Studies Break Ground in Controlling Inflammation
Investigators in our Division published four important papers that suggest improved ways to control dangerous disease-related inflammation.
In a paper published in Nature Medicine, Jörg Kohl, PhD, and colleagues reported discovering an important and potent anti-inflammatory mechanism: the immune complex-mediated association of the inhibitory receptor, FcgRIIb, with a C-type lectin-like receptor, dectin-1, inhibits signaling through the proinflammatory receptor for the complement-derived anaphylatoxin, C5a. Because immune complex binding to the dectin-1 receptor depends heavily on galactosylation of the IgG in these complexes, the observations reported in this paper suggest that artificially galactosylated IgG can be used to inhibit the many inflammatory diseases that are mediated by C5a.
Marat Khodoun, PhD, Fred Finkelman, MD, and colleagues published findings in the Journal of Allergy and Clinical Immunology that demonstrate a novel approach that safely suppresses IgE-mediated allergy in a mouse model. Mice were injected with rising doses of a monoclonal antibody until inducing anaphylaxis. This approach gradually removed all IgE from these cells, without causing any apparent signs of disease. As a result, the approach eliminated sensitivity to IgE-mediated anaphylaxis. A similar approach could be used to treat human allergic disorders, including food and drug allergies, insect venom sensitivities, allergic skin disease, allergic rhinitis and asthma.
In a paper published in the journal Blood, Michael Jordan, MD, and C.E. Terrell explained how humans and mice with impaired perforin-dependent cytotoxic function can develop excessive T-cell activation and the fatal inflammatory disorder hemophagocytic lymphohistiocytosis (HLH) after infection. Using a mouse model of HLH, they defined a feedback loop that is critical for immune homeostasis. This endogenous feedback loop involves perforin-dependent elimination of antigen-presenting dendritic cells (DCs) by CD8‑ T cells; the abnormal persistence of antigen presentation in perforin-deficient mice drove T-cell activation well beyond normal limits, leading to the inflammatory disease. These new findings suggest that interventions to limit DC antigen presentation may be useful to treat HLH.
Julio Aliberti, MS, PhD, and colleagues published findings in PLoS One demonstrating that exogenous administration of anti-inflammatory lipoxins can protect against lethal inflammation in experimental malaria by inhibiting the production of the cytokines IL-12 and IFN-γ in the brain. Malaria-infected mice that lack the ability to produce lipoxins developed accelerated mortality, while treatment of wild-type mice with lipoxins as late as 3 days after malaria inoculation prevented early mortality. This suggests that lipoxins may be useful for treating cerebral malaria, a form of malaria that causes mortality and disability, particularly in children.
Regulating the Growth of Leukemia Cells
James Phelan, H. Leighton Grimes, PhD, and colleagues published findings in Cancer Cell showing that leukemic cells depend on growth factor independence 1 (Gfi1) for survival. Acute lymphoblastic leukemia (ALL) cells rely on Gfi1 to escape the tumor-suppressing capabilities of another protein, p53, which normally initiates DNA repair that involves apoptosis, or programmed cell death, of cancer cells. . Removal of Gfi1 in lymphoid tumors in mice caused ALL to regress through p53-induced apoptosis. Furthermore, removal of Gfi1 from human T-cell ALL cells implanted into mice again stopped the progression of leukemia in the mice, without any harmful effects. This suggests an approach that might be useful for the suppression of human ALL and, possibly, other malignancies.
After an 18-month search, Harinder Singh, PhD, was chosen to direct the Division of Immunobiology. He joins us after having led Immunology programs at the University of Chicago and at Genentech. David Hildeman, PhD, Edith Janssen, PhD, and Fred Finkelman, MD, were active participants in the search. Meanwhile, the German Federal Republic approved funding for a large, integrated immunology graduate program between the University of Lübeck and Cincinnati Children’s. Hildeman and Jörg Köhl, MD, led the effort with participation from several Division members. Graduate students from each institution are already rotating in labs at the other institution. This program promises to improve the quality of our future graduate students and post-doctoral fellows and could enhance recognition of Cincinnati Children’s in Europe.