Skip to main content

Advertisement

SpringerLink
Log in

Oral Administration of OKT3 Monoclonal Antibody to Human Subjects Induces a Dose-Dependent Immunologic Effect in T Cells and Dendritic Cells

  • Published:
Journal of Clinical Immunology Aims and scope Submit manuscript

Abstract

Introduction

Parenteral OKT3 is used to treat transplant rejection and a humanized anti-CD3 Mab has shown positive clinical effects in new onset diabetes. Oral administration of anti-CD3 has not been tested in humans, but suppresses autoimmunity in animal models. Beta-glucosylceramide enhances NKT cell and regulatory T cell activity and enhances the effects of oral anti-CD3 in animals.

Materials and methods

Fifteen healthy volunteers (three per group) received orally administered OKT3 over a dose range of 0.2 to 5.0 mg daily with or without beta-glucosylceramide 7.5 mg for 5 days. Safety and immune parameters were measured on days 5, 10, and 30.

Results and discussion

Oral OKT3 enhanced T cell proliferation, suppressed Th1 and Th17 responses by 43% and 41%, respectively, increased TGF-β/IL-10 expression and decreased IL-23/IL-6 expression by dendritic cells, and affected the IgG repertoire as measured by antigen arrays. Co-administration of oral beta-glucosylceramide induced similar effects. No side effects were observed and no subjects developed human anti-mouse antibodies.

Conclusion

These findings demonstrate that oral anti-CD3 monoclonal antibody is safe and biologically active in humans and presents a new avenue for the treatment of autoimmune diseases.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3
Fig. 4
Fig. 5
Fig. 6
Fig. 7
Fig. 8
Fig. 9

Similar content being viewed by others

References

  1. Chatenoud L, Bluestone JA. CD3-specific antibodies: a portal to the treatment of autoimmunity. Nat Rev Immunol. 2007;7:622–32.

    Article  PubMed  CAS  Google Scholar 

  2. Herold KC, Hagopian W, Auger JA, Poumian-Ruiz E, Taylor L, Donaldson D, et al. Anti-CD3 monoclonal antibody in new-onset type 1 diabetes mellitus. N Engl J Med. 2002;346:1692–8.

    Article  PubMed  CAS  Google Scholar 

  3. Keymeulen B, Vandemeulebroucke E, Ziegler AG, Mathieu C, Kaufman L, Hale G, et al. Insulin needs after CD3-antibody therapy in new-onset type 1 diabetes. N Engl J Med. 2005;352:2598–608.

    Article  PubMed  CAS  Google Scholar 

  4. Friend PJ, Hale G, Chatenoud L, Rebello P, Bradley J, Thiru S, et al. Phase I study of an engineered aglycosylated humanized CD3 antibody in renal transplant rejection. Transplantation. 1999;68:1632–7.

    Article  PubMed  CAS  Google Scholar 

  5. Ishikawa H, Ochi H, Chen ML, Frenkel D, Maron R, Weiner HL. Inhibition of autoimmune diabetes by oral administration of anti-CD3 monoclonal antibody. Diabetes. 2007;56:2103–9.

    Article  PubMed  CAS  Google Scholar 

  6. Ochi H, Abraham M, Ishikawa H, Frenkel D, Yang K, Basso AS, et al. Oral CD3-specific antibody suppresses autoimmune encephalomyelitis by inducing CD4+ CD25- LAP+ T cells. Nat Med. 2006;12:627–35.

    Article  PubMed  CAS  Google Scholar 

  7. Wu H, Center E, Tsokos G, Weiner H: Oral anti-CD3 induces CD4 + CD25-LAP+ regulatory T cells and suppresses murine SLE by downregulatiing pathogenic IL-17 + CD4 + ICOS+CXCR5+ follicular helper T cells. In press. Lupus. 2009;18(7):586–96

    Google Scholar 

  8. Wu HY, Quintana FJ, Weiner HL. Nasal anti-CD3 antibody ameliorates lupus by inducing an IL-10-secreting CD4+ CD25- LAP+ regulatory T cell and is associated with down-regulation of IL-17+ CD4+ ICOS+CXCR5+ follicular helper T cells. J Immunol. 2008;181:6038–50.

    PubMed  CAS  Google Scholar 

  9. Stanic AK, De Silva AD, Park JJ, Sriram V, Ichikawa S, Hirabyashi Y, et al. Defective presentation of the CD1d1-restricted natural Va14Ja18 NKT lymphocyte antigen caused by beta-D-glucosylceramide synthase deficiency. Proc Natl Acad Sci U S A. 2003;100:1849–54.

    Article  PubMed  CAS  Google Scholar 

  10. Lalazar G, Preston S, Zigmond E, Ben Yaacov A, Ilan Y. Glycolipids as immune modulatory tools. Mini Rev Med Chem. 2006;6:1249–53.

