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Generation and characterisation of maturation-resistant tolerogenic dendritic cells for adoptive cell therapies

Prof. Volk (first supervisor), Prof. Reinke (second supervisor), Prof. Sawitzki (mentor); Charité

The major goal in transplantation medicine as well as in treatment of autoimmune diseases is the development of short term therapies for the safe induction and maintenance of tolerance. Such therapies will overcome the necessity for life-long treatment with conventional immunosuppressive drugs and prevent their associated side effects. Regulatory-cell-based therapies have become an attractive treatment option. The major advantage of this novel approach is the antigen-specificity of adoptively transferred cells, e.g. ex vivo expanded regulatory T cells (Tregs) or antigen-presenting cells (APC). Among the latter, dendritic cells (DCs) have the innate ability to home to T cell areas of secondary lymphoid tissues. DCs are equipped to capture antigen integrating proand anti-inflammatory signals from their environment. As major professional antigen presenting cells DCs control adaptive immunity. In their activated, mature form they exhibit a strong immunostimulatory capacity, whereas immature or alternatively activated DCs induce and maintain antigen-specific peripheral tolerance. The latter unique characteristic has led to the concept of ‘tolerogenic’ DC therapy. Adoptive transfer of tolerogenic DC of donor origin offers the potential to inhibit immune responses to alloantigens in a donorspecific manner. Transfer of DCs has been successfully tested in experimental transplant as well as autoimmune models. However, upon recognition of pathogen-associated molecular patterns (PAMP) or danger-associated molecular patterns (DAMP) by Toll like receptors (TLR) DCs mature and initiate adaptive immune responses. Indeed, when applied into more clinically relevant models such as high responder strain combinations in vivo maturation of the transferred cells has been observed and the beneficial effect was lost. Thus, risk of maturation upon in vivo transfer has hampered the use of tolerogenic DCs as cellular therapies in clinical trials.
Therefore, we will 1) investigate intrinsic processes which control DC maturation, e.g. endogenous negative regulators of signalling pathways such as SIGIRR, 2) perform phenotypic and qualitative characterisation of DC subpopulations involved in alloantigen presentation after transplantation, 3) test tolerogenic DCs in experimental transplant models which mimic the clinical situation (e.g. in the presence of preformed memory T cells or infections), 4) develop standardised protocols for the generation of tolerogenic cells.

References
Thomson AW, Turnquist HR, Zahorchak AF, Raimondi G. Tolerogenic dendritic cell-regulatory T-cell interaction and the promotion of transplant tolerance. Transplantation. 2009 May 15;87(9 Suppl):S86-90.

Garlanda C, Anders HJ, Mantovani A. TIR8/SIGIRR: an IL-1R/TLR family member with regulatory functions in inflammation and T cell polarization. Trends Immunol. 2009 Sep;30(9):439-46.