Abstract

Uncontrolled T helper type 1 (TH1) and TH17 cells are associated with autoimmune responses. We identify surface lymphotoxin-α (LT-α) as common to TH0, TH1 and TH17 cells and employ a unique strategy to target these subsets using a depleting monoclonal antibody (mAb) directed to surface LT-α. Depleting LT-α–specific mAb inhibited T cell–mediated models of delayed-type hypersensitivity and experimental autoimmune encephalomyelitis. In collagen-induced arthritis (CIA), preventive and therapeutic administration of LT-α–specific mAb inhibited disease, and immunoablated T cells expressing interleukin-17 (IL-17), interferon-γ and tumor necrosis factor-α (TNF-α), whereas decoy lymphotoxin-β receptor (LT-βR) fusion protein had no effect. A mutation in the Fc tail, rendering the antibody incapable of Fcγ receptor binding and antibody-dependent cellular cytotoxicity activity, abolished all in vivo effects. Efficacy in CIA was preceded by a loss of rheumatoid-associated cytokines IL-6, IL-1β and TNF-α within joints. These data indicate that depleting LT-α–expressing lymphocytes with LT-α–specific mAb may be beneficial in the treatment of autoimmune disease.

Access optionsAccess options

Rent or Buy article

Get time limited or full article access on ReadCube.

from$8.99

All prices are NET prices.

References

  1. 1.

    & B cell immunobiology: evolving concepts from the clinic. Annu. Rev. Immunol. 24, 467–496 (2006).

  2. 2.

    et al. Immunocompetent T-cells with a memory-like phenotype are the dominant cell type following antibody-mediated T-cell depletion. Am. J. Transplant. 5, 465–474 (2005).

  3. 3.

    The roaring twenties. Immunity 28, 437–439 (2008).

  4. 4.

    et al. IL-23 drives a pathogenic T cell population that induces autoimmune inflammation. J. Exp. Med. 201, 233–240 (2005).

  5. 5.

    , & TH-17 cells in the circle of immunity and autoimmunity. Nat. Immunol. 8, 345–350 (2007).

  6. 6.

    A shift from adaptive to innate immunity: a potential mechanism of disease progression in multiple sclerosis. J. Neurol. 255 Suppl 1, 3–11 (2008).

  7. 7.

    , , & IL-17 and TH17 cells. Annu. Rev. Immunol. 27, 485–517 (2009).

  8. 8.

    et al. Loss of T-bet, but not STAT1, prevents the development of experimental autoimmune encephalomyelitis. J. Exp. Med. 200, 79–87 (2004).

  9. 9.

    et al. Effect of targeted disruption of STAT4 and STAT6 on the induction of experimental autoimmune encephalomyelitis. J. Clin. Invest. 108, 739–747 (2001).

  10. 10.

    et al. Transcription factor T-bet regulates inflammatory arthritis through its function in dendritic cells. J. Clin. Invest. 116, 414–421 (2006).

  11. 11.

    , & An interleukin (IL)-10/IL-12 immunoregulatory circuit controls susceptibility to autoimmune disease. J. Exp. Med. 187, 537–546 (1998).

  12. 12.

    et al. Divergent pro- and antiinflammatory roles for IL-23 and IL-12 in joint autoimmune inflammation. J. Exp. Med. 198, 1951–1957 (2003).

  13. 13.

    et al. Interleukin-23 rather than interleukin-12 is the critical cytokine for autoimmune inflammation of the brain. Nature 421, 744–748 (2003).

  14. 14.

    et al. IL-17 plays an important role in the development of experimental autoimmune encephalomyelitis. J. Immunol. 177, 566–573 (2006).

  15. 15.

    , , & Suppression of immune induction of collagen-induced arthritis in IL-17-deficient mice. J. Immunol. 171, 6173–6177 (2003).

  16. 16.

    et al. Cutting edge: TH1 cells facilitate the entry of TH17 cells to the central nervous system during experimental autoimmune encephalomyelitis. J. Immunol. 181, 3750–3754 (2008).

  17. 17.

    , , & Phenotypic differences between TH1 and TH17 cells and negative regulation of TH1 cell differentiation by IL-17. J. Leukoc. Biol. 81, 1258–1268 (2007).

  18. 18.

    et al. Immune response in silico (IRIS): immune-specific genes identified from a compendium of microarray expression data. Genes Immun. 6, 319–331 (2005).

  19. 19.

    Network communications: lymphotoxins, LIGHT and TNF. Annu. Rev. Immunol. 23, 787–819 (2005).

  20. 20.

    Immunopathologic aspects of rheumatoid arthritis: who is the conductor and who plays the immunologic instrument? J. Rheumatol. Suppl. 79, 9–14 (2007).

