title: A xenograft model of macrophage activation syndrome amenable to anti-CD33 and anti-IL-6R treatment.
abstract: Transgenic expression of key myelosupportive human cytokines in immune-deficient mice corrects for the lack of cross-species activities of stem cell factor (SCF), IL-3, and GM-CSF. When engrafted with human umbilical cord blood (UCB), these triple-transgenic mice produce BM and spleen grafts with much higher myeloid composition, relative to nontransgenic controls. Shortly after engraftment with UCB, these mice develop a severe, fatal macrophage activation syndrome (MAS) characterized by a progressive drop in rbc numbers, increased reticulocyte counts, decreased rbc half-life, progressive cytopenias, and evidence of chronic inflammation, including elevated human IL-6. The BM becomes strikingly hypocellular, and spleens are significantly enlarged with evidence of extramedullary hematopoiesis and activated macrophages engaged in hemophagocytosis. This manifestation of MAS does not respond to lymphocyte-suppressive therapies such as steroids, i.v. immunoglobulin, or antibody-mediated ablation of human B and T cells, demonstrating a lymphocyte-independent mechanism of action. In contrast, elimination of human myeloid cells using gemtuzumab ozogamicin (anti-CD33) completely reversed the disease. Additionally, the IL-6R antibody tocilizumab delayed progression and prolonged lifespan. This new model of MAS provides an opportunity for investigation of the mechanisms driving this disease and for the testing of directed therapies in a humanized mouse.
authors.affiliation: Division of Experimental Hematology and Cancer Biology and.
authors.forename: Mark
authors.initials: M
authors.lastname: Wunderlich
authors.affiliation: Division of Experimental Hematology and Cancer Biology and.
authors.forename: Courtney
authors.initials: C
authors.lastname: Stockman
authors.affiliation: Division of Experimental Hematology and Cancer Biology and.
authors.forename: Mahima
authors.initials: M
authors.lastname: Devarajan
authors.affiliation: Division of Experimental Hematology and Cancer Biology and.
authors.forename: Navin
authors.initials: N
authors.lastname: Ravishankar
authors.affiliation: Division of Experimental Hematology and Cancer Biology and.
authors.forename: Christina
authors.initials: C
authors.lastname: Sexton
authors.affiliation: Division of Bone Marrow Transplantation and Immune Deficiency, Cancer and Blood Disease Institute, Cincinnati Children's Hospital Medical Center (CCHMC), Cincinnati, Ohio, USA.
authors.forename: Ashish R
authors.initials: AR
authors.lastname: Kumar
authors.affiliation: Division of Experimental Hematology and Cancer Biology and.
authors.forename: Benjamin
authors.initials: B
authors.lastname: Mizukawa
authors.affiliation: Division of Experimental Hematology and Cancer Biology and.
authors.forename: James C
authors.initials: JC
authors.lastname: Mulloy
mesh_terms: D000617:Aminoglycosides / Q000494:pharmacology; D000818:Animals; D061067:Antibodies, Monoclonal, Humanized / Q000494:pharmacology; D004195:Disease Models, Animal; D005312:Fetal Blood; D000079982:Gemtuzumab; D016178:Granulocyte-Macrophage Colony-Stimulating Factor; D006410:Hematopoiesis; D006412:Hematopoietic Stem Cells; D064593:Heterografts; D006801:Humans; D007377:Interleukin-3; D008262:Macrophage Activation; D055501:Macrophage Activation Syndrome / Q000188:drug therapy* / Q000503:physiopathology; D051379:Mice; D008822:Mice, Transgenic; D019947:Receptors, Interleukin-6 / Q000037:antagonists & inhibitors*; D063268:Sialic Acid Binding Ig-like Lectin 3 / Q000037:antagonists & inhibitors*; D019089:Stem Cell Factor
chemical_list: D000617:Aminoglycosides; D061067:Antibodies, Monoclonal, Humanized; D007377:Interleukin-3; D019947:Receptors, Interleukin-6; D063268:Sialic Acid Binding Ig-like Lectin 3; D019089:Stem Cell Factor; D016178:Granulocyte-Macrophage Colony-Stimulating Factor; D000079982:Gemtuzumab; C502936:tocilizumab