The immune system is in a stringent vigilance recognizing and defending endogenous and exogenous threats. In case of an over-reactivity, as in autoimmunity, self-reactive T-cells or antibodies target the body's own cells and tissues and may cause severe organ damage even leading to death. Therefore several immunosuppressive treatment options are available to medicate autoimmune diseases. One of these inhibitory agents is cyclosporine A, a naturally-occurring circular depsipeptide, which interferes in interleukin-2 signaling in T-lymphocytes to prevent proliferation. However this and other treatment options often produce severe and life-threatening side-effects.
Recently we identified circular peptides from plants, which exhibit promising anti-proliferative effects towards T-cells 1. These so-called cyclotides are composed of about 30 amino acids with six conserved cysteines that are arranged in a typical cyclic cystine-knot motif, which confers them with resistance to enzymatic, chemical or thermal degradation, making them attractive pharmaceutical tools 2. The aim of this study is to investigate the immunosuppressive properties of native and synthetic cyclotides and its underlying mechanism in human and mouse immune cells in vitro and to compare their mode-of-action to known immunosuppressive drugs. Furthermore we want to examine a proliferation inhibition in vivo using a murine autoimmune model.
We were able to demonstrate an interleukin-2 specific anti-proliferative effect of cyclotides towards human activated lymphocytes in vitro 3. This significant inhibition was dose-dependent without inducing cytotoxicity in the active concentration range. To test the therapeutic impact in vivo an experimental autoimmune encephalomyelitis mouse model was performed. Here a significant delay and minor symptoms of disease in mice treated with cyclotides were observed. This anti-proliferative effect could additionally be confirmed in isolated restimulated mouse splenocytes in vitro. Plant cyclotides, due to their unique structural topology, have great potential as peptide-based drugs and display promising immunosuppressive properties towards lymphocytes in vitro and in vivo.