On mice and humans: the role of thymic stromal lymphopoietin in human B-cell development and leukemia

Abstract

T he development of immunodeficient mouse models has revolutionized the ability to study human disease in vivo. One of the difficulties is that many mouse and human cytokines are not cross-reactive. For this reason, the in vivo models currently used are not optimized enough to recapitulate the correct environment for every type of human hematopoietic or leukemic cell. This problem has been recently addressed by the development of several models of humanized mice expressing human cytokines, as described in detail by the recent excellent review in Haematologica by Theocarides et al. 1 In this issue of Haematologica, Francis et al. 2 created a chimeric mouse able to produce human thymic stromal lymphopoietin (TSLP) to study the effect of human TSLP on human B-cell development and human B-cell precursor acute lymphoblastic leukemias (BCP-ALLs) with abnormal expression of the TSLP receptor (TSLPR) (Figure 1). The generation of this mouse was required since the homology between mouse and human TSLP is only 43% and 35% for the TSLPR, with no cross reactivity between the species. Thymic stromal lymphopoietin is a cytokine that was first described as a constituent of medium conditioned by thymic stromal cells. TSLP is important in many allergic disorders, Figure 1. Schematic representation of the humanized mouse model and the effect of human TSLP on normal and malignant hemopoiesis. Only human TSLP is able to induce a conformational change in human heterodimeric receptor and to activate the JAK/STAT or PI3K/mTOR downstream pathway (red dots indicate phosphorylation). The injection of human stromal cells transduced to produce TSLP in NSG mice, induced marked increase of B-cell lymphopoiesis upon transplantation with CD34+ cells derived from human cord blood and, after transplantation with CRLF2 positive leukemia, induced a gene expression similar to the original patient. The increased expression of genes involved in mTOR signaling could be associated with chemoresistance.

Disrupting TSLP–TSLP receptor interactions via putative small molecule inhibitors yields a novel and efficient treatment option for atopic diseases

“…This decision was driven by the fact that conducting these studies in animal models proved difficult. While murine and human TSLP operate in a similar manner (Verstraete et al, 2014 ; Verstraete et al, 2017 ), they only share 43% and 35% homology for TSLPR, respectively, with no cross-reactivity between the species (Savino and Izraeli, 2016 ). Therefore, to the best of our knowledge, there is no animal model available to accurately mimic human TSLP-mediated Th2 inflammation in atopic diseases.…”

Thymic stromal lymphopoietin induces platelet mitophagy and promotes thrombosis in Kawasaki disease

“…Thymic stromal lymphopoietin (TSLP) is an interleukin (IL)‐7 like cytokine that is mainly derived from epithelial cells, fibroblasts and mast cells 18 . Accumulating evidence implicates the dysregulated expression of TSLP in multiple diseases such as asthma, allergic rhinitis, leukaemia and atherosclerosis 19–22 . Recently, Dazhu Li et al 23 used recombinant TSLP to stimulate human platelets in vitro and TSLP receptor (TSLPR) knockout mice to evaluate the effect on platelet function.…”

“…18 Accumulating evidence implicates the dysregulated expression of TSLP in multiple diseases such as asthma, allergic rhinitis, leukaemia and atherosclerosis. [19][20][21][22] Recently, Dazhu Li et al 23 used recombinant TSLP to stimulate human platelets in vitro and TSLP receptor (TSLPR) knockout mice to evaluate the effect on platelet function. Furthermore, a perfusion chamber model was employed to study the effect of TSLPR knockout mice on thrombosis in vitro.…”