| First Author | Sun W | Year | 2018 |
| Journal | Blood | Volume | 132 |
| Issue | 26 | Pages | 2730-2743 |
| PubMed ID | 30361263 | Mgi Jnum | J:269655 |
| Mgi Id | MGI:6272952 | Doi | 10.1182/blood-2018-05-844928 |
| Citation | Sun W, et al. (2018) Macrophage TNF-alpha licenses donor T cells in murine bone marrow failure and can be implicated in human aplastic anemia. Blood 132(26):2730-2743 |
| abstractText | Interferon-gamma (IFN-gamma) and tumor necrosis factor-alpha (TNF-alpha) have been implicated historically in the immune pathophysiology of aplastic anemia (AA) and other bone marrow (BM) failure syndromes. We recently defined the essential roles of IFN-gamma produced by donor T cells and the IFN-gamma receptor in the host in murine immune-mediated BM failure models. TNF-alpha has been assumed to function similarly to IFN-gamma. We used our murine models and mice genetically deficient in TNF-alpha or TNF-alpha receptors (TNF-alphaRs) to establish an analogous mechanism. Unexpectedly, infusion of TNF-alpha(-/-) donor lymph node (LN) cells into CByB6F1 recipients or injection of FVB LN cells into TNF-alphaR(-/-) recipients both induced BM failure, with concurrent marked increases in plasma IFN-gamma and TNF-alpha levels. Surprisingly, in TNF-alpha(-/-) recipients, BM damage was attenuated, suggesting that TNF-alpha of host origin was essential for immune destruction of hematopoiesis. Depletion of host macrophages before LN injection reduced T-cell IFN-gamma levels and reduced BM damage, whereas injection of recombinant TNF-alpha into FVB-LN cell-infused TNF-alpha(-/-) recipients increased T-cell IFN-gamma expression and accelerated BM damage. Furthermore, infusion of TNF-alphaR(-/-) donor LN cells into CByB6F1 recipients reduced BM T-cell infiltration, suppressed T-cell IFN-gamma production, and alleviated BM destruction. Thus, TNF-alpha from host macrophages and TNF-alphaR expressed on donor effector T cells were critical in the pathogenesis of murine immune-mediated BM failure, acting by modulation of IFN-gamma secretion. In AA patients, TNF-alpha-producing macrophages in the BM were more frequent than in healthy controls, suggesting the involvement of this cytokine and these cells in human disease. |
