Specific Immunotherapy of Experimental Myasthenia by Genetically Engineered APCs

Abstract

Although treatment of MG with general immunosuppressive agents is often effective, it has important drawbacks, including suppression of the immune system as a whole, with the risks of infection and neoplasia, and numerous other adverse side effects. Ideally, treatment of MG should eliminate the specific pathogenic autoimmune response to AChR, without otherwise suppressing the immune system or producing other adverse side effects. Although antibodies to AChR are directly responsible for the loss of AChRs at neuromuscular junctions in MG, the AChR antibody response is T cell-dependent, and immunotherapy directed at T cells can abrogate the autoantibody response, with resulting benefit. As in other autoimmune diseases, the T cell response in MG is highly heterogeneous. The design of specific immunotherapy must take this heterogeneity into account and target the entire repertoire of AChR-specific T cells. We describe our investigation of a novel strategy for specific immunotherapy of MG, involving gene transfer to convert antigen-presenting cells (APCs) to "guided missiles" that target AChR-specific T cells, and that induce apoptosis and elimination of those T cells. This strategy uses the ability of APCs from a given individual to present the entire spectrum of AChR epitopes unique for that individual, and thereby to target the entire repertoire of antigen-specific T cells of the same individual. Using viral vectors, we have genetically engineered the APCs to process and present the most important domain of the AChR molecule, and to express a "warhead" of Fas ligand (FasL) to eliminate the activated AChR-specific T cells with which they interact. Our results show that the APCs express the appropriate gene products, and effectively and specifically eliminate AChR-specific T cells by the Fas/FasL pathway, while sparing T cells of other specificities.

Autonomic “myasthenia”: the case for an autoimmune pathogenesis

“…From the clinical perspective, these studies highlight the importance of searching for an occult neoplasm in all patients with AAN, and raise the question of whether immunomodulatory treatment should be tried in all patients with AAN, with or without positive α3 AChR antibody results. Ultimately, knowledge of the antigen should lead to antigen-specific therapeutic strategies, like those being developed for MG (17). Diabetes, a leading cause of morbidity and mortality in industrialized countries, is caused by an absolute insulin deficiency due to the destruction of insulin secreting pancreatic β cells (type 1 diabetes) or by a relative insulin deficiency due to decreased insulin sensitivity, usually observed in overweight individuals (type 2 diabetes).…”

Aktuelle Aspekte in der Pathogenese, Diagnostik und Therapie der Myasthenia gravis

“…Angesichts des meist klar definierten Autoantigens bietet die Myasthenia gravis prinzipiell ideale Voraussetzungen für die antigenspezifische Immuntherapie [86,87]. Experimentell erprobt ist einerseits die orale, nasale, subkutane oder intrathymische Verabreichung gentechnisch oder synthetisch hergestellter Fragmente des AChR [88 ± 92], andererseits der Einsatz gentechnisch modifizierter antigenpräsentierender Zellen [93]. Mit beiden Strategien kommt es bei der EAMG zu einer drastischen Abmilderung klinischer, elektrophysiologischer und immunologischer Aktivitätsparameter.…”

Fas Ligand as a Tool for Immunosuppression and Generation of Immune Tolerance

“…Wu et al [142,143] demonstrated the ability of APCs engineered to express both acetylcholine receptor (AchR) and FasL to eliminate AchR‐specific T cells. AchR‐specific T cells from lpr mice were not eliminated, showing the involvement of the Fas/FasL‐apoptotic pathway in T‐cell depletion [144]. Preliminary studies in vivo demonstrated the immunotherapeutic potential of this strategy for MG [144].…”

“…AchR‐specific T cells from lpr mice were not eliminated, showing the involvement of the Fas/FasL‐apoptotic pathway in T‐cell depletion [144]. Preliminary studies in vivo demonstrated the immunotherapeutic potential of this strategy for MG [144].…”