Characterization of the specific CD40 receptor based inhibitor, CD40dn, in antigen presenting cells and in the transgenic autoimmune mouse model to analyze its potential as a therapeutic tool

• Applicant: Dr. Kirsten Falk
• Subject Area: Immunology
• Term: from 2002 to 2008
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 5369813

Dendritic cells (DC) are professional antigen-presenting cells (APC), which stimulate T lymphocytes and play a critical role in the generation and maintenance of T-cell tolerance. During DC activation, CD40 is one of the key molecules that is induced. So far very little is known about the precise signalling mechanisms triggered in DC after CD40 stimulation. One aim of this proposal is to investigate the CD40 induced signal transduction pathways in DC in more detail. For this purpose we will use the dominant negative CD40 molecule, CD40dn, which we have shown to be functional, efficient and specific for CD40 induced signalling pathways in B cell lines. This receptor based inhibitor is a very powerful tool to explore CD40 specific functions. By using techniques such real time PCR and gene array analysis it will be employed to identify the signal transducing pathways involved in DC activation and differentiation. CD40 is also crucial for the induction of immune reactions such as allograft rejections and autioimmune responses. Anti-CD40 treatment is known to protect against CD40/CD40-ligand (CD40L) induced immune reactions but application of anti-CD40L antibody based therapy has its limitations. Therefore the second aim of this proposal is to characterize the potential of CD40dn as a therapeutic tool. For this purpose we will develop a transgenic mouse model to analyse the effects of CD40dn in an in vivo situation by testing its capacity to inhibit autoimmune reactions. Aim of this study is therefore to improve our understanding of cell-type specific effects of the CD40dn inhibitor and to test its capacity in an alternative, receptor based human gene therapy.

• DFG Programme: Research Grants
• Participating Person: Dr. Anja Mehl