The ups and downs of multiple sclerosis therapeutics.
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Humans↗
Biomedical subjects
H Wiendl
Publications and source records attributed to H Wiendl.
Multiple sclerosis: comparison of copolymer-1- reactive T cell lines from treated and untreated subjects reveals cytokine shift from T helper 1 to T helper 2 cells.
Copolymer 1 (COP), a standardized mixture of synthetic polypeptides consisting of l-glutamic acid, l-lysine, l-alanine, and l-tyrosine, has beneficial effects in multiple sclerosis and experimental autoimmune encephalomyelitis. We selected a panel of 721 COP-reactive T cell lines (TCL) from the blood of COP-treated and untreated multiple sclerosis patients and from healthy donors by using the split-well cloning technique. All TCL selected with COP proliferated in response to COP but not to myelin basic protein (MBP). Conversely, 31 control TCL selected with MBP proliferated in response to MBP but not to COP. We used intracellular double-immunofluorescence flow cytometry for quantitative analysis of cytokine production (IL-4, IFN-gamma) by the TCL. The majority of the COP-reactive TCL from untreated multiple sclerosis patients and normal donors predominantly produced IFN-gamma and, accordingly, were classified as T helper 1 cells (TH1). In contrast, the majority of the COP-reactive TCL from COP-treated patients predominantly (but not exclusively) produced IL-4-i.e., were TH2 (P < 0.05 as assessed by using a suitable preference intensity index). Longitudinal analyses revealed that the cytokine profile of COP-reactive TCL tends to shift from TH1 to TH2 during treatment. Interestingly, although there was no proliferative cross-reaction, about 10% of the COP-reactive TCL responded to MBP by secretion of small amounts of IL-4 or IFN-gamma, depending on the cytokine profile of the TCL. These results are consistent with a protective effect of COP-reactive TH2 cells. It is hypothesized that these cells are activated by COP in the periphery, migrate into the central nervous system, and produce immunomodulatory cytokines after local recognition of MBP.
Adolescent↗
[Multiple sclerosis. Current review of failed and discontinued clinical trials of drug treatment].
Recent immunobiological findings together with advances in biotechnology, ameliorations in clinical trial design, and MRI developments have led to a variety of therapeutical approaches in multiple sclerosis (MS). However, in contrast to successfully introduced new treatments, a number of therapeutical failures exist as well: despite impressive data from animal models, convincing concepts, and promising phase I/II studies, some investigated drugs and strategies showed no positive effects in clinical trials, or trials had to be terminated because of unexpected side effects. This article provides an overview of clinical studies that have failed or been abandoned for other reasons. Tumor necrosis factor (TNF) alpha-antagonists which have led to negative effects in two studies (Lenercept, Infliximab) are discussed in detail. These results raise critical questions concerning the hypothetical pathogenesis of MS lesions and the value of MRI in the assessment of clinically relevant therapeutic drug effects. In addition to a description of the immunobiological background, studies on the immunosuppressive agents linomide, deoxyspergualin, sulfasalazine and cladribine, trials for the cytokines interleukin-10 and TGF-beta 2, the studies on remyelination by intravenous immunoglobulins (IVIg), oral tolerance, and extracorporeal photopheresis are discussed.
Adjuvants, Immunologic↗
Muscle fibers in inflammatory myopathies and cultured myoblasts express the nonclassical major histocompatibility antigen HLA-G.
We demonstrate that HLA-G, a nonclassical major histocompatibility complex class I antigen, is expressed in muscle fibers in various inflammatory myopathies. Further, interferon-gamma induces surface expression and upregulation of mRNA transcripts corresponding to different isoforms of HLA-G in myoblasts cultured from control subjects and patients. HLA-G may have important immunological functions in inflammatory myopathies and other local immune reactions as they occur during vaccination, myoblast transplantation, and gene therapy.
Cells, Cultured↗
[The therapy of Rasmussen encephalitis].
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Antiviral Agents↗
[The pathogenesis and diagnosis of Rasmussen encephalitis].
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Animals↗
Acute and chronic structural effects of pilocarpine on monkey outflow tissues.
PURPOSE: Determine the effects of supraclinical topical doses of pilocarpine on the structure of the trabecular meshwork (TM), ciliary muscle (CM), and ciliary processes in monkeys. METHODS: Cynomolgus monkeys received topical pilocarpine hydrochloride doses of 1 to 2 mg unilaterally once or twice daily for 1 to 211 days. Both eyes were examined by light and electron microscopy. RESULTS: After 1 dose, the TM was expanded and the flow pathways open. Some elastic anterior CM tendons were disconnected from the muscle tips and/or the tips themselves were disrupted; macrophage-like cells accumulated in these regions. In eyes that had long-term treatment, scar tissue at the muscle tips and disruption of myofibrils within muscle cells indicated regions of previous disconnection. Most collagen tendons inserting into the peripheral cornea were unaffected. With increasing treatment duration in younger monkeys, there was anteroposterior shortening of Schlemm's canal, TM densification due to collapse, and increased cellularity in the subendothelial region of Schlemm's canal. TM densification and Schlemm's canal shortening were not found in older monkeys, implicating posterior movement of the elastic young limbal region induced by strong CM contraction, rather than pilocarpine toxicity. In the ciliary body we found vasodilation, Greeff's vesicles, and blood-aqueous barrier breakdown in the anterior ciliary processes and vasodilation, edema, and round-cell infiltration in the posterior pars plana. CONCLUSIONS: Large pilocarpine doses induce morphologic changes in the monkey anterior segment, likely consequent to intense CM contraction. Changes in the TM and Schlemm's canal are seen only in young monkeys, apparently owing to mechanical deformation of the elastic limbal region.
Animals↗
Combined therapy of cerebral arteriovenous malformations: histological differences between a non-adhesive liquid embolic agent and n-butyl 2-cyanoacrylate (NBCA).
OBJECTIVE: Based on 2 casuistics, the intraoperative qualities of a new, non-adhesive liquid embolic agent (Onyx, Micro Therapeutics. Inc., Irvine, CA, USA) are to be compared to those of n-butyl 2-cyanoacrylate (NBCA) with regard to the histopathological results after preoperative embolization of a cerebral arteriovenous malformation (AVM). PATIENTS AND METHODS: In a case example, the intraoperative quality of the nidus after embolization of a parieto-occipital AVM with Onyx--a new, non-adhesive liquid embolic agent--consisting of ethylene-vinyl alcohol copolymer (EVOH), dimethyl sulfoxide (DMSO) and tantalum, is described. In the second patient, embolization of a frontal high-flow AVM was performed with NBCA. Both patients underwent surgery with complete resection ofthe AVM. RESULTS: From a neurosurgical point of view, Onyx is suitable for preoperative embolization of AVMs, because the nidus intraoperatively remains elastic and formable and can be dissected from the surrounding brain tissue quite well by microsurgical technique. Inflammatory reactions can be found mainly in the lumina of the vessels. CONCLUSIONS: Onyx promises to be an embolic agent well suitable for subsequent neurosurgical resection. Further studies considering various intervals of time between embolization and resection as well as histopathological and electron microscopical examinations are necessary for evaluation of our first experience with this new embolization agent.
Adult↗