    Article  PubMed  CAS  Google Scholar 

  11. Margalit M, Ghazala SA, Alper R, Elinav E, Klein A, Doviner V, et al. Glucocerebroside treatment ameliorates ConA hepatitis by inhibition of NKT lymphocytes. Am J Physiol Gastrointest Liver Physiol. 2005;289:G917–25.

    Article  PubMed  CAS  Google Scholar 

  12. Margalit M, Shalev Z, Pappo O, Sklair-Levy M, Alper R, Gomori M, et al. Glucocerebroside ameliorates the metabolic syndrome in OB/OB mice. J Pharmacol Exp Ther. 2006;319:105–10.

    Article  PubMed  CAS  Google Scholar 

  13. Safadi R, Zigmond E, Pappo O, Shalev Z, Ilan Y. Amelioration of hepatic fibrosis via beta-glucosylceramide-mediated immune modulation is associated with altered CD8 and NKT lymphocyte distribution. Int Immunol. 2007;19:1021–9.

    Article  PubMed  CAS  Google Scholar 

  14. Zigmond E, Preston S, Pappo O, Lalazar G, Margalit M, Shalev Z, et al. Beta-glucosylceramide: a novel method for enhancement of natural killer T lymphoycte plasticity in murine models of immune-mediated disorders. Gut. 2007;56:82–9.

    Article  PubMed  CAS  Google Scholar 

  15. Quintana FJ, Hagedorn PH, Elizur G, Merbl Y, Domany E, Cohen IR. Functional immunomics: microarray analysis of IgG autoantibody repertoires predicts the future response of mice to induced diabetes. Proc Natl Acad Sci U S A. 2004;101(Suppl 2):14615–21.

    Article  PubMed  CAS  Google Scholar 

  16. Coutinho A, Kazatchkine MD, Avrameas S. Natural autoantibodies. Curr Opin Immunol. 1995;7:812–8.

    Article  PubMed  CAS  Google Scholar 

  17. Quintana FJ, Cohen IR. The natural autoantibody repertoire and autoimmune disease. Biomed Pharmacother. 2004;58:276–81.

    Article  PubMed  CAS  Google Scholar 

  18. Stekel D. Microarray bioinformatics. Cambridge: Cambridge University Press; 2003.

    Book  Google Scholar 

  19. Fujii S, Shimizu K, Hemmi H, Steinman RM. Innate Valpha14(+) natural killer T cells mature dendritic cells, leading to strong adaptive immunity. Immunol Rev. 2007;220:183–98.

    Article  PubMed  CAS  Google Scholar 

  20. Milling SW, Yrlid U, Jenkins C, Richards CM, Williams NA, MacPherson G. Regulation of intestinal immunity: effects of the oral adjuvant Escherichia coli heat-labile enterotoxin on migrating dendritic cells. Eur J Immunol. 2007;37:87–99.

    Article  PubMed  CAS  Google Scholar 

  21. Shimizu K, Kurosawa Y, Taniguchi M, Steinman RM, Fujii S. Cross-presentation of glycolipid from tumor cells loaded with alpha-galactosylceramide leads to potent and long-lived T cell mediated immunity via dendritic cells. J Exp Med. 2007;204:2641–53.

    Article  PubMed  CAS  Google Scholar 

  22. Stronge VS, Salio M, Jones EY, Cerundolo V. A closer look at CD1d molecules: new horizons in studying NKT cells. Trends Immunol. 2007;28:455–62.

    Article  PubMed  CAS  Google Scholar 

  23. Merbl Y, Zucker-Toledano M, Quintana FJ, Cohen IR. Newborn humans manifest autoantibodies to defined self molecules detected by antigen microarray informatics. J Clin Invest. 2007;117:712–8.

    Article  PubMed  CAS  Google Scholar 

  24. Quintana FJ, Cohen IR. Autoantibody patterns in diabetes-prone NOD mice and in standard C57BL/6 mice. J Autoimmun. 2001;17:191–7.

    Article  PubMed  CAS  Google Scholar 

  25. Quintana FJ, Getz G, Hed G, Domany E, Cohen IR. Cluster analysis of human autoantibody reactivities in health and in type 1 diabetes mellitus: a bio-informatic approach to immune complexity. J Autoimmun. 2003;21:65–75.

    Article  PubMed  CAS  Google Scholar 

  26. Goldschmidt Y, Sharon E, Quintana FJ, Cohen IR, Brandt A. Adaptive methods for classification of biological microarray data from multiple experiments. 2003.

  27. Hueber W, Kidd BA, Tomooka BH, Lee BJ, Bruce B, Fries JF, et al. Antigen microarray profiling of autoantibodies in rheumatoid arthritis. Arthritis Rheum. 2005;52:2645–55.

