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Subproject 8

Clinical phase Ib trial: T cell-targeted immunotherapy of pemphigus vulgaris

Summary

TP8.PNG

Pemphigus vulgaris (PV) is a severe prototypic autoantibody mediated skin disorder whose pathogenesis largely depends on the B cell help of autoreactive T helper (Th) cells that recognize epitopes of the PV autoantigen, desmoglein 3 (Dsg3), in association with the PV-associated HLA class II allele, HLA-DRB1*04:02. Currently, PV is treated with systemic immunosuppressants, such as glucocorticoids and adjuvants which leads to considerable co-morbidities on long-term treatment. Here we aim to therapeutically target autoreactive Th cells in PV with Dsg3 peptide-coupled tolerizing particles to induce a specific immune tolerance against Dsg3. Dsg3 T cell epitopes are attached to such particles which deliver their cargo to liver sinusoidal endothelial cells (LSEC). Embedded in the tolerogenic environment of the liver LSECs have the potential to convert naive and effector T cells into regulatory T cells. As shown recently, this immunotherapy led to the down regulation of the autoreactive, pathogenic T cell response in EAE, an animal model of multiple sclerosis, resulting in prevention of disease. In the anticipated phase Ia/b trial in PV we will not only study safety and toxicity of Dsg3 peptide immunotherapy but also thoroughly investigate the impact of this treatment on Dsg3-reactive pathogenic T cells and potentially regulatory T cells as well as other pro-inflammatory immune cells and humoral factors such as Dsg3-specific autoantibodies. The findings of this trial may also be applicable to other antibody-mediated human disorders which are regulated by autoreactive T cells.

Applicants:

Prof. Dr. Michael Hertl
Philipps-Universität Marburg
Fachbereich Medizin
Klinik für Dermatologie und Allergologie