Abstract
Inflammatory neuropathies represent disabling human autoimmune disorders with considerable disease variability. Animal models provide insights into defined aspects of their disease pathogenesis. Forkhead box P3 (FoxP3)+ regulatory T lymphocytes (Treg) are anti-inflammatory cells that maintain immune tolerance and counteract tissue damage in a variety of immune-mediated disorders. Dysfunction or a reduced frequency of Tregs have been associated with different human autoimmune disorders. We here analyzed the functional relevance of Tregs in determining disease manifestation and severity in murine models of autoimmune neuropathies. We took advantage of the DEREG mouse system allowing depletion of Treg with high specificity as well as anti-CD25 directed antibodies to deplete Tregs in mice in actively induced experimental autoimmune neuritis (EAN). Furthermore antibody-depletion was performed in an adoptive transfer model of chronic neuritis. Early Treg depletion increased clinical EAN severity both in active and adoptive transfer chronic neuritis. This was accompanied by increased proliferation of myelin specific T cells and histological signs of peripheral nerve inflammation. Late stage Treg depletion after initial disease manifestation however did not exacerbate inflammatory neuropathy symptoms further. We conclude that Tregs determine disease severity in experimental autoimmune neuropathies during the initial priming phase, but have no major disease modifying function after disease manifestation. Potential future therapeutic approaches targeting Tregs should thus be performed early in inflammatory neuropathies.
Highlights
Inflammatory polyneuropathies constitute disabling disorders of the peripheral nervous system (PNS) including acute and chronic variants
Active Experimental autoimmune neuritis (EAN) was induced by subcutaneous injection of 200 mg myelin protein zero peptide spanning amino acids 180–199 (P0180–199) (JPT peptide technologies) emulsified in 100 ml complete Freund’s adjuvant (CFA) (Difco) containing 1 mg/ml heat inactivated Mycobacterium tuberculosis strain H37RA mixed with 100 ml phosphate buffered saline (PBS) into the flanks
Active immunization – which is required for EAN induction – triggers lethal toxicity of diphtheria toxin (DTx) independent of its Treg depleting effect already in conventional C57BL/6 mice [31]
Summary
Inflammatory polyneuropathies constitute disabling disorders of the peripheral nervous system (PNS) including acute and chronic variants. The acute Guillain-Barresyndrome (GBS) features rapid onset, monophasic PNS inflammation [1,2]. Experimental autoimmune neuritis (EAN) induced with myelin protein peptides serves as an animal model of the demyelinating GBS variant [3]. Animal models for the axonal variants have been generated by immunization against ganglioside components of the axonal membrane [4]. Chronic inflammatory demyelinating polyradiculo-neuropathy (CIDP) – the most common chronic inflammatory neuropathy – presents with chronic progressive or relapsing remitting sensory and motor impairments and features immune cell infiltration of peripheral nerves [5,6,7]. Animal models replicating the clinical and pathological hallmarks of chronic inflammatory neuropathies are less well established compared to models of acute neuritis. Mice of the autoimmune-prone non obese diabetic (NOD) strain with deficiency in the costimulatory molecules B7-2 [8] and intercellular adhesion molecule (ICAM)-1
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