Grants Awarded

Principal Investigator
Michael Jordan MD
Cincinnati Children’s Hospital Medical Center – Cincinnati, Ohio USA

Date of Award
September 2008

Amount of Award
$50,000

Layperson Summary
Despite excellent progress over the last decade, too many patients still die from hemophagocytic lymphohistiocytosis (HLH). In order to improve the outcome for patients with HLH, we need to develop new therapies that are both more effective and more highly targeted. To accomplish this, we need to gain a better understanding of how HLH develops and how it makes patients ill.

We recognized this problem and developed a mouse model of HLH several years ago. We found that abnormal elevations of a substance called interferon gamma (which generally plays an important and beneficial role in our immune systems) can cause HLH. However, we still don’t understand how interferon gamma does this. Recently, we have begun to unravel the details of this process. We have been studying the same cells in mice which wreak havoc on the blood counts in patients with HLH (‘hemophagocytic’ cells).

We have discovered that these cells are causing damage by a unique sort of ‘drinking’ process. In fact, it would be quite literally accurate to describe these cells as ‘blood thirsty.’ We have also found that mice lacking another molecule, which normally promotes blood counts, are protected from the development of these cells.

Because we do not yet understand how these two molecules may interact in the immune system, we plan to study these mice carefully, and test several experimental therapies that our ongoing research suggests will stop the hemophagocytic cells. We strongly suspect that understanding these cells will help us to develop entirely new (and improved) strategies for treating patients with HLH.

Twelve Month Report 
Despite excellent progress over the last decade, hemophagocytic lymphohistiocytosis (HLH) remains a disorder which is poorly understood and often fatal, even with the best current therapies. In general, we know that HLH is characterized by extreme and unusual immune activation, and that treatment involves suppressing various aspects of the immune system. Patients with HLH who die, usually do so for one of two reasons; 1 the underlying disease process is resistant to current treatments, or; 2 therapy suppresses the patient’s immune system so broadly that they develop fatal infections. Thus, in order to improve the outcome for patients with HLH, we need to develop new therapies that are both more effective and more highly targeted. To accomplish this, we need to better understand how HLH develops and, specifically, how this process makes patients ill.

We recognized this problem and developed a mouse model of HLH several years ago. We found that abnormal elevations of a substance called interferon gamma (which generally plays an important and beneficial role in our immune systems) can cause HLH. However, we still don’t understand how interferon gamma does this.  Recently, we have begun to unravel the details of this process. We have found that this substance directly causes a principle feature of HLH, called ‘hemophagocytosis’ (or ‘blood eating’), to develop in animals exposed to large amounts of it.  Evidence suggests that the cells which are doing this eating (called ‘hemophagocytic’ cells) are causing many of the medical problems in HLH. Thus, we have focused on trying to understand what interferon gamma is doing to the hemophagocytic cells.

In our research proposal, we planned to explore this process by exposing mice to interferon gamma under various contexts. In these animals, we have defined precisely which cells have become hemophagocytic. We have also characterized how interferon alters the normal ‘eating’ process in these cells.  We have made two key observations that have led to new ideas about how to treat HLH. First, we have better defined the nature of the ‘blood eating’ seen in HLH.  Understanding this process has led us to test drugs which are known to block this pathway in cell culture (in the ‘test tube’). Unfortunately, while we can block hemophagocytosis in the test tube with these drugs, they have not yet been effective in animals. Second, we have found a molecule (in a completely different pathway) which is critical for the hemophagocytic process. Mice that lack this molecule, which normally promotes good blood counts, are protected from the development of hemophagocytosis.  We have now determined that these mice have normal numbers of the ‘eating’ cells and these cells respond to interferon normally, yet they are unable to develop hemophagocytosis. We have now developed new tools to block or promote this molecule and will soon test two new therapies related to this molecule in animals. We plan to publish some of these results this year and to apply for future funding from the National Institutes of Health. We are grateful for support from the Histiocytosis Association of America.