Evaluation of immunogenicity of LY2963016 insulin glargine compared with Lantus® insulin glargine in patients with type 1 or type 2 diabetes mellitus.

AIMS: To compare the immunogenicity profiles and the potential effects on clinical outcomes of LY2963016 insulin glargine (LY IGlar) and Lantus® insulin glargine (IGlar), products with identical primary amino acid sequences, in patients with type 1 or type 2 diabetes mellitus (T1DM or T2DM). METHODS: To assess immunogenicity, anti-insulin glargine antibodies (measured as percent binding) were compared between treatments in 52-week (open-label) and 24-week (double-blind) randomized studies in total study populations of patients with T1DM (N = 535) and T2DM (N = 756), respectively, and two subgroups of patients with T2DM: insulin-naïve patients and those reporting prestudy IGlar treatment (prior IGlar). Relationships between insulin antibody levels and clinical outcomes were assessed using analysis of covariance and partial correlations. Insulin antibody levels were assessed using Wilcoxon rank sum. Treatment comparisons for treatment-emergent antibody response (TEAR) and incidence of detectable antibodies were analysed using Fisher's exact test. RESULTS: No significant treatment differences were observed for insulin antibody levels, incidence of detectable anti-insulin glargine antibodies, or incidence of TEAR [overall and endpoint, by last-observation-carried-forward (LOCF)] in patients with T1DM or patients with T2DM, including the insulin-naïve subgroup. A statistically significant difference was noted in the overall incidence of detectable antibodies but not at endpoint (LOCF) nor in TEAR for the prior IGlar subgroup of patients with T2DM. Insulin antibody levels were low (<5%) in both treatment groups. Insulin antibody levels or developing TEAR was not associated with clinical outcomes. CONCLUSIONS: LY IGlar and IGlar have similar immunogenicity profiles; anti-insulin glargine antibody levels were low for both treatments, with no observed effect on efficacy and safety outcomes.

Susceptibility to collagen-induced arthritis: cytokine-mediated regulation.

Collagen-induced arthritis is an animal model of inflammatory polyarthritis that is induced in susceptible strains of rats and mice by intradermal immunization with heterologous type II collagen emulsified in complete Freund's adjuvant. Previous studies have demonstrated that disease induction is highly MHC-restricted, with only mice of H-2(q) or H-2(r) haplotypes being susceptible. We have used a panel of both susceptible and resistant strains of mice in which either IFN-gamma or IL-10 signaling has been abolished by gene deletion and show that disease can be readily induced in several resistant strains of the H-2(b) and H-2(d) haplotype; susceptibility was highly dependent on IL-12. IL-4 was also shown to be crucial for disease induction in this model. These results suggest that both Th1 and Th2 cytokines may be important in the etiopathogenesis of disease and that disease susceptibility may be a function of a dysregulated cytokine environment.

Janus kinases and signal transducers and activators of transcription: their roles in cytokine signaling, development and immunoregulation.

Cytokines play a critical role in the normal development and function of the immune system. On the other hand, many rheumatologic diseases are characterized by poorly controlled responses to or dysregulated production of these mediators. Over the past decade tremendous strides have been made in clarifying how cytokines transmit signals via pathways using the Janus kinase (Jak) protein tyrosine kinases and the Signal transducer and activator of transcription (Stat) proteins. More recently, research has focused on several distinct proteins responsible for inhibiting these pathways. It is hoped that further elucidation of cytokine signaling through these pathways will not only allow for a better comprehension of the etiopathogenesis of rheumatologic illnesses, but may also direct future treatment options.

Update on cyclophosphamide for systemic lupus erythematosus.

Over the past decade cyclophosphamide has come to assume an increasingly prominent role in the management of severe, life-threatening manifestations of SLE. Intermittent, intravenous pulse cyclophosphamide has become the standard of treatment of diffuse proliferative lupus nephritis (WHO Class IV), and there is now substantial clinical literature to suggest an indication for intermittent cyclophosphamide therapy in most other forms of serious lupus affecting major organ systems, in particular lupus vasculitis and acute central nervous system manifestations. This update reviews the use of cyclophosphamide in the management of lupus nephritis, expands on its role in other manifestations of SLE, and discusses potential complications of the drug.

Comparison of different methods for the purification of eosinophils from human peripheral blood.

Eosinophils are often purified in discontinuous gradients. Since continuous gradients usually provide a greater recovery of more highly purified cells, the present investigation was undertaken to compare the purification of eosinophils from normal whole blood in continuous and discontinuous gradients of Percoll. Contrary to our expectations, recovery and purity of eosinophils obtained from the discontinuous gradients were comparable to or higher than those from the continuous gradients of Percoll that were tested with whole blood. The purity of the modal fractions of eosinophils from the discontinuous gradients was between 88 and greater than 99% of the nucleated cells and from the continuous gradients, 80 to 93% of the nucleated cells. We have compared continuous and discontinuous gradients with many different kinds of cells. This is the first time we have found continuous and discontinuous gradients equally effective. We speculate this finding is related to the fact that the band capacities are vastly overloaded in these gradients. In addition, we tested the rate of superoxide production by eosinophils from the same donors after their purification by two different methods in discontinuous gradients. Eosinophils purified from normal whole blood in gradients of Percoll by a modification of the method of Roberts and Gallin [1985) Blood 65, 433-440) had a higher rate of superoxide production after stimulation with phorbol myristate acetate than those purified from leukocyte-rich plasma in gradients of Metrizamide by the method of Vadas et al. [1979) J. Immunol. 122, 1228-1236).