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Our History of Research Funding

At the very heart of the Histiocytosis Association is the steadfast commitment to finding a cure for histiocytic disorders. The Histiocytosis Association Research Grant Program was established in 1990 by the Association’s Board of Trustees with the objective of identifying and funding the most important and promising research initiatives – those that will lead to more effective treatments and, ultimately, a cure.

The Histiocytosis Association Research Grant Program operates very much on a “parallel highway” – funding grants for laboratory research, financially supporting clinical trials, and managing and participating in the evolution of the Histiocyte Society. All these functions make research possible. It is a concept known as “bench to bedside” – translating research at the “bench” in the laboratory into clinical trials, or at the “bedside.” The Association is extremely proud to be leading the search for a cure while ensuring that patients are being treated today.

The Histiocytosis Association’s Annual Research Grant Program funded research projects across histiocytic disorders every year, based on the generosity of the community. At the close of 2021, this equated to over $7 million in research funds and 194 projects, with 2020 being the only year that research funding halted due to unprecedented events of the pandemic.

In addition, the Association is dedicated to advancing and participating in research efforts around the world.  The Association team serves as a Patient Advocate on the National Comprehensive Cancer Network’s Histiocytic Neoplasms Panel, serves on the Steering Committee for the INTO-HLH Registry, serves on the Rare Disease Advisory Panel for the Patient-Centered Outcomes Research Institute (PCORI), and continuously shares opportunities to participate in research with the histio community.

Our team has aided in the funding of the LCH-IV Trial Database, partnered with the University of Alabama to support the ongoing Follow Up Study, has joined talks with medical professional working groups in countries, including Mumbai and the Philippines, to learn more about the research advancements taking place. This is also demonstrated through our longstanding partnership with the Histiocyte Society as Secretariat. Participation in research is important to helping us get ever closer to cures for histiocytic disorders.

In 2022, the Association proudly committed to funding another 4 research projects, each in the amount of $50,000. Called seed grants, these $50,000 grants are used to support new projects as they seek to establish new indications within histiocytic disorders, allowing progress in the field to occur.

I’m thrilled to share more about the projects that were funded in 2022. They are listed and summarized as simply as possible below!

This Year’s Research Grant Recipients

Defining and Testing the Hyperinflammatory Immune Synapse, led by Scott Canna, MD, Children’s Hospital of Philadelphia, PA:

Hyperinflammation is a rapidly progressive, life-threatening inflammatory state that occurs in roughly 11% of all systemic (system-wide) inflammatory response syndrome (SIRS) cases. There are several genetic, acquired, environmental contexts in which hyperinflammation is common and suggest likely contributing factors. How these factors further the progress of hyperinflammation is often unclear, and for many patients their array of factors is unknown.

Our group has been focused on the intersecting but distinct processes by which two well-established vulnerability factors, perforin deficiency and excess IL-18. Perforin is a critical component of T-and-NK-cell toxcity. When present, it prevents hyperinflammation; when defective it causes a small fraction of all hyperinflammation. IL-18 is a protein which in humans is encoded by the IL18 gene; the protein encoded by this gene is a proinflammatory cytokine.

Both perforin and IL-18 drive Interferon-gamma (IFNg), which appears central to and promotes most forms of hyperinflammation. Biomarker measurements demonstrating overabundance of IL-18 provide a strong link to hyperinflammation in genetic and rheumatic causes of Macrophage Activation Syndrome (MAS).

We propose using these clinical insights to help define the parameters of a hyperinflammatory immunological synapse (hIS). In addition, we will measure cytokine secretion in CD8 T-cell/target cell co-cultures. Once established, we will begin to test the system by changing features of the target including cell-type of origins and activation state and assessing whether these changes affect duration and/or cytokine production.

Completion of these aims will establish synapse duration and cytokine production as distinct and scalar (a quantity of) qualities defining a hyperinflammatory immunological synapse (hIS), providing preliminary data for future projects and a platform for identifying/testing diagnostically-and therapeutically relevant hyperinflammatory risk factors.

