Topical steroid therapy induces pro-tolerogenic changes in Langerhans cells in human skin.

We have investigated the efficacy of conditioning skin Langerhans cells (LCs) with agents to promote tolerance and reduce inflammation, with the goal of improving the outcomes of antigen-specific immunotherapy. Topical treatments were assessed ex vivo, using excised human breast skin maintained in organ bath cultures, and in vivo in healthy volunteers by analysing skin biopsies and epidermal blister roof samples. Following topical treatment with a corticosteroid, tumour necrosis factor-α levels were reduced in skin biopsy studies and blister fluid samples. Blister fluid concentrations of monocyte chemoattractant protein-1, macrophage inflammatory proteins -1α and 1ß and interferon-γ inducible protein-10 were also reduced, while preserving levels of interleukin-1α (IL-1α), IL-6, IL-8 and IL-10. Steroid pre-treatment of the skin reduced the ability of LCs to induce proliferation, while supernatants showed an increase in the IL-10/interferon-γ ratio. Phenotypic changes following topical steroid treatment were also observed, including reduced expression of CD83 and CD86 in blister-derived LCs, but preservation of the tolerogenic signalling molecules immunoglobulin-like transcript 3 and programmed death-1. Reduced expression of HLA-DR, CD80 and CD86 were also apparent in LCs derived from excised human skin. Topical therapy with a vitamin D analogue (calcipotriol) and steroid, calcipotriol alone or vitamin A elicited no significant changes in the parameters studied. These experiments suggest that pre-conditioning the skin with topical corticosteroid can modulate LCs by blunting their pro-inflammatory signals and potentially enhancing tolerance. We suggest that such modulation before antigen-specific immunotherapy might provide an inexpensive and safe adjunct to current approaches to treat autoimmune diseases.

Pancreatic volume is reduced in adult patients with recently diagnosed type 1 diabetes.

CONTEXT: Pancreatic atrophy is common in longstanding type 1 diabetes, but there are limited data concerning pancreas size at diagnosis. OBJECTIVE: Our objective was to determine whether pancreatic size was reduced in patients with recently diagnosed type 1 diabetes and assess whether pancreatic volume was related to residual ß-cell function or islet autoantibodies. DESIGN AND SETTING: We conducted a controlled cohort study with strict inclusion criteria, recruiting from hospital diabetes clinics between 2007 and 2010. PATIENTS AND HEALTHY CONTROLS: Participants included 20 male adult patients (median age 27 yr) with recent-onset type 1 diabetes (median duration 3.8 months) and 24 male healthy controls (median age 27 yr). INTERVENTION: Interventions included noninvasive magnetic resonance imaging, collection of fasting blood samples, and glucagon stimulation testing in patients. MAIN OUTCOME MEASURES: We compared pancreatic volume estimates between patients with recent-onset type 1 diabetes and healthy controls as planned a priori. RESULTS: Scans were analyzed by an experienced radiologist blinded to diabetes status. Pancreatic volume correlated with body weight in patients and controls (P = 0.007). After adjustment for body weight, mean pancreatic volume index was 26% less in patients (1.19 ml/kg, se 0.07 ml/kg) than in controls (1.61 ml/kg, se 0.08 ml/kg) (P = 0.001). No correlation was seen between pancreatic volume index in patients and diabetes duration, glucose or C-peptide levels, glycated hemoglobin, and islet autoantibodies. CONCLUSIONS: Pancreatic volume is reduced by 26% in patients with type 1 diabetes within months of diagnosis, suggesting that atrophy begins years before the onset of clinical disease. Pancreatic atrophy within individuals is therefore a potential clinical marker of disease progression.