IMMUNOTHERAPY FOR CHRONIC LIVER DISEASES
Immunotherapy of chronic hepatitis B is particularly difficult as the hepatic microenvironment is limiting local cytotoxic T lymphocyte (CTL) proliferation after infection. However, CTLs are an important element for overcoming chronic infections of the liver. So far only a prophylactic vaccination against hepatitis B virus is available and a protection post-infection by means of vaccination has not been possible to this point. Accordingly, there is a strong demand for new therapeutic options.
A so far unrecognized anatomic compartment within the liver tissue consisting of myeloid cells - called iMATEs (“intrahepatic myeloid-cell aggregates for T cell population expansion”) - can be exploited as a novel vaccination strategy against chronic viral liver infections. iMATEs overcome regulatory cues that limit immune response during chronic liver infections and support local CTL expansion by generation of cocoon- like structures. A dramatic expansion of CTLs in the liver can be achieved by targeted stimulation of iMATEs with TLR9-L as a prophylactic or therapeutic vaccine. The proof-of concept has been shown in vivo in mouse models.
The present invention provides a convenient and reliable prophylactic as well as therapeutic vaccine strategy. The use of TLR9 agonists induces the formation of iMATEs, which generate a sufficient number of CTLs resulting in the overcoming of chronic viral infections.
Further advantages and opportunities:
- use as prime - jump strategy for enhancement of CTLs
- entities of CTLs are increased at least 5 fold in peripheral organs (e.g. liver)
- use as a prophylactic or therapeutic vaccine against infections with an intracellular pathogen
- readily available as a kit, containing a prime agent and a multiplying jump agent
Proof of concept in vivo.
- Knolle, P.A., Böttcher, J. & Huang, L. The role of hepatic immune regulation in systemic immunity to viral infection. Med Microbiol Immunol. 204, 21 (2015).
- Hunag, L.R., et al. Intrahepatic myeloid-cell aggregates enable local proliferation of CD8+ T cells and successful immunotherapy against chronic viral liver infection. Nat. Immunol. 14, 574–583 (2013).
- Protzer, U., Maini, M.K. & Knolle, P.A. Living in the liver: hepatic infections. Nat. Rev. Immunol. 12, 201–213 (2012).