    Article  PubMed  CAS  Google Scholar 

  28. Faria AM, Weiner HL. Oral tolerance. Immunol Rev. 2005;206:232–59.

    Article  PubMed  CAS  Google Scholar 

  29. Roncarolo MG, Battaglia M. Regulatory T-cell immunotherapy for tolerance to self antigens and alloantigens in humans. Nat Rev Immunol. 2007;7:585–98.

    Article  PubMed  CAS  Google Scholar 

  30. Kabelitz D, Wesch D, Oberg HH. Regulation of regulatory T cells: role of dendritic cells and toll-like receptors. Crit Rev Immunol. 2006;26:291–306.

    PubMed  CAS  Google Scholar 

  31. Kelsall BL, Leon F. Involvement of intestinal dendritic cells in oral tolerance, immunity to pathogens, and inflammatory bowel disease. Immunol Rev. 2005;206:132–48.

    Article  PubMed  CAS  Google Scholar 

  32. Awasthi A, Carrier Y, Peron JP, Bettelli E, Kamanaka M, Flavell RA, et al. A dominant function for interleukin 27 in generating interleukin 10-producing anti-inflammatory T cells. Nat Immunol. 2007;8:1380–9.

    Article  PubMed  CAS  Google Scholar 

  33. Weiner HL. The mucosal milieu creates tolerogenic dendritic cells and T(R)1 and T(H)3 regulatory cells. Nat Immunol. 2001;2:671–2.

    Article  PubMed  CAS  Google Scholar 

  34. Vaknin-Dembinsky A, Balashov K, Weiner HL. IL-23 is increased in dendritic cells in multiple sclerosis and down-regulation of IL-23 by antisense oligos increases dendritic cell IL-10 production. J Immunol. 2006;176:7768–74.

    PubMed  CAS  Google Scholar 

  35. Vaknin-Dembinsky A, Murugaiyan G, Hafler DA, Astier AL, Weiner HL. Increased IL-23 secretion and altered chemokine production by dendritic cells upon CD46 activation in patients with multiple sclerosis. J Neuroimmunol. 2008;195:140–5.

    Article  PubMed  CAS  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Center for Neurologic Diseases, Brigham and Women’s Hospital, Harvard Medical School, 77 Avenue Louis Pasteur, HIM 720, Boston, MA, 02115, USA

    Yaron Ilan, Roopali Gandhi, Claire Baecher-Allan, Henry Wu, Gopal Murugaiyan, Pia Kivisakk, Mauricio F. Farez, Francisco J. Quintana, Samia J. Khoury & Howard L. Weiner

  2. Department of Medicine, Hebrew University-Hadassah Medical Center, Jerusalem, Israel

    Yaron Ilan, Ehud Zigmond, Gadi Lalazar, Adi Dembinsky, Ami Ben Ya’acov, Nila Hemed, Ibrahim Kasis, Elizabeth Axelrod, Lidya Zolotarov, Athalia Klein & Madi El Haj

Authors
  1. Yaron Ilan
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Ehud Zigmond
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Gadi Lalazar
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Adi Dembinsky
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Ami Ben Ya’acov
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Nila Hemed
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Ibrahim Kasis
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Elizabeth Axelrod
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. Lidya Zolotarov
    View author publications

    You can also search for this author in PubMed Google Scholar

  10. Athalia Klein
    View author publications

    You can also search for this author in PubMed Google Scholar

  11. Madi El Haj
    View author publications

    You can also search for this author in PubMed Google Scholar

  12. Roopali Gandhi
    View author publications

    You can also search for this author in PubMed Google Scholar

  13. Claire Baecher-Allan
    View author publications

    You can also search for this author in PubMed Google Scholar

  14. Henry Wu
    View author publications

    You can also search for this author in PubMed Google Scholar

  15. Gopal Murugaiyan
    View author publications

    You can also search for this author in PubMed Google Scholar

  16. Pia Kivisakk
    View author publications

    You can also search for this author in PubMed Google Scholar

  17. Mauricio F. Farez
    View author publications

    You can also search for this author in PubMed Google Scholar

  18. Francisco J. Quintana
    View author publications

    You can also search for this author in PubMed Google Scholar

  19. Samia J. Khoury
    View author publications

    You can also search for this author in PubMed Google Scholar

  20. Howard L. Weiner
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Howard L. Weiner.

Electronic supplementary material

Below is the link to the electronic supplementary material.

ESM Table 1

(XLS 67 KB).

Rights and permissions

Reprints and permissions

About this article

Cite this article

Ilan, Y., Zigmond, E., Lalazar, G. et al. Oral Administration of OKT3 Monoclonal Antibody to Human Subjects Induces a Dose-Dependent Immunologic Effect in T Cells and Dendritic Cells. J Clin Immunol 30, 167–177 (2010). https://doi.org/10.1007/s10875-009-9323-7

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s10875-009-9323-7

Keywords

Search

Navigation