Heterogeneity in a mouse model of histiocytosis: transformation of Langerin+ dendritic cells, macrophages, and precursors

Abstract

Neoplastic diseases of macrophages (M phi) and dendritic cells (DC), collectively called histiocytoses, are relatively rare. The etiology of most forms of histiocytosis is poorly understood, and the development of animal models is crucial for further research in this field. Previously, an animal model for malignant histiocytosis (MH), involving transformed histiocytic cells, has been generated by infecting mice with malignant histiocytosis sarcoma virus (MHSV). However, increased insight into the heterogeneity of M phi and DC, and the associated reappraisal of human proliferative diseases involving these cells inspired us to re-evaluate the mouse model. We analyzed spleen, bone marrow, and lymph nodes of susceptible mice at various time points after infection. From day 11 onwards, a heterogeneous population of cells, consisting of CD8 alpha(+) Langerin(+) DC, ER-MP58(+) CD11b(+) myeloid precursor cells, CD169(+) metallophilic M phi, and CD71(hi) erythroblasts, was affected by viral transformation. In different mice, these subsets expanded at different rates in different organs, causing a variable disease profile in terminal stages. Cell lines, which were generated from MHSV-transformed tumors, showed a DC-like morphology and phenotype, and appeared to be arrested in different stages of maturation. Upon injection into healthy mice, different preferential homing patterns were observed for the various cell lines, and the cells acquired distinct phenotypes depending on the organ of homing. This indicates that these transformed cells adapt to their microenvironment by switching between precursor, DC/Langerhans cell, and M phi phenotypes. Our results demonstrate that the MHSV model represents a heterogeneous neoplastic disease with characteristics of M phi/DC sarcomas.

Langerhans cell histiocytosis: fascinating dynamics of the dendritic cell–macrophage lineage

“…Moreover, improved molecular diagnostics have indicated that many cases diagnosed earlier as malignant histiocytosis appeared to represent either anaplastic large cell lymphoma, involving malignant lymphocytes that show a histiocyte‐like appearance, or malignancies of dendritic cell origin (86, 87). Thus, the reappraisal of malignant histiocytosis as a human disease as well as the recently increased awareness of the heterogeneity of the dendritic cell lineage inspired us to re‐evaluate the identity of the cells transformed in the MHSV mouse model (88).…”

Transgenic Expression of GM-CSF in T Cells Causes Disseminated Histiocytosis

“…34,37 A previous model of histiocytosis was generated by infecting mice with malignant histiocytosis sarcoma virus, leading to transitional macrophages/DC sarcomas. 38 Another experimental model was induced by transgenic expression of the SV40 T oncogene in DCs. 39 These mice developed infiltration of spleen, liver, bone marrow, thymus, and mesenteric lymph node with CD11c þ CD8 þ CD207 þ DCs, resembling the aggressive form of LCH.…”