  21. 21.

    et al. Lymphoid neogenesis in rheumatoid synovitis. J. Immunol. 167, 1072–1080 (2001).

  22. 22.

    , , , & Lymphotoxin but not tumor necrosis factor functions to maintain splenic architecture and humoral responsiveness in adult mice. Eur. J. Immunol. 27, 2033–2042 (1997).

  23. 23.

    & Lymphotoxin/light, lymphoid microenvironments and autoimmune disease. Nat. Rev. Immunol. 3, 642–655 (2003).

  24. 24.

    et al. Blockade of lymphotoxin pathway exacerbates autoimmune arthritis by enhancing the TH1 response. Arthritis Rheum. 52, 3202–3209 (2005).

  25. 25.

    , , , & Lymphotoxin alphabeta is expressed on recently activated naive and TH1-like CD4 cells but is down-regulated by IL-4 during TH2 differentiation. J. Immunol. 162, 1333–1338 (1999).

  26. 26.

    et al. High resolution mapping of the binding site on human IgG1 for Fc γ RI, Fc γ RII, Fc γ RIII, and FcRn and design of IgG1 variants with improved binding to the Fc γ R. J. Biol. Chem. 276, 6591–6604 (2001).

  27. 27.

    et al. Antigen-specific T cell sensitization is impaired in IL-17–deficient mice, causing suppression of allergic cellular and humoral responses. Immunity 17, 375–387 (2002).

  28. 28.

    et al. A role for the lymphotoxin/LIGHT axis in the pathogenesis of murine collagen-induced arthritis. J. Immunol. 171, 115–126 (2003).

  29. 29.

    et al. B-cell depletion inhibits arthritis in a collagen-induced arthritis (CIA) model, but does not adversely affect humoral responses in a respiratory syncytial virus (RSV) vaccination model. Blood 106, 2235–2243 (2005).

  30. 30.

    et al. In vivo blockade of OX40 ligand inhibits thymic stromal lymphopoietin driven atopic inflammation. J. Clin. Invest. 117, 3868–3878 (2007).

  31. 31.

    Even though T-cell–directed trials have been of limited success, is there reason for optimism? Nat. Clin. Pract. Rheumatol. 2, 58–59 (2006).

  32. 32.

    et al. Overexpression of IL-17 in the knee joint of collagen type II immunized mice promotes collagen arthritis and aggravates joint destruction. Inflamm. Res. 51, 102–104 (2002).

  33. 33.

    , , , & IL-17 derived from juxta-articular bone and synovium contributes to joint degradation in rheumatoid arthritis. Arthritis Res. 3, 168–177 (2001).

  34. 34.

    Interleukin-17 in fashion, at last: ten years after its description, its cellular source has been identified. Arthritis Rheum. 56, 2111–2115 (2007).

  35. 35.

    et al. IL-23 is essential for T cell–mediated colitis and promotes inflammation via IL-17 and IL-6. J. Clin. Invest. 116, 1310–1316 (2006).

  36. 36.

    et al. Monoclonal anti-interleukin 23 reverses active colitis in a T cell-mediated model in mice. Gastroenterology 132, 2359–2370 (2007).

  37. 37.

    et al. Interleukin-22, a TH17 cytokine, mediates IL-23–induced dermal inflammation and acanthosis. Nature 445, 648–651 (2007).

  38. 38.

    et al. LIGHT, a new member of the TNF superfamily, and lymphotoxin α are ligands for herpesvirus entry mediator. Immunity 8, 21–30 (1998).

  39. 39.

    et al. Both the lymphotoxin and tumor necrosis factor pathways are involved in experimental murine models of colitis. Gastroenterology 115, 1464–1475 (1998).

  40. 40.

    et al. A role for surface lymphotoxin in experimental autoimmune encephalomyelitis independent of LIGHT. J. Clin. Invest. 112, 755–767 (2003).

  41. 41.

    et al. In vivo blockade of OX40 ligand inhibits thymic stromal lymphopoietin driven atopic inflammation. J. Clin. Invest. 117, 3868–3878 (2007).

  42. 42.

    , , , & Expression of surface lymphotoxin and tumor necrosis factor on activated T, B, and natural killer cells. J. Immunol. 149, 3881–3888 (1992).

  43. 43.

    , , & B cell-deficient mice do not develop type II collagen-induced arthritis (CIA). Clin. Exp. Immunol. 111, 521–526 (1998).

  44. 44.

    et al. Dissecting the role of lymphotoxin in lymphoid organs by conditional targeting. Immunol. Rev. 195, 106–116 (2003).

