseases. , 1995, Immunology today.

[50]  J. Leonard,et al.  Prevention of experimental autoimmune encephalomyelitis by antibodies against interleukin 12 , 1995, The Journal of experimental medicine.

[51]  K. Mohler,et al.  Analysis of cytokine mRNA expression in the central nervous system of mice with experimental autoimmune encephalomyelitis reveals that IL-10 mRNA expression correlates with recovery. , 1992, Journal of immunology.

[52]  V. ter meulen,et al.  Isolation and direct characterization of resident microglial cells from the normal and inflamed central nervous system. , 1991, Proceedings of the National Academy of Sciences of the United States of America.

[53]  W. Hickey.  Migration of Hematogenous Cells Through the Blood‐Brain Barrier and the Initiation of CNS Inflammation , 1991, Brain pathology.

[54]  A. Billiau,et al.  Enhancement of experimental allergic encephalomyelitis in mice by antibodies against IFN-gamma. , 1988, Journal of immunology.