Limitations of IL-2 and Rapamycin in Immunotherapy of Type 1 Diabetes

Administration of low-dose interleukin-2 (IL-2) alone or combined with rapamycin (RAPA) prevents hyperglycemia in NOD mice. Also, low-dose IL-2 cures recent-onset type 1 diabetes (T1D) in NOD mice, partially by boosting pancreatic regulatory T cells (T_reg cells). These approaches are currently being evaluated in humans. Our objective was to study the effect of higher IL-2 doses (250,000–500,000 IU daily) as well as low-dose IL-2 (25,000 IU daily) and RAPA (1 mg/kg daily) (RAPA/IL-2) combination. We show that, despite further boosting of T_reg cells, high doses of IL-2 rapidly precipitated T1D in prediabetic female and male mice and increased myeloid cells in the pancreas. Also, we observed that RAPA counteracted IL-2 effects on T_reg cells, failed to control IL-2–boosted NK cells, and broke IL-2–induced tolerance in a reversible way. Notably, the RAPA/IL-2 combination failure to cure T1D was associated with an unexpected deleterious effect on glucose homeostasis at multiple levels, including β-cell division, glucose tolerance, and liver glucose metabolism. Our data help to understand the therapeutic limitations of IL-2 alone or RAPA/IL-2 combination and could lead to the design of improved therapies for T1D.In type 1 diabetes (T1D), the immune system destroys the pancreatic β-cells (1). At clinical onset, ∼30% of β-cells are still able to produce insulin (2), thus stopping autoimmune destruction, which at this stage is a promising approach (3). Along the same lines, there is a growing list of phase I/II clinical trials based on immunomodulation that are currently being conducted in T1D patients (4).NOD mice, which develop spontaneous T1D, represent an accepted model for testing new therapies (5), the gold standard being that treatments that cure overt hyperglycemia in these mice may be most appropriate for translation into the clinic, as was the case for anti-CD3 antibodies (Abs) (6), which have been tested in patients with promising results (7). In addition, results from our own group showing that low-dose interleukin-2 (IL-2) can prevent (8) and revert disease in NOD mice (9) have led to the translation of this strategy into clinical trials in T1D patients (clinical trial reg. no. {"type":"clinical-trial","attrs":{"text":"NCT01353833","term_id":"NCT01353833"}}NCT01353833, clinicaltrials.gov).We have shown that in NOD mice, administration of low-dose IL-2 for 5 days induced the remission of new-onset T1D by specifically boosting regulatory T cells (T_reg cells) in the pancreas without activating pathogenic effector T cells (T_eff cells). However, remission was obtained in only 60% of treated mice, and half of them became diabetic again during the following months (9). Consequently, improving IL-2 therapy by optimizing dosing or combining IL-2 with other immunomodulatory drugs, such as rapamycin (RAPA), could be of great importance for the goal of translating this therapy to humans.RAPA has been used in clinical transplantation for many years (10), and it has been safely administered to T1D patients during islet transplantation (11,12). In mice, RAPA monotherapy can prevent T1D development (13); however, it is unable to induce disease reversal (14). Moreover, RAPA and IL-2 were found to be synergistic for the prevention of diabetes in NOD mice (13). Consequently, we decided to test whether RAPA could synergize with short-term IL-2 therapy to reverse T1D and reinforce the development of long-term tolerance.In this work, we have further studied the mechanisms of action of IL-2 and RAPA alone or in combination in the NOD model of T1D.     

Associations between trunk, leg and total body adiposity with arterial stiffness

BackgroundObesity and arterial stiffness are associated, but fat distribution patterns may be more strongly related to arterial stiffness than general obesity because of the possible increased inflammation associated with increased abdominal adiposity. The aims of this study were to examine whether fat patterning is associated with arterial stiffness, and determine whether these associations are mediated by low-grade inflammation.MethodsAdult participants from the Fels Longitudinal Study (228 males and 254 females) were assessed for brachial-ankle pulse wave velocity (BaPWV) to determine arterial stiffness. Dual energy X-ray absorptiometry was used to estimate fat percentage of the trunk and legs (e.g., TRUNKFAT% and LEGFAT%). High-sensitivity C-reactive protein (hs-CRP) levels were assayed as a general marker of inflammation. General linear regression analyses were used.ResultsBaPWV was positively associated with TRUNKFAT% (r = 0.44 in men and r = 0.38 in women), whereas it was inversely related to LEGFAT% (r = -0.40 in men and r = -0.39 in women). In multiple regression analyses, each SD increase in TRUNKFAT% was associated with an ~1.03 m/s increase in BaPWV in both men and women. Each SD increase in LEGFAT% was related to a similar magnitude of decrease (1.03 m/s) in BaPWV in both sexes. The relationships of TRUNKFAT% and LEGFAT% with BaPWV were attenuated slightly when including hs-CRP in the models, but remained significant.ConclusionsWe found that trunk and leg fat are related to BaPWV in opposite directions when total body adiposity was accounted for. However, the associations between regional fat patterning and arterial stiffness did not appear to be mediated by low-grade inflammation.American Journal of Hypertension, 2012; doi:10.1038/ajh.2012.92.     

