While inflammation is a common component of many clinical disorders, the contributing factors can be distinct. In recent years, the complement system has been associated with a growing number of inflammatory conditions that include acute and chronic tissue inflammation, adverse reactions to biomaterials, and transplant rejection. It is evident that excessive or insufficiently controlled complement activation on host cells can cause an immune imbalance that, exacerbated by factors such as oxidative stress or infection, may fuel a vicious cycle between complement, inflammation, and tissue damage. As a consequence, therapeutic modulation of complement emerges as attractive target for upstream inhibition of inflammatory processes but requires profound understanding of underlying processes, identification of rewarding targets, and careful selection of suitable inhibitors. This Program Project therefore employs a highly integrated and holistic approach to describe common and distinct denominators of complement involvement in inflammatory conditions and open avenues for improved therapeutic strategies. For this purpose, three disease models that are representative of the wide spectrum of complement-mediated conditions and have high impact for health care and the clinic will be thoroughly investigated. Whereas inflammatory reactions to hemodialysis and kidney transplantation (Project 2) represent distinct disorders of complement activation by artificial and foreign surfaces and major complications in end-stage renal disease, periodontitis (Project 3) is an emerging and very attractive model of local tissue inflammation with a strong infectious component. Using relevant in vitro assays, sensitive instrumental methods (Core 6), and translational models in rodents and non-human primates, disease processes will be investigated in relation to complement triggers and activity, but also to associated pathways (e.g., TLR), effects on downstream inflammatory processes, and influences of modulating factors (e.g., oxidative damage, infection). A diverse panel of potent, validated, pathway-specific and/or targeted complement inhibitors will be generated (Project 1, Core B) that allows for the dissection of involved complement pathways and processes in each disease. This 'inhibitor toolbox'includes analogs of the central C3 inhibitor compstatin, which will serve as a benchmark compound, and entities acting at individual initiation, amplification, and effector pathways. Optimization of efficacy, pharmacokinetic, administration, and targeting properties will be guided by results and requirements of the disease models of Projects 2 &3. At the same time, the evaluation of promising and pre-validated inhibitor candidates in such relevant disease models is expected to allow rapid translation into therapeutic concepts. Established models, methods, and inhibitors of this P01 can easily be applied to future disease studies. Thus, this P01 will have a high impact on the elucidation and management of complement-related disease and benefit patients and the research community.
The purpose of this study is to comprehensively elucidate the role of the complement system in inflammatory diseases and provide options for their therapeutic management. The generation and use of validated and pathway-specific inhibitors, highly relevant disease models, and sensitive analytical assays will ensure high translational value to the benefit of patients suffering from inflammatory and immune diseases.
|Blom, Anna M; Magda, Michal; Kohl, Lisa et al. (2017) Factor H-IgG Chimeric Proteins as a Therapeutic Approach against the Gram-Positive Bacterial Pathogen Streptococcus pyogenes. J Immunol 199:3828-3839|
|Blatt, Adam Z; Saggu, Gurpanna; Cortes, Claudio et al. (2017) Factor H C-Terminal Domains Are Critical for Regulation of Platelet/Granulocyte Aggregate Formation. Front Immunol 8:1586|
|Hajishengallis, G; Krauss, J L; Jotwani, R et al. (2017) Differential capacity for complement receptor-mediated immune evasion by Porphyromonas gingivalis depending on the type of innate leukocyte. Mol Oral Microbiol 32:154-165|
|Kovtun, Anna; Bergdolt, Stephanie; Hägele, Yvonne et al. (2017) Complement receptors C5aR1 and C5aR2 act differentially during the early immune response after bone fracture but are similarly involved in bone repair. Sci Rep 7:14061|
|Hajishengallis, George; Korostoff, Jonathan M (2017) Revisiting the Page & Schroeder model: the good, the bad and the unknowns in the periodontal host response 40 years later. Periodontol 2000 75:116-151|
|Primikyri, Alexandra; Papanastasiou, Malvina; Sarigiannis, Yiannis et al. (2017) Method development and validation for the quantitation of the complement inhibitor Cp40 in human and cynomolgus monkey plasma by UPLC-ESI-MS. J Chromatogr B Analyt Technol Biomed Life Sci 1041-1042:19-26|
|Harder, Markus J; Kuhn, Nadine; Schrezenmeier, Hubert et al. (2017) Incomplete inhibition by eculizumab: mechanistic evidence for residual C5 activity during strong complement activation. Blood 129:970-980|
|Kajikawa, Tetsuhiro; Briones, Ruel A; Resuello, Ranillo R G et al. (2017) Safety and Efficacy of the Complement Inhibitor AMY-101 in a Natural Model of Periodontitis in Non-human Primates. Mol Ther Methods Clin Dev 6:207-215|
|Abicht, Jan-Michael; Kourtzelis, Ioannis; Reichart, Bruno et al. (2017) Complement C3 inhibitor Cp40 attenuates xenoreactions in pig hearts perfused with human blood. Xenotransplantation 24:|
|Kajikawa, Tetsuhiro; Meshikhes, Fatimah; Maekawa, Tomoki et al. (2017) Milk fat globule epidermal growth factor 8 inhibits periodontitis in non-human primates and its gingival crevicular fluid levels can differentiate periodontal health from disease in humans. J Clin Periodontol 44:472-483|
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