TY - JOUR AU - Xystrakis, Emmanuel AU - Kusumakar, Siddharth AU - Boswell, Sandra AU - Peek, Emma AU - Urry, Zoë AU - Richards, David F. AU - Adikibi, Tonye AU - Pridgeon, Carol AU - Dallman, Margaret AU - Loke, Tuck-Kay AU - Robinson, Douglas S. AU - Barrat, Franck J. AU - O’Garra, Anne AU - Lavender, Paul AU - Lee, Tak H. AU - Corrigan, Christopher AU - Hawrylowicz, Catherine M. T1 - Reversing the defective induction of IL-10–secreting regulatory T cells in glucocorticoid-resistant asthma patients PY - 2006/01/04/ AB - We previously reported that human CD4+ Tregs secrete high levels of IL-10 when stimulated in the presence of dexamethasone and calcitriol (vitamin D3). We now show that following stimulation by allergen, IL-10–secreting Tregs inhibit cytokine secretion by allergen-specific Th2 cells in an IL-10–dependent manner. A proportion of patients with severe asthma fail to demonstrate clinical improvement upon glucocorticoid therapy, and their asthma is characterized as glucocorticoid resistant (SR, abbreviation derived from “steroid resistant”). Dexamethasone does not enhance secretion of IL-10 by their CD4+ T cells. Addition of vitamin D3 with dexamethasone to cultures of SR CD4+ T cells enhanced IL-10 synthesis to levels observed in cells from glucocorticoid-sensitive patients cultured with dexamethasone alone. Furthermore, pretreatment with IL-10 fully restored IL-10 synthesis in these cells in response to dexamethasone. Vitamin D3 significantly overcame the inhibition of glucocorticoid-receptor expression by dexamethasone while IL-10 upregulated glucocorticoid-receptor expression by CD4+ T cells, suggesting potential mechanisms whereby these treatments may overcome poor glucocorticoid responsiveness. We show here that administration of vitamin D3 to healthy individuals and SR asthmatic patients enhanced subsequent responsiveness to dexamethasone for induction of IL-10. This strongly suggests that vitamin D3 could potentially increase the therapeutic response to glucocorticoids in SR patients. JF - The Journal of Clinical Investigation JA - J Clin Invest SN - 0021-9738 DO - 10.1172/JCI21759 VL - 116 IS - 1 UR - https://doi.org/10.1172/JCI21759 SP - 146 EP - 155 PB - The American Society for Clinical Investigation ER -