Can Money Prevent the Spread of HIV? A Review of Cash Payments for HIV Prevention

Cash payments to improve health outcomes have been used for many years; however, their use for HIV prevention is new and the impact not yet well understood. We provide a brief background on the rationale behind using cash to improve health outcomes, review current studies completed or underway using cash for prevention of sexual transmission of HIV, and outline some key considerations on the use of cash payments to prevent HIV infections. We searched the literature for studies that implemented cash transfer programs and measured HIV or HIV-related outcomes. We identified 16 studies meeting our criteria; 10 are completed. The majority of studies have been conducted with adolescents in developing countries and payments are focused on addressing structural risk factors such as poverty. Most have seen reductions in sexual behavior and one large trial has documented a difference in HIV prevalence between young women getting cash transfers and those not. Cash transfer programs focused on changing risky sexual behaviors to reduce HIV risk suggest promise. The context in which programs are situated, the purpose of the cash transfer, and the population will all affect the impact of such programs; ongoing RCTs with HIV incidence endpoints will shed more light on the efficacy of cash payments as strategy for HIV prevention.     

Orbital Preservation in Patients with Esthesioneuroblastoma

Objectives Surgical resection in addition to adjuvant radiation with or without chemotherapy is the mainstay of treatment for esthesioneuroblastoma (ENB). However, management of patients with orbital involvement remains controversial. Historically, orbital exenteration has been advocated when there is evidence of periorbital invasion. Recently, the indications for orbital exenteration have become more selective and orbital preservation has been advocated. We report our experience with anterior craniofacial resection and orbital preservation in patients with ENB.Design Retrospective review of all patients diagnosed with esthesioneuroblastoma who underwent traditional open anterior craniofacial resection at the Massachusetts General Hospital/Massachusetts Eye and Ear Infirmary Cranial Base Center from 1997 to 2008.Results Sixteen patients were identified with a mean follow-up of 76 months. All patients underwent anterior craniofacial resection via an open approach and adjuvant proton beam radiation. Six of the 16 patients had evidence of either periorbital or lacrimal sac involvement at the time of surgery. All of these patients underwent periorbital resection to negative histologic margins with preservation of the orbit.Conclusion In our study, patients with ENB and periorbital invasion—who were treated with anterior craniofacial resection and periorbital resection with orbital preservation—had no evidence of decreased survival. In all patients, negative histologic margins of the periorbital resection were achieved.     

Use of a randomised single case experimental design to evaluate therapy for unilateral neglect

Unilateral spatial neglect is a disabling disorder, or set of disorders, that commonly occurs after stroke. Previous research suggests that tactile stimulation may reduce neglect, albeit temporarily. This study evaluated the effectiveness of a therapy package combining stimulation of the affected hand and the behavioural technique of self‐instructional training. A randomised single case design, consisting of 12 phases (six treatment and six no treatment) administered in a random order, was used. Two research participants were assessed three times per phase using measures of impairment and activity. Analyses were by visual inspection, fitting linear regression lines to each phase and t test comparisons of these slopes in the treatment and no treatment phases. Visual inspection showed (1) marked variability within a phase, and (2) positive slopes were not more likely for treatment than no treatment for either participant. There was no significant difference on t test between the mean treatment and no treatment slopes on impairment or activity level measures. This study did not demonstrate evidence of effectiveness of the new therapy for neglect. Compliance by participants was poor indicating low acceptability of the therapy regime. Despite the results from these two participants, the study raises important methodological issues for practising clinicians and researchers. Clinical randomised single case designs have difficulties as well as advantages when used with a condition as variable as neglect. Despite this, these designs and the analysis of differential recovery rates warrant further investigation, and could be used to determine the effectiveness of therapy for other post‐stroke cognitive impairments.     

Immunoglobulin G4–related sclerosing disease Mimicking sjogren's syndrome: A case report

Immunoglobulin G4–related sclerosing disease (IgG4‐RSD) is a fibroinflammatory condition that has the potential to affect nearly every organ system. Classic histological findings include storiform fibrosis and lymphoplasmacytic infiltrates of immunoglobulin G4 (IgG4)–positive plasma cells. The clinical features of IgG4‐RSD may be an under‐recognized disease process that can mimic other autoimmune disorders, including Sjogren's syndrome. We describe a rare case of IgG4‐RSD involving the salivary glands, initially misdiagnosed as Sjogren's syndrome. Clinical features of IgG4‐RSD can mimic those of other autoimmune disorders affecting the head and neck. Therefore, otolaryngologists should have IgG4‐RSD on their differential when evaluating patients with diffuse salivary gland swelling. Laryngoscope, 126:2242–2245, 2016