Blockade of self-reactive IgM significantly reduces injury in a murine model of acute myocardial infarction

Haas, Michael S.
Alicot, Elisabeth M.
Schuerpf, Franziska
Chiu, Isaac
Li, Jinan
Moore, Francis D.
Carroll, Michael C.

¹DecImmune Therapeutics, Inc., Boston, MA, USA
²Department of Pediatrics, Children's Hospital Boston, Harvard Medical School, Boston, MA 02115, USA
³Department of Pathology, Children's Hospital Boston, Harvard Medical School, Boston, MA 02115, USA
⁴Immune Disease Institute and Program in Cellular and Molecular Medicine, Children's Hospital Boston, Harvard Medical School, Boston, MA 02115, USA
⁵Department of Medical Chemistry and Biophysics, Umea University, Umea, Sweden
⁶Department of Surgery, Harvard Medical School, Boston, MA, USA
⁷Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA

Corresponding author. Tel: +1 617 713 8700, Fax: +1 617 713 8715, Email: [email protected]

Received January 19, 2010

Accepted May 7, 2010

Cardiovascular Research 87(4):p 618-627, September 1, 2010. | DOI: 10.1093/cvr/cvq141

Aims

Coronary artery occlusion resulting in ischaemia/reperfusion (I/R) injury is a major cause of mortality in the western world. Circulating natural IgM has been shown to play a significant role in reperfusion injury, leading to the notion of a pathogenic response against self by the innate immune system. A specific self-antigen (non-muscle myosin heavy chain II) was recently identified as the major target of pathogenic natural IgM. Therefore, we hypothesized that a synthetic peptide mimetope (N2) or monoclonal antibodies directed against the self-antigen would prevent specific IgM binding to the self-antigen and reduce reperfusion injury in the heart.

Methods and results

We find that treatment with N2 peptide reduces infarct size by 47% and serum cardiac troponin-I levels by 69% following 1 h ischaemia and 24 h reperfusion. N2 peptide or an anti-N2 F(ab′)₂ (21G6) is also effective at preventing IgM and complement deposition. Additionally, N2 peptide treatment significantly reduces monocyte and neutrophil infiltration at 24 h and collagen deposition at 5 days. Finally, we show that human IgM (hIgM) also includes specificity for the highly conserved self-antigen and that myocardial injury in antibody-deficient mice reconstituted with hIgM is blocked by treatment with N2 peptide or 21G6 F(ab′)₂.

Conclusion

The findings in this study identify potential therapeutics [i.e. N2 peptide or 21G6 F(ab′)₂] that prevent specific IgM binding to ischaemic antigens in the heart, resulting in a significant reduction in cardiac I/R injury.