The role of fibrin(ogen) in T cell inflammation

We have identified a novel function of fibrin(ogen) in inflammation. In cell culture assays, this molecule induces T cell adhesion and transmigration through endothelial barriers. Our studies are indicative for a novel motif on fibrin(ogen), which supports T cell migration. We now wish to extend these studies and identify the molecular basis of this function of fibrin, test the in vivo relevance of this finding and develop inhibitory peptides. This work ultimately aims on the development of new peptide drugs to prevent fibrin-based inflammatory reactions of the vascular system. Candidate diseases are reperfusion injury and arteriosclerosis during graft rejection, but also chronic skin diseases like psoriasis and subgroups of chronic vasculitis. Endothelium, VE-cadherin, fibrin, fibrinogen, T-cell-ligand, transmigration

Inflammation is a desired defence reaction to keep the human body free of foreign particles or of infectious agents. However, in many disease states inflammation is harmful and self destructive and requires anti-inflammatory treatment. Inflammation is a multi-step reaction involving several redundant pathways regulating cell activation and cell adhesion. The bottle neck of any inflammatory reaction is the transmigration step, which is the traverse of inflammatory cells from the blood stream across the wall of blood vessels into the tissues. We have defined a novel role for naturally occurring human fibrin fragments in inflammation. These fragments build a bridge between the cells investing the vessel wall, the endothelial cells and the inflammatory cells within the circulating blood stream. The fibrin fragments cause inflammatory cell transmigration and, as a result the tissue inflammation. The core element to define the role of fibrin fragments was our computerised cell culture assay (Gröger et al. J. Immunol. Meth. 222 (1999), 101-109), which allows to mimic the `bottle neck of inflammation`, the transmigration step. This assay was instrumental for the identification and characterisation of a peptide which blocks fibrin-induced cell transmigration and thus inflammation. This peptide matches to a sequence within the beta chain of fibrin, Bß 15-42. Myocardial infarction is caused by occlusion of a coronary vessel. Standard treatments aim to reperfuse the infarcted area in order to reduce the damage to the heart. Although reperfusion is the prerequisite for tissue salvage, there is a price to pay in terms of initiation of the so called reperfusion injury. The sudden re-initiation of blood flow causes irreversible tissue damage, which significantly cuts down the benefit coming from reperfusion treatment. Reperfusion injury is mainly effectuated by the deposition of fibrin and fibrin(ogen) fragments to vascular surfaces and by an inflammatory reaction. We have therefore studied the reperfusion injury in an in-vivo animal model in great detail. Mimicking myocardial infarction followed by reperfusion in rats, we have shown that peptide Bß 15-42 reduces the resulting infarct size by a mean of 40 %. The protective potential of this peptide stems from the prevention of fibrin deposition on vessel walls resulting in a very potent anti-inflammatory and cardioprotective function. Thus this peptide suggest itself for the treatment of reperfusion injury in humans.