Macrophage Activation Syndrome (MAS) is a life threatening complication of many pediatric rheumatology diseases. MAS consist of high levels of inflammatory cytokines, multi-system organ failure, coagulopathy, and the development of hemophagocytosis. It bears a similar appearance to another genetic cytokine storm syndrome, Familial Hemophagocytic Lymphohistiocytosis (fHLH). However, unlike fHLH, patients with MAS do not have genetic mutations associated with the disease. According, the initial events leading to the disease are likely different in MAS than in fHLH. We have recently developed a novel mouse model of MAS, the first model to produce an MAS-like disease without the need for genetic manipulations or infections. This model provides the first link between the observations that patients with MAS tend to heightened states of inflammatory Toll-like receptor (TLR) activation. By using repeated TLR9 stimulation, mice develop an MAS-like syndrome. Like fHLH, the disease is mediated by Interferon-gamma (IFN?). Unlike fHLH, this IFN? is made in large part myeloid cells, again demonstrating the difference between MAS and fHLH and the need for unique models. This model has also demonstrated a critical role for Interleukin-10 (IL-10) in protecting against the development of MAS and hemophagocytosis. This proposal seeks to identify the cellular responders to IFN?, the nature of these responses, and the source of protective IL-10 in MAS using complementary genetic and pharmacologic techniques. Bone marrow chimera will be used to generate mice lacking the receptors for IFN? on specific cellular populations to determine the responding cells. Adoptive transfer techniques will be used to determine the cell type important for making the protective IL-10 response. Recombinant cytokines will be administered to investigate the temporal relationship between cytokine exposure and TLR stimulus. The data generated from these studies will provide a basis for rational targeting of IFN? and IL-10, and their associated cellular responses in treating MAS. This will mark an important step forward in developing MAS specific therapies as opposed to the standard of care of borrowing inappropriately from the fHLH protocols.

Public Health Relevance

This project seeks to characterize the cells that produce and respond to the major cytokines responsible for the development of Macrophage Activation Syndrome (MAS), a deadly complication of pediatric rheumatologic disease. We will make use of a novel mouse model of MAS that we have developed to understand the cells involved in the Interferon-gamma and Interleukin-10 cytokine responses in MAS. These results will direct the development rational therapies to target these cells anwd cytokine to better treat children with MAS.

National Institute of Health (NIH)
National Heart, Lung, and Blood Institute (NHLBI)
Research Project (R01)
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Innate Immunity and Inflammation Study Section (III)
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Kindzelski, Andrei L
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Children's Hospital of Philadelphia
United States
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Canna, Scott W; Costa-Reis, PatrĂ­cia; Bernal, William E et al. (2014) Brief report: alternative activation of laser-captured murine hemophagocytes. Arthritis Rheumatol 66:1666-71
Weaver, Lehn K; Behrens, Edward M (2014) Hyperinflammation, rather than hemophagocytosis, is the common link between macrophage activation syndrome and hemophagocytic lymphohistiocytosis. Curr Opin Rheumatol 26:562-9