Poster Presentation Asia-Pacific Vaccine and Immunotherapy Congress 2023

An in vivo model of human Hemophagocytic Lymphohistiocytosis (#166)

Liam J O'Brien 1 , Carina Walpole 1 , Svetlana Shatunova 1 , Andrew Moore 2 , Ingrid M Leal Rojas 1 , Kristen Radford 3
  1. Mater Research, WOOLLOONGABBA, QLD, Australia
  2. Childrens Health QLD Hospital and Health Service, Brisbane
  3. Mater Research, The University of Queensland, Woolloongabba, Queensland, Australia, kristen.radford@mater.uq.edu.au.

 Background/ Motivation

Hemophagocytic lymphohistiocytosis (HLH) is a rare but deadly autoimmune condition affecting both adults and pediatric patients, where large numbers of T and myeloid cells are sustained in positive feedback loops of pro-inflammatory signalling causing fatal organ damage without prompt clinical intervention. HLH can be triggered by genetic mutations (familial HLH), infection, chemotherapy or malignancy - most commonly, leukaemia or lymphoma (secondary or malignancy-associated HLH). Both adult and pediatric HLH patients suffer a poor prognosis, with median survival of 0.9 and 1.2 years in chemotherapy and malignancy-induced HLH respectively1.

 Results

During experiments utilizing NOD-SCID-il2gr -/-(NSG) mice transgenically expressing human Stem Cell Factor (SCF), Granulocyte-Macrophage Colony Stimulating-Factor (GM-CSF), and IL-3 (NSG-SGM3), we observed an extreme sensitivity to myelosuppressive chemotherapy, along with a decline in red blood cell and platelet counts when mice were kept for extended periods (>15 weeks) post-engraftment of human hematopoietic stem cells (HSC). Further investigation of hematopoiesis in NSG-SGM3 mice and comparison to non-cytokine transgenic NSG mice revealed hypocellular bone marrow, splenomegaly, elevated mean corpuscular and platelet volumes, and elevated levels of human IL-6 and MCP-1 in NSG-SGM3. Levels of human IL-6, MCP-1 (CCL2), IL-8, and most notably IL-18 were highly correlated with anemia severity in NSG-SGM3 mice.

Conclusion

These data in corroboration with several recently published papers demonstrate complete penetrance of a HLH-like syndrome in NSG-SGM3 mice engrafted with HSC to generate a human immune system. This model can be used to evaluate novel cytokine inhibitors or other immunotherapies before testing in human HLH patients.

  1. Lehmberg, K., Sprekels, B., Nichols, K.E., Woessmann, W., Müller, I., Suttorp, M., Bernig, T., Beutel, K., Bode, S.F.N., Kentouche, K., Kolb, R., Längler, A., Minkov, M., Schilling, F.H., Schmid, I., Vieth, S., Ehl, S., Zur Stadt, U. and Janka, G.E. (2015), Malignancy-associated haemophagocytic lymphohistiocytosis in children and adolescents. Br J Haematol, 170: 539-549. https://doi.org/10.1111/bjh.13462