The mechanism(s) underlying this common form of lymphocyte steroid resistance is unknown, although several ideas arising from in vitro studies have been proposed18-20 and in the clinical setting, mediators of inflammation may exacerbate this trait.20 Interleukin 2 (IL-2), a key growth factor secreted by T cells, has been shown to antagonize the response to steroids in vitro, reducing the degree of lymphocyte suppression when cells are cultured in the presence

of high-dose dexamethasone.21 T cells expressing higher levels of the high affinity IL-2 receptor, CD25, demonstrate steroid resistance.22 Furthermore, inhibition of IL-2, either by cytokine neutralization or receptor blockade, has been shown to enhance sensitivity to steroids in vitro,16 raising the possibility that in vivo blockade of the IL-2 pathway might represent a treatment strategy in steroid-resistant patients. Two monoclonal antibodies targeting FK506 CD25 are currently available (and used as part of immunosuppressive regimes for transplantation), one chimeric (basiliximab), and one

humanized (daclizumab). We hypothesize that, as seen in other inflammatory diseases, intrinsic resistance to steroids (indicated by testing in vitro the percentage of lymphocyte suppression in the presence of high-dose dexamethasone) may play a role in individuals who fail to respond to steroids in vivo in SAH. If confirmed, this raises the possibility that IL-2 www.selleckchem.com/products/17-AAG(Geldanamycin).html receptor blockade might be able to reverse this. We report here a prospective study to test these hypotheses in which in vitro lymphocyte steroid resistance and the effects of CD25 blockade (with basiliximab) Olopatadine in vitro were measured in a consecutive series of patients presenting to our unit with SAH (MdF >32). In vitro steroid response

values were measured on admission and then compared to the clinical response to steroids in vivo, as indicated both by the early biochemical response (drop in bilirubin >25% in the first 7 days of treatment) and 6-month mortality rates. AH, alcoholic hepatitis; DILPA, dexamethasone suppression of lymphocyte proliferation test; GAHS, Glasgow Alcoholic Hepatitis Score; Imax, maximal proliferation count; MdF, Maddrey’s discriminant function; PBMC, peripheral blood mononuclear cells; PHA, phytohemagglutinin; SAH, severe alcoholic hepatitis. Consecutive patients aged 18-75 presenting to our unit with decompensated chronic liver disease, an MdF >32, and a history of excess alcohol consumption were recruited to the study. Those with overt signs of sepsis or serum creatinine levels >400 μmol/L were excluded. Other exclusion criteria were evidence of nonalcohol-related liver disease, current or recent treatment (in the last 3 months) with oral or intravenous steroids or other immunosuppressants, documented human immunodeficiency virus (HIV) infection, or any history of autoimmune disease.