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Immunomodulatory Effect of Vancomycin on Treg in Pediatric Inflammatory Bowel Disease and Primary Sclerosing Cholangitis

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Abstract

Vancomycin has been shown to affect tumor necrosis factor-alpha (TNF-α) pathways as an immunomodulator; this is thought to be separate from its function as an antibiotic [1]. Previous studies have shown that oral vancomycin (OV) is an effective treatment for concomitant primary sclerosing cholangitis (PSC) and inflammatory bowel disease (IBD) in children [2, 3]. Since both diseases are associated with immune dysfunction, we hypothesized that vancomycin’s therapeutic effect in IBD and PSC occurs through immunomodulation. Therefore, we examined the in vivo immunological changes that occur during OV treatment of 14 children with PSC and IBD. Within 3 months of OV administration, peripheral gamma-glutamyl transpeptidase (GGT) and alanine aminotransferase (ALT) concentrations, white blood cell (WBC) counts, and neutrophil counts normalized from elevated levels before treatment. Patients also demonstrated improved biliary imaging studies, liver biopsies and IBD symptoms and biopsies. Additionally, plasma transforming growth factor beta (TGF-β) levels were increased without concurrent shifts in Th1-or Th2-associated cytokine production. Peripheral levels of CD4 + CD25hiCD127lo and CD4 + FoxP3+ regulatory T (Treg) cells also increased in OV-treated PSC + IBD patients compared to pretreatment levels. A unique case study shows that the therapeutic effects of OV in the treatment of PSC + IBD do not always endure after OV discontinuation, with relapse of PSC associated with a decrease in blood Treg levels; subsequent OV retreatment was then associated with a rise in blood Treg levels and normalization of liver function tests (LFTs). Taken together, these studies support immune-related pathophysiology of PSC with IBD, which is responsive to OV.

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Acknowledgements

The project described in this publication was supported by the Stanford NIH/NCRR CTSA award number UL1 RR025744 and by the Lucile Packard Foundation for Children’s Health. The authors would like to thank the families of the Lucile Packard Foundation for Child Health, the Wadsworth family, the Stanford Digestive Disease Center, and the Human Immune Monitoring Core of Stanford University for their generous support of these studies. The authors would additionally like to acknowledge the following individuals for their assistance with this report: Katharine Eng, M.D., Cameron McDonald-Hyman, and Ruhi Nath.

Sources of support

Stanford NIH/NCRR CTSA Award Number UL1 RR025744 (Cox); Lucile Packard Foundation for Child Health (Cox); Stanford Digestive Disease Center, NIH P30DK56339 (Nadeau); Vice Provost for Undergraduate Education (VPUE) Major Grant Award at Stanford University (Seki).

Disclosures

The authors declare that they have no conflict of interest.

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Authors and Affiliations

  1. Department of Pediatrics, Division of Immunology and Allergy, Stanford University School of Medicine, Stanford, CA, 94305, USA

    David N. Abarbanel, Scott M. Seki & Kari C. Nadeau

  2. Department of Pediatrics, Division of Gastroenterology, Hepatology, and Nutrition, Stanford University School of Medicine, 750 Welch Road, Suite #116, Stanford, CA, 94305-5731, USA

    Joseph A. Benavides, Kathleen Cox & Kenneth L. Cox

  3. Lucile Packard Children’s Hospital, Stanford University, Stanford, CA, 94305, USA

    Kathleen Cox, Kari C. Nadeau & Kenneth L. Cox

  4. Sutter Institute for Medical Research, Sacramento, CA, 95816, USA

    Yinka Davies & Natalie Marlen

Authors
  1. David N. Abarbanel
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  2. Scott M. Seki
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  6. Kathleen Cox
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  7. Kari C. Nadeau
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  8. Kenneth L. Cox
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Corresponding author

Correspondence to Kenneth L. Cox.

Additional information

David N. Abarbanel and Scott M. Seki contributed equally to this work.

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Abarbanel, D.N., Seki, S.M., Davies, Y. et al. Immunomodulatory Effect of Vancomycin on Treg in Pediatric Inflammatory Bowel Disease and Primary Sclerosing Cholangitis. J Clin Immunol 33, 397–406 (2013). https://doi.org/10.1007/s10875-012-9801-1

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  • DOI: https://doi.org/10.1007/s10875-012-9801-1

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