Journal
KIDNEY INTERNATIONAL
Volume 78, Issue 1, Pages 79-88Publisher
ELSEVIER SCIENCE INC
DOI: 10.1038/ki.2010.84
Keywords
IL-17; inosine-monophosphate dehydrogenase; mycophenolate; neutropenia
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Funding
- Deutsche Forschungsgemeinschaft [VI508/1-1]
- National Institutes of Health [HL 073361]
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Mycophenolic acid is a commonly used immunosuppressant after organ transplantation and in autoimmune diseases; however, myelosuppression is a major complication despite its largely favorable side-effect profile. Mycophenolic acid targets inosine monophosphate dehydrogenase, which is essential for T-cell proliferation. The T-cell cytokine interleukin-17 (IL-17 or IL-17A) and its receptor maintain normal neutrophilic granulocyte numbers in mice by induction of granulocyte-colony-stimulating factor. To test whether mycophenolic acid induces neutropenia by inhibiting IL-17-producing T cells, we treated C57Bl/6 mice with mycophenolate-mofetil (the orally available pro-drug) and found a dose-dependent decrease in blood neutrophils. This myelosuppressive effect was completely abolished in mice that lack the IL-17 receptor. Mycophenolic acid delayed myeloid recovery after bone marrow transplantation and decreased the percentage of IL-17-producing T cells in the spleen and thymus, and inhibited IL-17 production in human and mouse T cells in vitro. Injection of IL-17 during mycophenolic acid treatment overcame the suppression of the circulating neutrophil levels. Our study shows that mycophenolic acid suppresses neutrophil production by inhibiting IL-17 expression, suggesting that measurement of this interleukin might be useful in estimating the risk of neutropenia in clinical settings. Kidney International (2010) 78, 79-88; doi: 10.1038/ki.2010.84; published online 7 April 2010
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