Immunomodulation par l'interleukine-7 au cours des infections par les virus de l'immunodéficience humaine (VIH) et simienne (VIS)

PARIS7-Bibliothèque centrale (751132105) / SudocSudocFranceF

Efficient Thymopoiesis Contributes to the Maintenance of Peripheral CD4 T Cells during Chronic Human Immunodeficiency Virus Type 2 Infection

International audienceHuman immunodeficiency virus type 2 (HIV-2) infection leads to a lifelong asymptomatic period in the majority of patients. Even in patients with progressive disease, a slow CD4 count decline characterizes the chronic phase of HIV-2 infection, suggesting that peripheral T-cell homeostasis is controlled better following HIV-2 infection than following HIV-1 infection. Herein we showed that, in contrast to HIV-1-infected patients, HIV-2-infected patients demonstrate enhanced thymic function compared to age-matched healthy individuals. The correlation between higher thymic production and lower CD4 T-cell loss in these patients suggests that efficient thymopoiesis is implicated in the long-lasting maintenance of CD4 T-cell counts in HIV-2 disease

Efficient Thymopoiesis Contributes to the Maintenance of Peripheral CD4 T Cells during Chronic Human Immunodeficiency Virus Type 2 Infection▿

Human immunodeficiency virus type 2 (HIV-2) infection leads to a lifelong asymptomatic period in the majority of patients. Even in patients with progressive disease, a slow CD4 count decline characterizes the chronic phase of HIV-2 infection, suggesting that peripheral T-cell homeostasis is controlled better following HIV-2 infection than following HIV-1 infection. Herein we showed that, in contrast to HIV-1-infected patients, HIV-2-infected patients demonstrate enhanced thymic function compared to age-matched healthy individuals. The correlation between higher thymic production and lower CD4 T-cell loss in these patients suggests that efficient thymopoiesis is implicated in the long-lasting maintenance of CD4 T-cell counts in HIV-2 disease

Abstract 6532: HFB9-2: a novel Gal-9 neutralizing antibody to reverse immune suppression in the tumor microenvironment [Abstract]

Although monoclonal antibodies targeting immune checkpoints have demonstrated clinical success in a range of tumor types, sustained responses are only observed in a fraction of patients due to primary or secondary resistance to treatment. Recent evidence has implicated the pleiotropic immunosuppressive modulator Galactoside-binding lectin Galectin 9 (Gal-9) as a key factor present in the tumor microenvironment that renders tumors resistant to current immunotherapies. High Gal-9 expression has been reported in different types of cancer including hematological malignancies such as AML and ALL, and multiple solid tumors. We hypothesize that targeting Gal-9 may represent a valuable strategy to overcome resistance and improve clinical response in selected cancer patients. We present a monoclonal antibody, HFB9-2, that specifically binds to human Gal-9 with sub-nanomolar affinity, recognizes recombinant Gal-9 and Gal-9 produced by human tumor cells, and is cross-reactive with mouse and monkey Gal-9 orthologs. HFB9-2 blocks the interaction of Gal-9 with its receptors TIM3 and CD44 in a dose dependent manner. These two receptors have been described to mediate Gal-9-immunosuppressive signals in effector and regulatory T cells. Treatment of human PBMCs from healthy donors with HFB9-2 prevents Gal-9-induced Th1 cell apoptosis and suppresses the expansion of regulatory T cells. A humanized variant of HFB9-2, HFB9-2hz11, was generated and further characterized for its stability and pharmacokinetic profile. HFB9-2hz11 has a favorable developability profile. It demonstrated stability for at least 14 days at 40°C, as well as for several hours at low pH, and following several freeze-thaw cycles. High plasma exposures following a single dose administration to mice were observed. Furthermore, several preclinical in vivo studies are ongoing to demonstrate the efficacy of HFB-2hz11. Gal-9 has been reported to play a dual role in AML as both a self-renewal factor for leukemic stem cells and a suppressor of anti-cancer immunity, suggesting that Gal-9 neutralization represents an attractive therapeutic approach for treatment of AML patients. To explore this hypothesis, we have initiated a predictive biomarker discovery effort, using HiFiBiO's proprietary Drug Intelligent Science (DIS™) platform, using AML primary patient cells and integrating single-cell technology to identify patient subpopulations likely to respond to HFB9-2hz11. Potential novel biomarkers for patient stratification, that could be applied to other tumor indications, will be identified for AML patients. Altogether, the data presented here provide evidence that neutralization of Gal-9 with HFB9-2hz11 blocks key immunosuppressive mechanisms known to limit the efficacy of current immunotherapies and position HFB9-2hz11 as a drug candidate for clinical exploration in AML and other indications

