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Published online before print January 9, 2007
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Laboratory of Allergic Diseases, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, Maryland, USA
1 Correspondence: Laboratory of Allergic Diseases, NIAID, NIH, Bethesda, MD 20892, USA. E-mail: hrosenberg{at}niaid.nih.gov
The article, "
-Galactosylceramide induces protection against lipopolysaccharide-induced shock" (doi:10.1189/jlb.0506298), was selected as a Pivotal Advance because the results suggest that -galactosylceramide (GalCer), a glycolipid isolated from marine sponges, can protect against the complete morbidity and mortality characterisitic of endotoxin shock by inducing NKT cells to produce TH2 cytokines.
Dr. Sireci, in these studies, you used GalCer, or, more correctly, the synthetic version, KRN7000, to reduce the negative sequelae of systemic shock. How was this compound discovered, and what is known about its mechanism of action?
GS: GalCer was originally isolated from marine sponges on the basis of its anti-tumor activity, initially attributed to NK cell activation. Later, GalCer was characterized as a glycolipid presented by CD1d-expressing antigen presenting cells (APCs) to NKT cells. KRN7000 is a synthetic homologue of GalCer, created by the Kirin Corporation. There are several reports describing the effects of KRN7000 on immune system function in mice. For example, Singh and colleagues [1
] reported that KRN7000 co-administered with ovalbumin induced an antigen-specific switch from TH1 to TH2 cytokine production. Matsuda and colleagues [2
] showed that KRN7000 induced time-dependent release of either IL-4 or IFN-
. Recently, Crowe and colleagues [3
] demonstrated reduced expression of TCR on NKT cells in response to prolonged exposure to KRN7000 in vivo.
In this work, you used an experimental model known as the "Shwartzman reaction" which may not completely familiar to all readers of JLB. Can you tell us a bit more about this model of systemic shock?
GS: Many years ago, Shwartzman found that if he injected rabbits intravenously with two sequential doses of lipopolysaccharide (LPS), they ultimately died of infarcts of the kidneys, heart, liver, and spleen due to disseminated intravascular coagulation (DIC). This is called the systemic Shwartzman reaction, which is an experimental model of septic shock. Shwartzman also found that if he administered the first dose of LPS intradermally and the second dose intravenously, he found instead that he had induced an area of necrosis at the site of priming. This is a localized Shwartzman reaction which we now know is due to a massive release of TNF- by IFN--activated macrophages. The study of the systemic Shwartzman reaction in mice gives immunologists a great opportunity to analyze the molecular events that result in shock and death under controlled experimental conditions, and to test various treatment strategies. We were able to suppress the Shwartzman reaction with KRN 7000 based, as we suggest, on its ability to induce NKT cells to switch from producing IFN to IL-4 and IL-10.
The data you have presented here suggests that there may be some limitations on the potential clinical usefulness of KRN7000. In your study, you demonstrated that KRN7000 needs to be administered before or very shortly after LPS challenge, which are time points that may not be precisely predictable in the clinical setting
GS: We know that there are several features of our work that might be difficult to translate into clinical terms. When we began this work, our intention was to use -GalCer to investigate the roles of NK, NKT cells, and macrophages in promoting the Shwartzman reaction [4
]. Further experimentation with KRN7000 and perhaps with other derivatives will be necessary in order to develop a useful therapeutic agent.
On a related topic, as you and others have noted, KRN7000 administration results in liver damage. Some novel biochemical derivatives of KRN7000 have been developed. What are your thoughts on how these derivatives might improve the clinical potential of this agent?
GS: The issue of liver damage in response to -GalCer is certainly one of significant concern. The work of Berkers and colleagues [5
] is certainly helpful in this regard. This group demonstrated that OCH- and C-glycosidic-derivatized -GalCer analogs selectively activated different cytokines, implying that these compounds might have a different protective vs. toxicity profile than the -GalCer parent compound.
Can you tell us about some of your other research interests?
GS: In addition to our work on GalCer, NK, and NKT cells, I’m involved in other two areas of research—specifically, tolerance to murine minor histocompatibility antigens and characterization of mucosal immune responses to mycobacterial antigens.
On a more personal note, can you tell JLB readers something about yourself apart from your life in science?
GS: When I am not engaged in scientific research, I also teach immunology for the Faculty of Medicine and the Faculty of Biological Sciences in Palermo. Another duty is HLA typing for bone marrow transplants and for supporting diagnosis of diseases statistically correlated with HLA alleles. I also like to spend time with my family.
I would also like to take a moment in this interview to thank two colleagues who contributed enormously to the success of my career. In particular, I would like to thank Professor Alfredo Salerno, who gave me the opportunity to develop knowledge of immunology via many fruitful discussions and Professor Francesco Dieli who provided me with much helpful criticism which most definitely improved my scientific work.
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-Galactosylceramide directs conventional T cells to the acquisition of a Th2 phenotype J. Immunol. 163,2373-237714i natural killer cells are resistant to cytokine polarization in vivo Proc. Natl. Acad. Sci. USA. 100,8395-8400
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