Modifying Graft-versus-Host Disease in a Humanized Mouse Model by Targeting Macrophages or B-Cells

Marieke C H Hogenes,Natalie Ter Hoeve,Joyce Van Kuik,Roel A De Weger,Liane Guedes,Anton C Martens,Suzanne Van Dorp,Marijke R Van Dijk,Filipa R P Monteiro

doi:10.1155/2019/3538963

Abstract

Humanized mouse models can well be modified to study specific aspects of Graft-versus-Host Disease (GvHD). This paper shows the results of both macrophage depletion and (early) B-cell depletion in a humanized mouse model using RAG2−/−γc−/− mice injected with HuPBMCs. Macrophage depletion showed a significant decrease in survival and also lead to a change in the histomorphology of the xenogeneic reaction. Higher levels of infiltrating B-cells were observed in various organs of mice depleted for macrophages. With (early) B-cell depletion using Rituximab, a clear improvement on clinical symptoms was observed, even when probably only inactivated B-cells were deleted. However, the histological examinations only showed a significant morphological effect on liver fibrosis. This may be related to a difference in the mRNA levels of TGF-β. Also, lower mRNA levels of Tregs in some organs were observed after Rituximab treatment, which contradicts that a higher number of Tregs would always be related to less severe GvHD. Our data show that both macrophage depletion and (early) B-cell depletion in a xenogeneic mouse model can influence the clinical, histological, and cytokine production of a GvHD response.

Highlights

Since researchers developed an interest in the pathogenesis and possible treatment targets of human Graft-versus-Host Disease (GvHD), the interest in mouse models has grown
Macrophage depletion was studied in duplo, using the same conditions described by van Rijn et al [26]
Both macrophagedepletion experiments showed a significant difference in survival, in which survival of mice depleted with macrophages was impaired (p = 0 0005 in experiment 1 and p = 0 0099 in experiment 2)

Summary

Introduction

Since researchers developed an interest in the pathogenesis and possible treatment targets of human Graft-versus-Host Disease (GvHD), the interest in mouse models has grown. Several mouse models, including humanized mouse models, are available as discussed in our previous paper [1] with endless options to modify the model to your needs. One of these models is the RAG2-/-γc-/- mouse model [1], in which the immunodeficient mice lack mature T-cells, mature B-cells, and NK-cells but maintain monocytes and macrophages. For B-cells, a positive influence on GvHD activity has been noted when using Rituximab, a B-cell-depleting antibody [3,4,5,6]. Rituximab was originally developed to treat non-Hodgkin lymphomas [4, 7] but is successful in a variety of autoimmune diseases as well [8]

Methods

Results

Conclusion