Ischemia/reperfusion (I/R) injury represent an acute inflammatory response following trauma, surgery, stroke, heart attack, or other events in which circulation is transiently blocked. I/R occurs when a blood vessel is occluded naturally or by injury for an extended period of time, and the blood flow is restored after an extended period of ischemia. IR is a generatl syndrome that is responsible for both acute and chronic injury to various tissues including, for example, myocardium, central nervous system, hing limb and intestine. IR can result in necrosis and irreversible cell injury (US 13/120125).
Mechanisms of Action: Although the mechanisms responsible for injury remains unclear, one general model is that injury occurs in two stages. The first stage represents intrinsic cell injury that can be due to various processes including hypoxia-induced increased levels of reactive oxygen species (ROS). A second pathway of injury is based on the induction of acute inflammation possible by neutrophil contact with the hypoxia-induced modified cell surface.
–involvement of complement system:
The complement pathway (including the alternative complement pathway ) is a major mediator of I/R injury (US 13/120125).
—-Self-Neo-peptides: A related hypotesis is that recognition of the modified surface is specific and results in activation of the innate immune system via the lectin complement pathway. In this model, intrinsic up-regulation of ROS leads to the exposure of a “neo” self-determinant on the cell surface and activation of the innate immune system. A single clone was identified that restored IP injury in a mouse model. This led to the identification of “non-muscle myosin heavy chain II (NMHC-II) as the target self-antigen for pathogenic IgM. NMHC-II is expressed in all eukaryotic cells and three forms (A, B, and C) of NMHC-II have been identified. They are highly conserved among mice and humans but the distribution of the three isoforms varies among tissues.
Ischemia-reperfusion injury can be initiated by clonally specific natural IgM that activates the classical pathway of complement. These studies have led to the identificaiton of pathogenic IgMs and, in turn, the identificaiton of self-peptides that bind natural IgM. US 7,442,783 describes a conserved region within type II NMHC proteins representing the major epitope for binding of natural IgM following ischmeia in an intestinal model.
Carrol (US13668515) describes antibodies that bind to the N2 self-peptide and inhibit this inflammation.
Puro (US2014/0271628 (US/14/206,368)) describes humanized antibodies that specifically bind N2 peptide
A synthetic pepide referred to as N2 which represents the highly conserved epitope within the myosin heavy chain and to which the IgM clone has specific affinity was shown to reduce I/R injury.