A brighter side to thalidomide: its potential use in immunological disorders

Thalidomide and its derivatives are immunomodulatory drugs (IMiDs) known for their sedative, teratogenic, anti-angiogenic, and anti-inflammatory properties. Commonly used in the treatment of cancers such as Multiple Myeloma and Myelodysplastic Syndrome, IMiDs have also been used in the treatment of an inflammatory skin pathology associated with Hansen’s disease/Leprosy and show promise in the treatment of autoimmune disorders including Systemic Lupus Erythmatosus and Inflammatory Bowel Disease. Recent structural and experimental observations have revolutionized our understanding of these properties by revealing the fundamental molecular events underpinning IMiD activity. Here, we review these findings, their relevance to IMiD therapy in immunological disorders, and discuss how further research might unlock the vast clinical potential of these compounds

Site-specific mutagenesis of human interleukin-6 and its biological activity

AbstractAmino acid substitutions of human interleukin-6 (IL-6) were performed. Single substitution Met162 → Ala and double substitutions Leu159, 166 → Val resulted in a significant decrease of IL-6 activity in the production of immunoglobulin (lg) from B-cells. Single substitution Leu166→Val or Leu159→Val gave a slight or no significant decrease in the Ig-induction activity, respectively. The receptor-binding activity of each IL-6 mutant was also examined. It was observed that the decrease of the receptor-binding activity was generally in parallel with that of the Ig-induction activity. We therefore suggest that hydrophobic side-chains existing in Met162, Leu159, and Leu164 are significantly involved in the receptor-binding of IL-6

Study of active controlled tocilizumab monotherapy for rheumatoid arthritis patients with an inadequate response to methotrexate (SATORI): significant reduction in disease activity and serum vascular endothelial growth factor by IL-6 receptor inhibition therapy

We investigated the clinical efficacy and safety of tocilizumab (a humanized anti-IL-6 receptor antibody) monotherapy in active rheumatoid arthritis (RA) patients with an inadequate response to low dose methotrexate (MTX). In a multicenter, double-blind, randomized, controlled trial, 125 patients were allocated to receive either tocilizumab 8 mg/kg every 4 weeks plus MTX placebo (tocilizumab group) or tocilizumab placebo plus MTX 8 mg/week (control group) for 24 weeks. The clinical responses were measured using the American College of Rheumatology (ACR) criteria and the Disease Activity Score in 28 joints. Serum vascular endothelial growth factor (VEGF) levels were also monitored. At week 24, 25.0% in the control group and 80.3% in the tocilizumab group achieved ACR20 response. The tocilizumab group showed superior ACR response criteria over control at all time points. Additionally, serum VEGF levels were significantly decreased by tocilizumab treatment. The overall incidences of adverse events (AEs) were 72 and 92% (serious AEs: 4.7 and 6.6%; serious infections: 1.6 and 3.3%) in the control and the tocilizumab groups, respectively. All serious adverse events improved by adequate treatment. Tocilizumab monotherapy was well tolerated and provided an excellent clinical benefit in active RA patients with an inadequate response to low dose MTX

Recombinant human interleukin 6 (B-cell stimulatory factor 2) is a potent inducer of differentiation of mouse myeloid leukemia cells (M1)

AbstractRecombinant human interleukin 6 (IL-6), a lymphokine involved in the final differentiation of activated B-cells into antibody-forming cells, greatly suppressed proliferation and induced differentiation of murine myeloid leukemia cells (M1) into mature macrophage-like cells. When M1 cells were treated with IL-6, their growth was completely arrested as early as on day 2, and they were induced to differentiate morphologically into macrophage-like cells. Differentiation-associated properties such as phagocytic activity, adherence to the dish surface, Fc and C3 receptors, were also induced within 24 h by IL-6, and they reached their respective maximal levels on day 2 or 3. The potency of IL-6 in suppressing proliferation and inducing differentiation was much greater than that of 1α,25-dihydroxyvitamin D3 one of the most potent inducers of M1 cells. The present report indicates that IL-6 is involved in the differentiation of not only B-cells but also myeloid leukemia cells

Recombinant human interleukin-6 (IL-6/BSF-2/HSF) regulates the synthesis of acute phase proteins in human hepatocytes

AbstractRecombinant human IL-6 (rhIL-6) is a potent inducer of the synthesis of acute phase proteins in adult human hepatocytes. A wide spectrum of acute phase proteins is regulated by this mediator. After labeling of rhIL-6 stimulated human hepatocytes with [35S]methionine acute phase protein synthesis was measured by immunoprecipitation. Serum amyloid A, C-reactive protein, haptoglobin, α1-antichymotrypsin and fibrinogen were strongly induced (26-, 23-, 8.6-, 4.6- and 3.8-fold increases, respectively). Moderate increases were found for α1-antitrypsin (2.7-fold) and α1-acid glycoprotein (2.7-fold). RhIL-6 had no effect on α1-macroglobulin, whereas fibronectin, albumin and transferrin decreased to 64, 56 and 55% of controls. In the cases of serum amyloid A, haptoglobin, α1-antichymotrypsin, α1-antitrypsin and α1-acid glycoprotein, dexamethasone enhanced the action of rhIL-6. We conclude that rhIL-6 controls the acute phase response in human liver cells