tacrolimus and Autoimmune-Diseases-of-the-Nervous-System

Mycophenolate mofetil (MMF) and tacrolimus are novel immunosuppressive drugs, both first established in transplantation medicine and now used increasingly in neuroimmunological diseases including myasthenia gravis, dysimmune polyneuropathies, and myositis. In myasthenia gravis, the efficacy and safety of MMF has been shown by one open-label trial; one small, double-blind, placebo-controlled trial; and a few retrospective analyses. Similarly, for tacrolimus the greatest experience and evidence for efficacy and safety have been gathered in myasthenia gravis. MMF and tacrolimus have both been used as an alternative treatment for various other autoimmune diseases in which azathioprine or cyclosporine were not sufficiently effective. However, experience with tacrolimus in dysimmune polyneuropathies and myositis is limited. At this time, the available data suggest that MMF and tacrolimus are well suited for long-term immunosuppression in patients with myasthenia gravis. The spectrum of neuroimmunological diseases in which these drugs may be used has not been finally delineated and will require further controlled studies.

Topics: Autoimmune Diseases of the Nervous System; Humans; Immunosuppressive Agents; Mycophenolic Acid; Neuroimmunomodulation; Tacrolimus

Autoimmune glial fibrillary acidic protein (GFAP) astrocytopathy is a recently defined autoimmune meningoencephalomyelitis, associated with GFAP-IgG antibody. A pooled analysis of 324 cases from published literature and a retrospective single-center study were performed, firstly reveals the possibility that patients with myelitic lesions respond better to initial immunotherapy, but are prone to relapse, suggesting a more aggressive and long-term immunosuppressive medication for them. Moreover, our results showed using tacrolimus at maintenance stage exhibited a less tendency to relapse, providing a possibly new choice to future clinical treatments.

Topics: Adolescent; Adrenal Cortex Hormones; Adult; Aged; Aged, 80 and over; Astrocytes; Autoantigens; Autoimmune Diseases of the Nervous System; Child; Child, Preschool; China; Encephalomyelitis; Female; Follow-Up Studies; Glial Fibrillary Acidic Protein; Humans; Immunosuppressive Agents; Maintenance Chemotherapy; Male; Meningoencephalitis; Middle Aged; Prognosis; Recurrence; Retrospective Studies; Tacrolimus; Young Adult

Oligonucleotide overloading results in type I interferonopathies such as the Aicardi-Goutiéres Syndrome, a progressive encephalopathy determined by an immune response against endogenous DNA/RNA molecules. No therapy targeting pathogenic mechanisms is available for affected patients. Accordingly, we set up an in vitro/in vivo experimental model aimed at reproducing the pathogenic mechanisms of type I interferonopathies, in order to develop an effective pharmacological modulation and toxicological alterations caused by intracranial delivery of encapsulated CpG. The in vitro model used Aicardi-Goutiéres Syndrome immortalized lymphocytes activated by interferon I and co-cultured with human astrocytes; lymphocyte neurotoxicity was attenuated by the calcineurin-inhibitor Tacrolimus and by the anti-interferon monoclonal antibody Sifalimumab. The in vivo model was set up in mice by subcutaneous injection of encapsulated CpG oligonucleotides; the immune-stimulating activity was demonstrated by cytometric analysis in the spleen. To mime pathogenesis of type I interferonopathies in the central nervous system, CpG oligonucleotides were administered intracranially in mice. In the brain, CpG overload induced a rapid activation of macrophage-like microglial cells and focal accumulation mononuclear cells. The subcutaneous administration of Tacrolimus and, more potently, Sifalimumab attenuated CpG-induced brain alterations. These findings shed light on molecular mechanisms triggered by oligonucleotides to induce brain damage. Monoclonal antibodies inhibiting interferon seem a promising therapeutic strategy to protect brain in type I interferonopathies.

Topics: Animals; Antibodies, Monoclonal; Antibodies, Monoclonal, Humanized; Astrocytes; Autoimmune Diseases of the Nervous System; Cells, Cultured; Coculture Techniques; Disease Models, Animal; Humans; Injections, Subcutaneous; Interferon Type I; Lymphocyte Activation; Lymphocytes; Male; Mice; Nervous System Malformations; Oligodeoxyribonucleotides; Tacrolimus