Natural IgM antibodies and inhibitors thereof
A carrier, nucleic acid technology, used in anti-inflammatory agents, non-central analgesics, drug combinations, etc., can solve problems such as tissue damage, systemic inflammation, and death
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[0191] Sterile injection solutions can be prepared by incorporating the natural antibody-binding peptide in the desired amount (eg, about 10 μg to about 10 mg / kg) in an appropriate solvent, followed by sterilization, eg, filtration. Additionally, powders can be prepared by standard techniques such as freeze-drying or vacuum-drying.
[0192]In another embodiment, the natural IgM antibody inhibitor is formulated with a biodegradable carrier for sustained release in the gastrointestinal tract, or for implantation of a long-acting active agent at the desired site of target organ activity. Has sustained release characteristics. Biodegradable polymers include, for example, ethylene vinyl acetate, polyanhydrides, polyglycolic acid, polylactic acid, collagen, polyorthoesters, and polyacetic acid. Liposomal formulations may also be used.
[0193] Another way to deliver natural IgM antibody inhibitors, such as natural IgM antibody binding peptides, is by delivering cells expressing na...
Embodiment 1
[0226] Example 1: Mechanisms of Ischemia-Reperfusion Injury
[0227] This example shows that mice deficient in the complement system are resistant to ischemia-reperfusion injury.
[0228] To examine the mechanism of ischemia-reperfusion injury, mice deficient in complement C3 were processed as a hindlimb model. C3- / - mice were partially protected from injury based on an approximately 50% reduction in permeability index (see Weiser et al. (1996) J. Exp. Med. 1857-1864). Thus, complement C3 is required for the induction of complete injury in this murine model.
[0229] The experiments of Weiser et al. did not identify how complement is activated. The serum complement system can be activated by at least three different pathways (classical activation pathway, lectin activation pathway or alternative activation pathway). Knowing which pathway is involved is important to uncovering the mechanism of damage. For example, the classical activation pathway is very efficiently activat...
Embodiment 2
[0230] Example 2: Native IgM Mediates Ischemia-Reperfusion (I / R) Injury
[0231] This example shows that immunoglobulin deficient mice are resistant to ischemia-reperfusion injury.
[0232] To determine whether the mediation of I / R injury involves antibodies, mice completely deficient in immunoglobulins RAG2- / - (recombinase-activating gene-2 deficient) were identified together with complement-deficient animals in an intestinal model. Notably, RAG2- / - mice were protected at levels similar to those observed in complement deficient animals (Weiser et al., supra). Since RAG2- / - animals also lack mature lymphocytes, it was important to establish that the pathogenic effects are antibody-dependent (Shinkai et al. (1992) Cell 68, 855-867). To confirm that injury was mediated by serum antibodies, deficient animals were reconstituted with normal mouse serum (Weiser et al. supra) or purified IgM (Williams et al. (1999) J. Appl. Physiol 86; 938-42). In both cases, reconstituted RAG2- / ...
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