Application of specific cell permeable cathepsin inhibitors in antigen processing of the MHC class II pathway

Research output: Chapter in Book/Report/Conference proceedingConference contribution

Abstract

Cathepsins of the cysteine, aspartyl, and serine classes are involved in antigen processing in the major histocompatibility complex (MHC) class II loading compartment. Investigation and manipulation of these proteases in living cells is difficult to perform due to the lack of highly specific cell permeable inhibitors. We tested several Cathepsin inhibitors for their ability to penetrate the cell membrane of peripheral blood mononuclear cells (PBMC). The commercially available reversible Cathepsin G-specific inhibitor I and the irreversible Suc-Val-Pro-PheP (OPh)2 (Suc-VPF), for instance, are both cell permeable and specifically inhibit intracellular Cathepsin G in the PBMC. Furthermore, selective inhibition of Cathepsin G resulted in reduced tetanus toxin C-fragment (TTC) and hemagglutinin (HA) processing and presentation to CD4+ T cells. An alternative strategy to modify immune reactions is the use of altered peptide ligands (APL). Therefore, we generated a glutamic acid decarboxylase 65 (GAD)-derived protease-resistant APL (prAPL) by cleavage site-directed modification. The resulting prAPL are resistant to lysosomal and serum proteases, bind with high-affinity to MHC class II molecules and have a prolonged half-life in the serum. These peptides significantly decreased the secretion of proinflammatory cytokines in peripheral blood lymphocytes from patients with type 1 diabetes mellitus (T1D). The strategy of designing specific immunomodulatory protease inhibitors and protease-resistant altered peptide ligands provides the basis for therapeutic intervention.
Original languageEnglish
Title of host publication20th Polish Peptide Symposium, Gdansk, Poland. Guest speaker
Publication statusPublished - 2009

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