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.

Public Health Relevance

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.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Program Projects (P01)
Project #
2P01AI068730-06
Application #
8608808
Study Section
Special Emphasis Panel (ZAI1-ESB-I (S1))
Program Officer
Palker, Thomas J
Project Start
2006-04-01
Project End
2019-05-31
Budget Start
2014-06-01
Budget End
2015-05-31
Support Year
6
Fiscal Year
2014
Total Cost
$1,921,458
Indirect Cost
$720,547
Name
University of Pennsylvania
Department
Pathology
Type
Schools of Dentistry
DUNS #
042250712
City
Philadelphia
State
PA
Country
United States
Zip Code
19104
Lamont, Richard J; Hajishengallis, George (2015) Polymicrobial synergy and dysbiosis in inflammatory disease. Trends Mol Med 21:172-83
Rafail, Stavros; Kourtzelis, Ioannis; Foukas, Periklis G et al. (2015) Complement deficiency promotes cutaneous wound healing in mice. J Immunol 194:1285-91
Reis, Edimara S; DeAngelis, Robert A; Chen, Hui et al. (2015) Therapeutic C3 inhibitor Cp40 abrogates complement activation induced by modern hemodialysis filters. Immunobiology 220:476-82
Maekawa, Tomoki; Krauss, Jennifer L; Abe, Toshiharu et al. (2014) Porphyromonas gingivalis manipulates complement and TLR signaling to uncouple bacterial clearance from inflammation and promote dysbiosis. Cell Host Microbe 15:768-78
Klapper, Yvonne; Hamad, Osama A; Teramura, Yuji et al. (2014) Mediation of a non-proteolytic activation of complement component C3 by phospholipid vesicles. Biomaterials 35:3688-96
Huang, Yijun; Reis, Edimara S; Knerr, Patrick J et al. (2014) Conjugation to albumin-binding molecule tags as a strategy to improve both efficacy and pharmacokinetic properties of the complement inhibitor compstatin. ChemMedChem 9:2223-6
Pio, Ruben; Corrales, Leticia; Lambris, John D (2014) The role of complement in tumor growth. Adv Exp Med Biol 772:229-62
Maekawa, Tomoki; Abe, Toshiharu; Hajishengallis, Evlambia et al. (2014) Genetic and intervention studies implicating complement C3 as a major target for the treatment of periodontitis. J Immunol 192:6020-7
Mastellos, Dimitrios C; Ricklin, Daniel; Yancopoulou, Despina et al. (2014) Complement in paroxysmal nocturnal hemoglobinuria: exploiting our current knowledge to improve the treatment landscape. Expert Rev Hematol 7:583-98
Clarkson, Benjamin D S; Ling, Changying; Shi, Yejie et al. (2014) T cell-derived interleukin (IL)-21 promotes brain injury following stroke in mice. J Exp Med 211:595-604

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