Burden of morbidity and premature mortality in patients with Langerhans cell histiocytosis, led by Gaurav Goyal, MD, University of Alabama, Birmingham:

Major advances have occurred in the past decade in LCH with the discovery of MAPK-ERK pathway mutations leading to targeted therapeutics. However, there is a lack of large studies informing the burden of disease prevalence and mortality among patients with LCH. Institutional studies in pediatric LCH suggest that 20-50% of survivors may have long-term health concerns or impairment of health. Studies have shown that cancer therapy and other treatment may also have an impact on quality of life or chronic medical conditions.

These findings pave a path towards a more definitive study to evaluate patterns in disease prevalence and mortality associated with LCH. This large questionnaire-based study aims to determine the risk of chronic medical conditions that caused disease prevalence and mortality in adults and children diagnosed with LCH.

It is anticipated that the results from this study will be instrumental in counseling LCH patients, designing survivorship programs to reduce the burden of chronic medical conditions/pain to conduct future research to improve patient outcomes.

The researchers plan to apply these methods to other histiocytic disorders like Erdheim Chester Disease and Rosai-Dorfman disease to define the health needs of this unique patient population.

Defining the pathophysiology of HLH in hematologic malignancies, led by Michael Jordan, MD, Cincinnati Children’s Hospital Medical Center:

HLH is a life-threatening inflammatory syndrome and is increasingly observed in patients with malignancies, repeated cell growth in certain parts of the body, or (M-HLH). The diagnosis and treatment of M-HLH is designed based on studies from familial HLH (F-HLH) which is most seen in young children due to mutation in cells of immune system.

Very little is known about the mechanism of action of M-HLH and its prevalence, nor its overlap with F-HLH, and survival rate remains low, 10-30%. Through a new set of laboratory criteria, called the ‘optimized HLH inflammatory (OHI) index’, which helps in better identification of inflammation, recent findings suggest that there is overlap between these acquired and genetic disorders.

By assessing specific proteins, gene expression, and cellular characteristics, the study aims at identifying key aspects of HLH driving mortality in these patients. The understanding of M-HLH pathophysiology (the functional changes associated with or resulting from disease) which will be developed in this project, will identify therapeutic targets and lead to improved therapies and outcomes for these high-risk patients.

Immunoproteasome inhibition as a novel therapy for hemophagocytic lymphohistiocytosis (HLH), led by Kim Nichols, MD, St. Jude Children’s Research Hospital:

HLH includes a wide array of disorders and complications that can be acquired (“secondary’) or inherited (“familial”), characterized by severe inflammation.  Despite several strong treatment advancements, nearly 40% of patients do not survive HLH due to the disease itself or complications of treatment. There is a pressing need to develop new and more effective therapies.

To date, much of what we have learned about the pathogenesis of HLH has come from the study of humans and mice lacking expression of perforin, a pore forming protein essential for the cytotoxic function of CD8+T cells and natural killer cells. Cytotxicity means toxic or deadly to cell; when infection is present and perforin is lacking, infected antigen presenting cells (APCs) cannot be eliminated from the body, ultimately culminating in the signs and symptoms of HLH.

The study team hypothesizes that reducing the expression of antigen presenting cells (APCs) and related immune action and proteins might act as a potential therapeutic strategy for HLH.

Aim 1 of the study will comprehensively characterize how immunoproteasome inhibition improves disease in LCMV-infected perforin-deficient mice, a model of primary HLH. Aim 2 of this study will rigorously examine immunoproteasome inhibition in C57BL/6 mice administered CpG-DNA +/-IL-10R -blockade, a model of secondary HLH.

The successful completion of these studies will make clear whether and how immunoproteasome inhibition lessens inflammation and set the stage for future clinical trials incorporating these drugs to improve the cure rate for patients with HLH.

Conclusion

We can’t wait to see what invaluable information is discovered through the studies we funded this year! If you would like to learn more about each project, you can see the full summary on our Grants Awarded page, here.

We hope to share the full scope of findings from these studies in a future year’s Executive Director’s Letter post.

Finally, a huge thank you to all of our donors who helped this program fund the above studies this year. We are forever grateful for all you do, for each and every one of you are helping to advance therapies, understanding of histiocytosis, and get us closer every day to a world free of histiocytosis!