Des transplantations itératives démasquent la contribution de la galectine-9 à la défaillance de l'immunité anti-tumorale dans le modèle murin MB49

International audienceMechanisms of tumor immune escape are quite diverse and require specific approaches for their exploration in syngeneic tumor models. In several human malignancies, galectin-9 (gal-9) is suspected to contribute to the immune escape. However, in contrast with what has been done for the infiltrating cells, the contribution of gal-9 produced by malignant cells has never been demonstrated in an animal model. Therefore, we derived isogenic clones—either positive or negative for gal-9—from the MB49 murine bladder carcinoma cell line. A progressive and consistent reduction of tumor growth was observed when gal-9-KO cells were subjected to serial transplantations into syngeneic mice. In contrast, tumor growth was unaffected during parallel serial transplantations into nude mice, thus linking tumor inhibition to the enhancement of the immune response against gal-9-KO tumors. This stronger immune response was at least in part explained by changing patterns of response to interferon-γ. One consistent change was a more abundant production of CXCL10, a major inflammatory factor whose production is often induced by interferon-γ. Overall, these observations demonstrate for the first time that serial transplantation into syngeneic mice can be a valuable experimental approach for the exploration of novel mechanisms of tumor immune escape.Les mécanismes d'échappement à l'immunité anti-tumorale sont assez divers et nécessitent des approches spécifiques pour être explorés de façon appropriée dans des modèles tumoraux syngéniques. Dans plusieurs affections malignies humaines, on suspecte la galectine-9 (gal-9) de contribuer à l'échappement immunitaire. Cependant, contrairement à ce qui a été fait pour les cellules infiltrantes, la contribution de la gal-9 produite par les cellules malignes n'a jamais été démontrée dans un modèle animal. Par conséquent, nous avons dérivé des clones isogéniques - positifs ou négatifs pour la gal-9 - à partir de la lignée cellulaire de carcinome vésical murin MB49. Une réduction progressive et reproductible de la croissance tumorale a été observée lorsque des cellules MB49 invalidées pour la gal-9 ont fait l'objet de transplantations en série dans des souris syngéniques. En revanche, la croissance tumorale n'a pas été affectée lors de transplantations en série réalisées de façon parallèle chez des souris nu/nu, démontrant ainsi le lien entre l'inhibition de la croissance tumorale et l'amélioration de la réponse immunitaire contre les tumeurs invalidées pour la gal-9. Cette réponse immunitaire plus forte s'expliquait au moins en partie par une modification des modalités de réponse à l'interféron-γ. Le changement le plus constamment observé était une production plus abondante de CXCL10, un facteur inflammatoire majeur dont la production est souvent induite par l'interféron-γ. Dans l'ensemble, ces observations démontrent pour la première fois que la transplantation tumorale itérative chez des souris syngéniques peut être une approche expérimentale précieuse pour l'exploration de nouveaux mécanismes d'échappement à l'immunité anti-tumorale

Modified interferon-α subtypes production and chemokine networks in the thymus during acute simian immunodeficiency virus infection, impact on thymopoiesis

