Development of Mast Cell and Eosinophil Hyperplasia and HLH/MAS-Like Disease in NSG-SGM3 Mice Receiving Human CD34+ Hematopoietic Stem Cells or Patient-Derived Leukemia Xenografts

Abstract

Immunocompromised mouse strains expressing human transgenes are being increasingly used in biomedical research. The genetic modifications in these mice cause various cellular responses, resulting in histologic features unique to each strain. The NSG-SGM3 mouse strain is similar to the commonly used NSG (NOD scid gamma) strain but expresses human transgenes encoding stem cell factor (also known as KIT ligand), granulocyte-macrophage colony-stimulating factor, and interleukin 3. This report describes 3 histopathologic features seen in these mice when they are unmanipulated or after transplantation with human CD34+ hematopoietic stem cells (HSCs), virally transduced hCD34+ HSCs, or a leukemia patient-derived xenograft. The first feature is mast cell hyperplasia: unmanipulated, naïve mice develop periductular pancreatic aggregates of murine mast cells, whereas mice given the aforementioned human cells develop a proliferative infiltrative interstitial pancreatic mast cell hyperplasia but with human mast cells. The second feature is the predisposition of NSG-SGM3 mice given these human cells to develop eosinophil hyperplasia. The third feature, secondary hemophagocytic lymphohistiocytosis/macrophage activation syndrome (HLH/MAS)–like disease, is the most pronounced in both its clinical and histopathologic presentations. As part of this disease, a small number of mice also have histiocytic infiltration of the brain and spinal cord with subsequent neurologic or vestibular signs. The presence of any of these features can confound accurate histopathologic interpretation; therefore, it is important to recognize them as strain characteristics and to differentiate them from what may be experimentally induced in the model being studied.

Stem Cell-Based Disease Models for Inborn Errors of Immunity

“…Although the NSG mice and NSG-derived models are considerably improved models for studying the humanized system, one must have the awareness that humanization can have unintended immunological consequences, as described by two recent studies from Blümich et al [ 175 ] and Janke and colleagues [ 176 ]. From the examination of a large cohort of humanized and non-humanized NSG mice with CD34 + cells, Blümich et al raised some important considerations, such as the poor correlation between engraftment level in the humanized mice and the presence of human circulating CD45 + cells in the PB [ 175 ].…”

The Price of “Humanization”

“…The findings described in these 2 article 2,6 will be relevant to pathologists and scientists alike because these changes potentially complicate or confound histopathological interpretation and experimental results obtained from these strains and their ever-increasingly refined versions. One anticipates the most obvious impact may be on preclinical cancer and infectious disease studies for therapeutic safety and efficacy endpoints.…”

“…13 Humanization, however, has unintended consequences that complicate and confound results and may pose significant hurdles by causing illness and euthanasia of study animals before study completion. In the current issue of Veterinary Pathology , 2 articles 2,6 document the clinicopathological consequences of the humanization of NSG/NRG mice.…”

“…These cytokines enable stable and enhanced engraftment of human myeloid-derived cells and regulatory T cells to support improved multilineage human hematopoietic reconstitution and function which may be inadequate in NSG mice. 1,17 Janke et al 6 characterized NSG-SGM3/NRG-SGM3 mice that were naive (unmanipulated) or engrafted with human CD34+ HSC or patient-derived leukemia xenografts. The authors made 3 fascinating observations that were consistent with the predominance of myeloid-derived proliferations: histiocytic (granulomatous) lesions reminiscent of secondary hemophagocytic lymphohistiocytosis/macrophage activation syndrome (HLH/MAS), mast cell hyperplasia, and eosinophil hyperplasia.…”

“…19 The pathogenesis and the clinicopathological outcome in this study could have been impacted by multiple variables affecting the engrafted cells or tissues (source, storage, and ex vivo manipulation) and the mouse (strain, genetics, irradiation and other manipulations). 9 However, the limited number of study cohorts may not have allowed parsing these and other factors in the study by Janke et al 6…”