ROTRF Recognition Prize – Recognising Excellence in Organ Transplantation Research

12:40: Therapeutic Potential of Heme Oxygenase-1 (HO-1): From Transplantation to Other Immune-mediated Inflammatory Diseases

Dr Miguel Soares, Instituto Gulbenkian de Ciência, Oeiras, Portugal

Cells have a variety of stress-responsive mechanisms that limit the extent of damage imposed by different forms of stress. These rely on the expression of stress-responsive genes that confer metabolic adaptation, cytoprotection and tissue repair. Expression of these stress-responsive genes in the context of transplantation should promote graft function and survival via two interrelated mechanisms. First, metabolic adaptation, cytoprotection and tissue repair should provide damage control in the context of different forms of stress associated with transplantation and thus promote graft function. Second, damage control should minimize sterile inflammation, an effect that is likely to down-modulate graft immunogenicity and thus promote graft survival. In 1999 we (Miguel P. Soares, principal investigator and Fritz H. Bach, Co-investigator) were awarded an ROTRF grant for the project entitled “Mechanisms of action of protective genes that promote organ graft survival”. The main objective of that project was to explore the mechanisms via which the expression of the stress-responsive enzyme heme oxygenase-1 (HO-1) in an organ promotes its survival after transplantation (1). We found that the protective effect of HO-1 acts, to a large extent, via carbon monoxide (CO) (2-4), produced through heme catabolism. We realized thereafter that this protective effect can be extended beyond transplantation, to a variety of other immune-mediated inflammatory diseases, including severe sepsis (5) and severe forms of malaria (6) that today remain major causes of morbidity and mortality worldwide. I will argue in this presentation that the common molecular mechanism underlying the broad protective effects of HO-1 and CO relies on preventing the deleterious effect of free heme, a cytotoxic molecule released from hemoproteins in the context of immune mediated inflammatory diseases (7). A detailed review of our work on the protective role of HO-1 in transplantation is described in Soares and Bach (8).

1. Soares MP, et al. Nat Med 1998; 4:1073.
2. Sato K, et al. J Immunol 2001; 166:4185.
3. Brouard S, et al. J Exp Med 2000; 192:1015.
4. Otterbein LE, et al. Nat Med 2000; 6:422.
5. Larsen R, et al. Sci Transl Med 2010; 2:51ra71.
6. Pamplona A, et al. Nat Med 2007; 13:703.
7. Gozzelino R, et al. Annu Rev Pharmacol Toxicol 2010; 50:323.
8. Soares MP, Bach FH. Front Biosci 2007; 12:4932.

Miguel Soares

Dr Miguel P. Soares is currently a Principal Investigator at Instituto Gulbenkian de Ciência in Oeiras, Portugal. He obtained his BSc in Biology (1990), MSc in Cellular Biology (1994) and PhD in Science (1995) at the University of Louvain, Belgium. He was a Research Fellow in the laboratory of Prof. Fritz. H. Bach at Harvard Medical School from 1995 to 1998 and then an Instructor in Surgery at Harvard Medical School from 1998 to 2004. He was a Staff Scientist at Beth Israel Deaconess Medical Center from 1995 to 2004 and a Lecturer at Harvard Medical School (2003-2004). The aim of his research is to gain further understanding of the mechanisms regulating inflammation. The projects developed by his group at the Instituto Gulbenkian de Ciência essentially address the mechanisms via which the expression of “protective genes” act in a manner that re-establishes homeostasis after a wide range of inflammatory conditions with diverse and multifarious underlying pathogenesis. Dr. Soares has published numerous papers in journals including Nature Medicine, Journal of Experimental Medicine, Science Translational Medicine, PNAS USA and Cell.