  45. 45.

    et al. Blocking lymphotoxin β receptor signalling exacerbates acute DSS-induced intestinal inflammation—opposite functions for surface lymphotoxin expressed by T and B lymphocytes. Mol. Immunol. 45, 34–41 (2008).

  46. 46.

    et al. Expression of lymphotoxin-αβ on antigen-specific T cells is required for DC function. J. Exp. Med. 204, 1071–1081 (2007).

  47. 47.

    , , , & Ectopic LT αβ directs lymphoid organ neogenesis with concomitant expression of peripheral node addressin and a HEV-restricted sulfotransferase. J. Exp. Med. 197, 1153–1163 (2003).

  48. 48.

    et al. Novel lymphotoxin α (LTα) knockout mice with unperturbed tumor necrosis factor expression: reassessing LTα biological functions. Mol. Cell. Biol. 26, 4214–4225 (2006).

  49. 49.

    et al. Interactions of tumor necrosis factor (TNF) and TNF receptor family members in the mouse and human. J. Biol. Chem. 281, 13964–13971 (2006).

  50. 50.

    et al. A novel inhibitor of the alternative pathway of complement reverses inflammation and bone destruction in experimental arthritis. J. Exp. Med. 204, 1319–1325 (2007).

Download references

Acknowledgements

We thank H. Nguyen, M. Zhou and the Translational Immunology group for animal studies; A. Gurney; B. Kearce, M.-H. Xie, C. Adams, K. McCutcheon and Antibody Engineering Department for antibody support; C. Austin for pathology support; N. Crellin and A. Iyer for FACS support; and W. Ouyang, F. Martin and H. Spits for manuscript critique.

Author information

Author notes

    • Eugene Y Chiang
    •  & Ganesh A Kolumam

    These authors contributed equally to this work.

Affiliations

  1. Departments of Immunology, South San Francisco, California, USA.

    • Eugene Y Chiang
    • , Ganesh A Kolumam
    • , Xin Yu
    • , Michelle Francesco
    • , Sinisa Ivelja
    • , Ivan Peng
    • , Peter Gribling
    • , Jean Shu
    • , Wyne P Lee
    • , Canio J Refino
    • , Mercedesz Balazs
    • , Andres Paler-Martinez
    • , Devavani Chatterjea
    •  & Jane L Grogan
  2. Assay and Automation Technology, South San Francisco, California, USA.

    • Allen Nguyen
    •  & Judy Young
  3. Tumor Biology and Angiogenesis, South San Francisco, California, USA.

    • Kai H Barck
    •  & Richard A D Carano
  4. Pathology, Genentech, Inc., South San Francisco, California, USA.

    • Ron Ferrando
    •  & Lauri Diehl

Authors

  1. Search for Eugene Y Chiang in:

  2. Search for Ganesh A Kolumam in:

  3. Search for Xin Yu in:

  4. Search for Michelle Francesco in:

  5. Search for Sinisa Ivelja in:

  6. Search for Ivan Peng in:

  7. Search for Peter Gribling in:

  8. Search for Jean Shu in:

  9. Search for Wyne P Lee in:

  10. Search for Canio J Refino in:

  11. Search for Mercedesz Balazs in:

  12. Search for Andres Paler-Martinez in:

  13. Search for Allen Nguyen in:

  14. Search for Judy Young in:

  15. Search for Kai H Barck in:

  16. Search for Richard A D Carano in:

  17. Search for Ron Ferrando in:

  18. Search for Lauri Diehl in:

  19. Search for Devavani Chatterjea in:

  20. Search for Jane L Grogan in:

Contributions

E.Y.C. performed in vitro assays and analyzed in vivo study end points. G.A.K. developed MBP-TCR–transgenic T cell transfer experiments. D.C., M.F. and X.Y. contributed to screening and characterization of mAbs, in vitro assays and paw joint ELISA. A.P.-M. performed Luminex assays. P.G., J.S. and W.P.L. performed collagen-induced arthritis studies. J.Y. and A.N. performed competition assays and established mouse LT-α3 ELISA. S.I., I.P. and C.J.R. performed delayed hypersensitivity and T cell transfer studies. M.B. supervised in vivo studies. L.D. and R.F. performed histology and immunohistochemistry. R.A.D.C. and K.H.B. performed micro-computed tomographic imaging and analysis. J.L.G. supervised the project and drafted manuscript.

Competing interests

All authors work for Genentech, which develops and markets drugs for a profit.

Corresponding author

Correspondence to Jane L Grogan.

Supplementary information

PDF files

  1. 1.

    Supplementary Text and Figures

    Supplementary Figs. 1–9, Supplementary Tables 1 and 2 and Supplementary Methods

About this article

Publication history

Received

Accepted

Published

DOI

https://doi.org/10.1038/nm.1984

Further reading