Projects per year
Abstract
Mucosa-associated lymphoid tissue (MALT) lymphoma is a B-cell tumour that develops over many decades in the stomachs of individuals with chronic Helicobacter pylori infection. We developed a new mouse model of human gastric MALT lymphoma in which mice with a myeloid-specific deletion of the innate immune molecule, Nlrc5, develop precursor B-cell lesions to MALT lymphoma at only 3 months post-Helicobacter infection versus 9–24 months in existing models. The gastric B-cell lesions in the Nlrc5 knockout mice had the histopathological features of the human disease, notably lymphoepithelial-like lesions, centrocyte-like cells, and were infiltrated by dendritic cells (DCs), macrophages, and T-cells (CD4+, CD8+ and Foxp3+). Mouse and human gastric tissues contained immune cells expressing immune checkpoint receptor programmed death 1 (PD-1) and its ligand PD-L1, indicating an immunosuppressive tissue microenvironment. We next determined whether CD40L, overexpressed in a range of B-cell malignancies, may be a potential drug target for the treatment of gastric MALT lymphoma. Importantly, we showed that the administration of anti-CD40L antibody either coincident with or after establishment of Helicobacter infection prevented gastric B-cell lesions in mice, when compared with the control antibody treatment. Mice administered the CD40L antibody also had significantly reduced numbers of gastric DCs, CD8+ and Foxp3+ T-cells, as well as decreased gastric expression of B-cell lymphoma genes. These findings validate the potential of CD40L as a therapeutic target in the treatment of human gastric B-cell MALT lymphoma.
Original language | English |
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Pages (from-to) | 402-414 |
Number of pages | 13 |
Journal | Journal of Pathology |
Volume | 259 |
Issue number | 4 |
DOIs | |
Publication status | Published - Apr 2023 |
Keywords
- APRIL
- B-cell
- BAFF
- CD40 ligand
- Helicobacter
- MALT lymphoma
- multiplex immunohistochemistry
- NLRC5
- PD-L1
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Defining a protective role for NLRC5 signalling in Helicobacter pylori disease
Ferrero, R., Kufer, T. & D'Elios, M.
1/01/22 → 31/12/25
Project: Research
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NLRC5, a new regulator of Helicobacter-induced inflammation
Ferrero, R.
National Health and Medical Research Council (NHMRC) (Australia)
1/01/16 → 31/12/19
Project: Research
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NHMRC Research Fellowship
Ferrero, R.
National Health and Medical Research Council (NHMRC) (Australia)
1/01/10 → 31/12/19
Project: Research
Equipment
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Histology Platform
Camilla Cohen (Manager)
Faculty of Medicine Nursing and Health Sciences Research PlatformsFacility/equipment: Facility
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MHTP Cell Therapies Platform
Gordon McPhee (Manager)
Hudson Institute - Department of Molecular and Translational ScienceFacility/equipment: Facility