International audienceObjectives: Thymus dysfunction characterizes human/simian immunodeficiency virus (SIV) infections and contributes to physiopathology. However, both the mechanisms involved in thymic dysfunction and its precise timing remain unknown. We here analyzed thymic function during acute SIV infection in rhesus macaques.Design and methods: Rhesus macaques were intravenously infected with SIVmac251 and bled every 2/3 days or necropsied at different early time points postinfection. Naive T-cell counts were followed by flow cytometry and their T-cell receptor excision circle content evaluated by qPCR. Thymic chemokines were quantified by reverse transcription-qPCR and localized by in-situ hybridization in thymuses collected at necropsy. Thymic interferon alpha (IFN-α) subtype production was quantified by reverse transcription-qPCR combined to heteroduplex tracking assay. The effect of thymic IFN-α subtypes was tested on sorted triple negative thymocytes cultured on OP9-hDL1 cells.Results: A reduced intrathymic proliferation history characterizes T cells produced during the first weeks of infection. Moreover, we evidenced a profound alteration of both chemokines and IFN-α subtypes transcriptional patterns in SIV-infected thymuses. Finally, we showed that IFN-α subtypes produced in the infected thymuses inhibit thymocyte proliferation, still preserving their differentiation capacity.Conclusion: Thymopoiesis is deeply impacted from the first days of SIV infection. Reduced thymocyte proliferation - a time-consuming process - together with modified chemokine networks is consistent with thymocyte differentiation speed-up. This may transiently enhance thymic output, thus increasing naive T-cell counts and diversity and the immune competence of the host. Nonetheless, long-lasting modification of thymic physiology may lead to thymic exhaustion, as observed in late primary HIV infection

IL-7 induces immunological improvement in SIV-infected rhesus macaques under antiviral therapy.

International audienceDespite efficient antiretroviral therapy (ART), CD4+ T cell counts often remain low in HIV-1-infected patients. This has led to IL-7, a crucial cytokine involved in both thymopoiesis and peripheral T cell homeostasis, being suggested as an additional therapeutic strategy. We investigated whether recombinant simian IL-7-treatment enhanced the T cell renewal initiated by ART in rhesus macaques chronically infected with SIVmac251. Six macaques in the early chronic phase of SIV infection received antiretroviral treatment. Four macaques also received a 3-wk course of IL-7 injections. Viral load was unaffected by IL-7 treatment. IL-7 treatment increased the number of circulating CD4+ and CD8+ memory T cells expressing activation (HLA-DR+, CD25+) and proliferation (Ki-67+) markers. It also increased naive (CD45RAbrightCD62L+) T cell counts by peripheral proliferation and enhanced de novo thymic production. The studied parameters returned to pretreatment values by day 29 after the initiation of treatment, concomitantly to the appearance of anti-IL-7 neutralizing Abs, supporting the need for a nonimmunogenic molecule for human treatment. Thus, IL-7, which increases T cell memory and de novo renewal of naive T cells may have additional benefits in HIV-infected patients receiving ART

Interleukin-7 treatment counteracts IFN-α therapy-induced lymphopenia and stimulates SIV-specific cytotoxic T lymphocyte responses in SIV-infected rhesus macaques

International audienceInterferon-α (IFN-α)-based therapy is presently the standard treatment for hepatitis C virus (HCV)-infected patients. Despite good effectiveness, this cytokine is associated with major side effects, including significant lymphopenia, that limits its use for HIV/HCV-coinfected patients. Interleukin-7 (IL-7) has recently shown therapeutic potential and safety in several clinical trials designed to demonstrate T-cell restoration in immunodeficient patients. The purpose of this study was to evaluate, in simian immunodeficiency virus-infected rhesus macaques, the relevance of IL-7 therapy as a means to overcoming IFN-α-induced lymphopenia. We showed that low-dose IFN-α treatment induced strong lymphopenia in chronically infected monkeys. In contrast, high-dose IFN-α treatment stimulated IL-7 production, leading to increased circulating T-cell counts. Moreover, IL-7 therapy more than abrogated the lymphopenic effect of low-dose IFN-α. Indeed, the association of both cytokines resulted in increased circulating T-cell counts, in particular in the naive compartments, as a consequence of central and peripheral homeostatic functions of the IL-7. Finally, reduced PD-1 expression by memory CD8(+) T cells and transient T-cell repertoire diversification were observed under IL-7 therapy. Our data strongly suggest that IL-7 immunotherapy will be of substantial benefit in the treatment of HIV/HCV coinfection and should enhance the likelihood of HCV eradication in poorly responding patients