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Characterization of CD28null T Cells in Idiopathic Pulmonary Fibrosis
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A1005 - Characterization of CD28null T Cells in Idiopathic Pulmonary Fibrosis
Author Block: D. M. Habiel1, M. Espindola2, C. Kitson3, A. V. Azzara4, A. Coelho5, C. M. Hogaboam6; 1Department of Medicine, Cedars-Sinai Medical Center, Los Angeles, CA, United States, 2Cedars-Sinai Medical Center, Los Angeles, CA, United States, 3Fibrosis Discovery, Bristol-Myers Squibb, Pennington, NJ, United States, 4Bristol Myers-Squibb, Pennington, NJ, United States, 5Pulmonary Division, Cedars-Sinai Medical Center, Los Angeles, CA, United States, 6Dept. of Medicine Research Scientist IV, Cedars-Sinai Medical Center, Los Angeles, CA, United States.
Rational: Idiopathic pulmonary fibrosis (IPF) is a fibrotic lung disease, with unknown etiopathogenesis and suboptimal therapeutic options. Due to the lack of clinical efficacy of standard immuno-suppressants in IPF, the role of the immune response in this disease remains elusive. Nevertheless, previous reports have shown that increased T cell numbers and CD28null phenotype is predictive of prognosis in IPF, suggesting that these cells might have a role in this disease.
Methods: Lung-associated T cells were purified from normal and IPF explanted lungs. Cells were characterized ex vivo by flow cytometric and transcriptomic analysis and in vivo via the intravenous administration into NOD SCID IL-2Rγ-/- (NSG) mice. Finally, to assess potential regulatory pathways of IPF T cells, IPF T cell-humanized mice were treated with T cell inhibitory (dexamethasone) and activation (anti-PD-1 and anti-CTLA4 antibodies) agents.
Results: IPF lung explant derived CD28null, but not normal donor lung CD28+, T cells induced lung remodeling in humanized NSG mice. CD28null T cell mediated lung remodeling was resistant to dexamethasone treatment in humanized NSG mice. Transcriptomic analysis of CD28null T cells isolated from IPF lung explants showed elevated checkpoint and lymphocyte activation pathways. Flow cytometric analysis showed higher PD-1 and CTLA4 proteins in IPF lymphocytes and PD-L1 expression on CD45- EpCAM+ and CD45- EpCAM- cells. Finally, in humanized NSG mice, anti-CTLA4, but not anti-PD1, mAb treatment induced an expansion of CD3+ T cells and accelerated lung fibrosis.
Conclusion:Together, these results demonstrate that CD28null IPF T cells are profibrotic but the immune checkpoint protein, CTLA-4, appears to limit this effect in IPF.
Author Block: D. M. Habiel1, M. Espindola2, C. Kitson3, A. V. Azzara4, A. Coelho5, C. M. Hogaboam6; 1Department of Medicine, Cedars-Sinai Medical Center, Los Angeles, CA, United States, 2Cedars-Sinai Medical Center, Los Angeles, CA, United States, 3Fibrosis Discovery, Bristol-Myers Squibb, Pennington, NJ, United States, 4Bristol Myers-Squibb, Pennington, NJ, United States, 5Pulmonary Division, Cedars-Sinai Medical Center, Los Angeles, CA, United States, 6Dept. of Medicine Research Scientist IV, Cedars-Sinai Medical Center, Los Angeles, CA, United States.
Rational: Idiopathic pulmonary fibrosis (IPF) is a fibrotic lung disease, with unknown etiopathogenesis and suboptimal therapeutic options. Due to the lack of clinical efficacy of standard immuno-suppressants in IPF, the role of the immune response in this disease remains elusive. Nevertheless, previous reports have shown that increased T cell numbers and CD28null phenotype is predictive of prognosis in IPF, suggesting that these cells might have a role in this disease.
Methods: Lung-associated T cells were purified from normal and IPF explanted lungs. Cells were characterized ex vivo by flow cytometric and transcriptomic analysis and in vivo via the intravenous administration into NOD SCID IL-2Rγ-/- (NSG) mice. Finally, to assess potential regulatory pathways of IPF T cells, IPF T cell-humanized mice were treated with T cell inhibitory (dexamethasone) and activation (anti-PD-1 and anti-CTLA4 antibodies) agents.
Results: IPF lung explant derived CD28null, but not normal donor lung CD28+, T cells induced lung remodeling in humanized NSG mice. CD28null T cell mediated lung remodeling was resistant to dexamethasone treatment in humanized NSG mice. Transcriptomic analysis of CD28null T cells isolated from IPF lung explants showed elevated checkpoint and lymphocyte activation pathways. Flow cytometric analysis showed higher PD-1 and CTLA4 proteins in IPF lymphocytes and PD-L1 expression on CD45- EpCAM+ and CD45- EpCAM- cells. Finally, in humanized NSG mice, anti-CTLA4, but not anti-PD1, mAb treatment induced an expansion of CD3+ T cells and accelerated lung fibrosis.
Conclusion:Together, these results demonstrate that CD28null IPF T cells are profibrotic but the immune checkpoint protein, CTLA-4, appears to limit this effect in IPF.
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