Natalizumab Treatment of Relapsing Remitting Multiple Sclerosis Has No Long-Term Effects on the Proportion of Circulating Regulatory T Cells.

INTRODUCTION: Natalizumab (NTZ), a monoclonal antibody against the integrin α4ß1 (VLA-4) found on activated T cells and B cells, blocks the interaction of this integrin with adhesion molecules of central nervous system (CNS) endothelial cells and lymphocyte migration through the blood-brain barrier, effectively preventing new lesion formation and relapses in multiple sclerosis (MS). Whether NTZ treatment has additional effects on the peripheral immune system cells, and how its actions compare with other MS disease-modifying treatments, have not been extensively investigated. In particular, its effect on the proportions of circulating regulatory T cells (Treg) is unclear. METHODS: In this study, we investigated the effect of NTZ treatment in 12 patients with relapsing MS, at 6 and 12 months after the start of treatment. We evaluated the proportions of regulatory T cells (Treg), defined by flow cytometry as CD4+ CD25++ FoxP3+ cells and CD4+ CD25++ CD127- cells at these intervals. As an exploratory study, we also investigated the NTZ effects on the proportions of bulk T and B lymphocyte populations, and of those expressing novel the markers CD195 (CCR5), CD196 (CCR6), or CD161 (KLRB1), which are involved in MS pathogenesis but have been studied less in the context of MS treatment. The effects of NTZ were compared to those obtained with 11 patients under interferon-beta-1a (IFN-ß1a) treatment, and against 9 healthy volunteers. RESULTS: We observed a transient increment in the proportion of Treg cells at 6 months, which was not sustained at 12 months. We observed a reduction in the proportion of T cells expressing CD195 (CCR5) and CD161 (KLRB1) subsets of T cells. CONCLUSION: We conclude that NTZ does not have an effect on the proportion of Treg cells over 1 year, but it may affect the expression of molecules important for some aspects MS pathogenesis, in a manner that is not shared with IFN-ß1a.

TLR2 stimulation regulates the balance between regulatory T cell and Th17 function: a novel mechanism of reduced regulatory T cell function in multiple sclerosis.

CD4(+)CD25(hi) FOXP3(+) regulatory T cells (Tregs) maintain tolerance to self-Ags. Their defective function is involved in the pathogenesis of multiple sclerosis (MS), an inflammatory demyelinating disease of the CNS. However, the mechanisms of such defective function are poorly understood. Recently, we reported that stimulation of TLR2, which is preferentially expressed by human Tregs, reduces their suppressive function and skews them into a Th17-like phenotype. In this study, we tested the hypothesis that TLR2 activation is involved in reduced Treg function in MS. We found that Tregs from MS patients expressed higher levels of TLR2 compared with healthy controls, and stimulation with the synthetic lipopeptide Pam3Cys, an agonist of TLR1/2, reduced Treg function and induced Th17 skewing in MS patient samples more than in healthy controls. These data provide a novel mechanism underlying diminished Treg function in MS. Infections that activate TLR2 in vivo (specifically through TLR1/2 heterodimers) could shift the Treg/Th17 balance toward a proinflammatory state in MS, thereby promoting disease activity and progression.

Neurotoxicity of immunosuppressive therapies in organ transplantation.

ABSTRACT: Immunosuppressive agents have revolutionized clinical transplantation medicine, allowing the avoidance of immune system attack on the transplanted graft. Nevertheless, the use of medications such as cyclosporine, tacrolimus and others also brought the side effects of these drugs. Early identification of drug-induced neurotoxicity in transplanted patients and of its specific causes is important, not only because of patient's poor clinical status but because of concomitant systemic and metabolic disorders which may obscure symptoms. Treatment and prognosis are highly dependent on the type of complication and it's early recognition. This review focuses on the clinical entities of neurotoxicity caused by immunosuppressive drugs in transplanted patients.

Innate immune responses in the CNS: role of toll-like receptors, mechanisms, and therapeutic opportunities in multiple sclerosis.

Multiple sclerosis (MS) is an inflammatory demyelinating disease of the central nervous system (CNS), which is considered immune-mediated. Our knowledge of innate immune mechanisms in the CNS and their implications for pathogenesis and treatment of multiple sclerosis (MS) are limited, particularly if compared with the body of literature on adaptive immune mechanisms. There is, however, growing understanding of the workings of the innate immune system and accordingly, of its potential role in driving immune-mediated pathology. Such mechanisms will be discussed in this review along with potential therapeutic opportunities. These may require blocking pathogenic innate immunity and in some cases, promoting its protective effects.

Nabiximols in the treatment of spasticity, pain and urinary symptoms due to multiple sclerosis.

INTRODUCTION: Over the last two decades, experimental and clinical data suggest a therapeutic benefit of cannabis-based medicines for a variety of multiple sclerosis (MS) symptoms. Clinical trials, both with synthetic or plant-derived cannabinoids, have demonstrated clinical efficacy of cannabinoids for the treatment of spasticity, neuropathic pain and bladder dysfunction. Nabiximols, a 1:1 mix of delta-9-tetrahydrocanabinol and cannabidiol extract from cloned chemovars, was licensed in the UK in 2010 and has also been approved in other European countries and Canada. The European Federation of Neurological Societies recommends that cannabis should be used only as a second or third line treatment in central neuropathic pain. AREAS COVERED: After a brief discussion of the endocannabinoid system, this review focuses on the use of cannabis to improve MS symptoms. More specifically, the authors have analyzed clinical studies on cannabis-based medicine extract (CBME), in particular nabiximols, in spasticity, as well as pain, and bladder dysfunction in MS. The authors have considered the large randomized controlled trials examining the psychological effects associated with cannabinoids use as well as long-term follow-up studies. EXPERT OPINION: Despite a number of trials with very promising results, there are still concerns related to relative paucity of data on long-term safety. Also, the long-term efficacy information in terms of the control of symptoms of a disease in which the natural history is progression is sparse. Therefore, further studies are required to improve the current knowledge of nabiximols.