Investigator: Jochen Zwerina, M.D.

Location: University of Erlangen, Germany

Timeline: February 1, 2007 - February 1, 2008

Abstract

Crescentic glomerulonephritis is a potentially devastating and outcome-limiting manifestation of ANCA-associated vasculitides. Upon unknown stimuli, infiltration of the glomerulum with inflammatory cells and glomerular crescent formation rapidly proceeds until irreversible organ damage.

Activation of p38 mitogen-activated protein kinases (p38MAPK) is a key signal transduction step in acute and chronic inflammatory disorders. Inhibition of p38MAPK has proven to be of therapeutic benefit in various animal models of inflammatory and autoimmune diseases including crescentic GN. However, early phase clinical trials in humans have been confronted with unfavorable safety profile of p38MAPK inhibitors. This might be related to the fact that four different isoforms of p38MAPK exist, expression and activation of which are differentially regulated.

In this project, expression and activation of p38MAPK isoforms will be analyzed in ANCA associated renal vasculitis (AARV) and in healthy donors (from living kidney transplantation donors) by immunohistochemical analysis of kidney biopsies. Further, the specific cell types expressing p38MAPK isoforms will be determined. Moreover, immortalized human podocytes will be used to confirm these findings. In vitro kinase assays are planned to determine, whether relevant pro-inflammatory cytokines for ANCA-associated nephritis are able to activate specific p38MAPK isoforms in vitro.

These results will add to our knowledge on tissue specific expression, localization and activation of p38MAPK and hence potentially allow development of more selective small-molecule p38MAPK inhibitors for AARV.

LAY PERSON SUMMARY

Vasculitis is an inflammation of the vessel wall. Certain forms of vasculitis, called ANCA- positive vasculitides are life-threatening diseases because they can destroy the architecture of the vessel walls and result in organ dysfunction. The kidney is key target organ of ANCA-positive vasculitides, which leads to rapid deterioration of organ function and often results in chronic renal failure. Inflammation in the context with vasculitis is triggered by proteins, which fuel the disease by facilitating the recruitment inflammatory cells and production of enzymes, which destroy the vessel wall. These inflammatory proteins are controlled by intracellular enzymes, which regulate their synthesis within the inflamed tissue. These enzymes, one of the most important ones is p38MAPK, are therefore considered as an interesting therapeutic target for new anti-inflammatory drug therapies. However, there are four different p38MAPK proteins and it is currently unknown which of them is the most important one for driving vasculitis. This project aims to define the nature of p38MAPK enzymes involved in human ANCA-positive vasculitis. To address this question it is planned to assess the expression and regulation of all 4 p38MAPK enzymes in kidney biopsy samples from patients with ANCA-positive vasculitis.

RESEARCH ACTIVITIES (of the PI for the past 3 years)

Since his thesis in 2003, Jochen Zwerina investigated the pathogenesis of experimental rheumatoid arthritis in the research group of Georg Schett. Within the three major pathologies of experimental and human rheumatoid arthritis (RA), he is predominantly interested in why arthritis causes major damage to the bone. There he explored the potential of different cytokines such as TNF, IL-1 and RANKL to drive bone damage. He could show that combined blockade of different cytokines is more effective than single blockade and that there is a hierarchy between different cytokines by using selective cytokine blockers (Zwerina et al, A&R 2004). Consequently, he pursued a research project on the role of IL-1 in TNF-mediated bone destruction by using gene-knockout mice. The results establish an important role for IL-1 in TNF-mediated bone destruction.

Additionally, he is interested in the role of iron-regulatory enzymes in the differentiation of osteoclasts. Heme oxygenase 1, an anti-inflammatory acting iron-regulating enzyme, inhibits generation of bone-resorbing osteoclasts. Interestingly, this enzyme can be up-regulated by anti-rheumatic drugs and is found in vivo in joint sections of RA patients thus representing a potential pharmacological target in RA (Zwerina et al, FASEBJ 2005).

Moreover, Jochen Zwerina is involved in research projects regarding the role of certain mitogen activated protein kinases (MAPK) in chronic inflammatory diseases. MAPK are activated upon extracellular stress (e.g. pro-inflammatory cytokines) and in turn activate themselves deleterious signaling cascades leading to perpetuation of inflammation and tissue destruction. Experimental and human RA are two examples, where MAPK are heavily activated and thought to drive the disease (Schett et al, A&R 2000; Gortz et al, Arthritis Research 2004). By using selective p38 MAPK inhibitors, he could demonstrate a marked amelioration of inflammation, cartilage and bone damage in experimental RA (Zwerina et al, A&R 2006). Currently, he investigates the role of p38 MAPK in different human inflammatory disorders including ANCA-associated diseases.

ANCA Vasculitis: Autoimmune B Cell...

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Gene Expression Profile of Temporal...