Yang Z.-Z.,Mayo Medical School |
Grote D.M.,Mayo Medical School |
Ziesmer S.C.,Mayo Medical School |
Niki T.,GalPharma Co. |
And 4 more authors.
Journal of Clinical Investigation | Year: 2012
The cytokine IL-12 induces IFN-γ production by T and NK cells. In preclinical models, it contributes to antitumor immunity. However, in clinical testing, it has shown limited benefit in patients with any one of a variety of malignancies. Moreover, in a clinical trial testing a combination of IL-12 and rituximab in patients with follicular B cell non-Hodgkin lymphoma (FL), those treated with IL-12 showed a lower response rate, suggesting that IL-12 actually plays a detrimental role. Here, we investigated whether the failure of IL-12 treatment for FL was due to T cell exhaustion, a condition characterized by reduced T cell differentiation, proliferation, and function, which has been observed in chronic viral infection. We found that extended exposure to IL-12 induced T cell exhaustion and contributed to the poor prognosis in FL patients. Long-term exposure of freshly isolated human CD4 + T cells to IL-12 in vitro caused T cell dysfunction and induced expression of TIM-3, a T cell immunoglobulin and mucin domain protein with a known role in T cell exhaustion, via an IFN-γ-independent mechanism. TIM-3 was required for the negative effect of IL-12 on T cell function. Importantly, TIM-3 also was highly expressed on intratumoral T cells that displayed marked functional impairment. Our findings identify IL-12- and TIM-3-mediated exhaustion of T cells as a mechanism for poor clinical outcome when IL-12 is administered to FL patients. Source
Galpharma Co. | Date: 2014-09-29
The object of the present invention is to provide a cell that can exhibit physiological activity based on galectin-9, a method for producing the cell, and use of the cell. In order to achieve the above object, the cell of the present invention contains galectin-9, and the galectin-9 is expressed on a cell surface.
Lv K.,Fudan University |
Xu W.,Fudan University |
Wang C.,Fudan University |
Niki T.,GalPharma Co. |
And 3 more authors.
Clinical Immunology | Year: 2011
In this study we explored the effects of galectin-9 on CVB3 induced myocarditis and its possible mechanisms involved. We demonstrated that galectin-9 expression was significantly up-regulated in the myocardium following CVB3 infection and was correlated with the severity of viral myocarditis. To explore whether galectin-9 may have therapeutic effect on the CVB3 induced myocarditis, galectin-9 was administered daily to mice following CVB3 infection. Significantly reduced CD4+ T cells and remarkably increased regulatory T cells frequency in the heart tissue were found as compared to the non-treated mice. It was accompanied by a significant decreased level of Th1 cytokines as TNF-α and IFN-γ both in the myocardium and serum, and an increased level of Th2 cytokines such as IL-4 and IL-10. Galectin-9 was further found to promote the proliferation of regulatory T cells and elevated IL-4-secreting Th2 cells. It may represent as a novel therapeutic strategy in treating Th1-mediated inflammatory cardiac disease. © 2011 Elsevier Inc. Source
Mrizak D.,Lille University of Science and Technology |
Martin N.,Lille University of Science and Technology |
Barjon C.,University Paris - Sud |
Jimenez-Pailhes A.S.,University Paris - Sud |
And 9 more authors.
Journal of the National Cancer Institute | Year: 2015
Background: Regulatory T cells (Treg) and tumor-exosomes are thought to play a role in preventing the rejection of malignant cells in patients bearing nasopharyngeal carcinoma (NPC). Methods: Treg recruitment by exosomes derived from NPC cell lines (C15/C17-Exo), exosomes isolated from NPC patients' plasma (Patient-Exo), and CCL20 were tested in vitro using Boyden chamber assays and in vivo using a xenograft SCID mouse model (n = 5), both in the presence and absence of anti-CCL20 monoclonal antibodies (mAb). Impact of these NPC exosomes (NPC-Exo) on Treg phenotype and function was determined using adapted assays (FACS, Q-PCR, ELISA, and MLR). Experiments were performed in comparison with exosomes derived from plasma of healthy donors (HD-Exo). The Student's t test was used for group comparisons. All statistical tests were two-sided. Results: CCL20 allowed the intratumoral recruitment of human Treg. NPC-Exo also facilitated Treg recruitment (3.30 ± 0.34 fold increase, P <.001), which was statistically significantly inhibited (P <.001) by an anti-CCL20 blocking mAb. NPC-Exo also recruited conventional CD4+CD25-T cells and mediated their conversion into inhibitory CD4+CD25high cells. Moreover, NPC-Exo enhanced (P =.0048) the expansion of human Treg, inducing the generation of Tim3Low Treg with increased expression of CD25 and FOXP3. Finally, NPC-Exo induced an overexpression of cell markers associated with Treg phenotype, properties and recruitment capacity. For example, GZMB mean fold change was 21.45 ± 1.75 (P <.001). These results were consistent with a stronger suppression of responder cells' proliferation and the secretion of immunosuppressive cytokines (IL10, TGFB1). Conclusion: Interactions between NPC-Exo and Treg represent a newly defined mechanism that may be involved in regulating peripheral tolerance by tumors and in supporting immune evasion in human NPC. © The Author 2014. Published by Oxford University Press. Source
Iqbal A.J.,Queen Mary, University of London |
Sampaio A.L.F.,Queen Mary, University of London |
Sampaio A.L.F.,GalPharma Co. |
Maione F.,Queen Mary, University of London |
And 6 more authors.
American Journal of Pathology | Year: 2011
The role of endogenous galectin-1 (Gal-1) in acute inflammation has been poorly investigated. We therefore performed the carrageenan-induced paw edema model in wild-type and Gal-1-/- mice. On subplantar injection of carrageenan, Gal-1-/- mice displayed a similar first phase of edema (≤24 hours) to wild-type mice; however, a much less pronounced second phase (48 to 96 hours) was evident in this genotype. This reduced inflammation was associated with lower paw expression of inflammatory genes and cell infiltrates. Analysis of galectin protein and mRNA expression revealed high expression of Gal-1 in wild-type paws during resolution (≥48 hours), with some expression of galectin-9 (Gal-9). Administration of stable Gal-1 to wild-type mice completely ablated the first phase of edema but was ineffective when administered therapeutically at the 24-hour time point. Conversely, Gal-9 administration did not alter the first phase of edema but significantly reduced the second phase when administered therapeutically. This suggests anti-inflammatory actions for both proteins in this model albeit at different phases of the inflammatory response. Collectively, these data indicate that the absence of endogenous Gal-1 results in an abrogated response during the second phase of the edema reaction. Copyright © 2011 American Society for Investigative Pathology. Published by Elsevier Inc. All rights reserved. Source