Modifying Graft-versus-Host Disease in a Humanized Mouse Model by Targeting Macrophages or B-Cells
Marieke C H Hogenes1,2, Suzanne van Dorp3, Joyce van Kuik2
1Laboratory for Pathology East Netherlands, (LABPON), P.O. Box 510, 7550 AM Hengelo, Netherlands.
Journal of Immunology Research
|June 18, 2019
Summary
Investigating humanized mouse models for Graft-versus-Host Disease (GvHD), this study found that depleting macrophages worsened outcomes, while B-cell depletion improved clinical symptoms but had limited histological impact.
Area of Science:
- Immunology
- Transplantation Biology
- Preclinical Models
Background:
- Humanized mouse models offer valuable platforms for studying Graft-versus-Host Disease (GvHD).
- Understanding the roles of specific immune cell populations, such as macrophages and B-cells, is crucial for GvHD pathogenesis.
- Modulating these cells may present therapeutic strategies for GvHD.
Purpose of the Study:
- To investigate the impact of macrophage depletion on GvHD in a humanized mouse model.
- To evaluate the therapeutic potential of early B-cell depletion using Rituximab in mitigating GvHD.
- To analyze the clinical, histological, and molecular changes associated with these interventions.
Main Methods:
- Utilized RAG2-/- γc-/- mice engrafted with human peripheral blood mononuclear cells (HuPBMCs) to establish a humanized GvHD model.
- Administered interventions targeting macrophage depletion and early B-cell depletion (using Rituximab).
- Assessed survival rates, performed histological examinations of various organs, and analyzed mRNA levels of key cytokines (e.g., TGF-β) and cell populations (e.g., Tregs).
Main Results:
- Macrophage depletion led to significantly decreased survival and altered histomorphology, with increased B-cell infiltration.
- Early B-cell depletion with Rituximab improved clinical GvHD symptoms but showed limited effects on liver fibrosis.
- Rituximab treatment was associated with lower mRNA levels of regulatory T-cells (Tregs) in some organs, challenging the notion that higher Treg numbers universally correlate with reduced GvHD severity.
Conclusions:
- Both macrophage depletion and early B-cell depletion significantly influence the clinical, histological, and cytokine profiles of GvHD in this xenogeneic model.
- Macrophage depletion exacerbates GvHD, while B-cell depletion offers clinical benefits with specific histological impacts.
- The complex interplay between immune cells and cytokines in GvHD warrants further investigation, particularly regarding Treg dynamics.
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