Issy-les-Moulineaux, France
Issy-les-Moulineaux, France

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Janot-Sardet C.,Cytheris S.A. | Assouline B.,Cytheris S.A. | Cheynier R.,Institute Pasteur Paris | Morre M.,Cytheris S.A. | Beq S.,Cytheris S.A.
Journal of Immunological Methods | Year: 2010

IL-7 is a crucial cytokine for T cell hematopoiesis and peripheral homeostasis which by signaling through its receptor alpha chain (CD127) is essential for inducing T cell proliferation and survival. Since the specific CD127 alpha chain is found in a soluble state (sCD127) and at a high level in plasma (ng/mL), it is important to develop a sensitive and reliable assay in order to investigate the potential role of this receptor in the regulation of IL-7 physiologic, physipathologic and therapeutic effects. We here report a fully validated method to measure sCD127 in human and simian plasma using a method based on ELISA MSD technology. We demonstrate that sCD127 is detectable at various levels in the plasma of healthy humans as well as in that of healthy Rhesus and Cynomolgus macaques (106.72, 205.26 and 366.95 ng/mL respectively). Moreover, as opposed to the sCD25/IL-2 tandem, we demonstrate that IL-7 treatment has no impact on sCD127 plasma concentration in patients infected by HIV. © 2009 Elsevier B.V.


Although great effort is being expended in the development of cancer immunotherapies, it is surprising that global lymphopenia and its various dimensions are not being systematically assessed in cancer patients. The incident pathologies associated with various immunosuppressed conditions such as those found in HIV infection have taught us that measuring various T cell populations including CD4 provides the clinician with a reliable measure for gauging the risk of cancer and opportunistic infections. Importantly, recent data emphasize the key link between lymphocyte T cell counts and overall survival in cancer patients receiving chemotherapy. Treatment of immunocompromised patients with interleukin-7 (IL-7), a critical growth and homeostatic factor for T cells, has been shown to produce a compelling profile of T cell reconstitution. The clinical results of this investigational therapy confirm data obtained from numerous preclinical studies and demonstrate the long-term stability of this immune reconstitution, not only on CD4 but also on CD8 T cells, involving recent thymic emigrants as well as naive, memory, and central memory T cells. Furthermore, IL-7 therapy also contributes to restoration of a broadened diversity of the T cell repertoire as well as to migration of these cells to lymph nodes and tissues. All these properties support the initiation of new clinical studies aimed at reconstituting the immune system of cancer patients before or immediately after chemotherapy in order to demonstrate a potentially profound increase in overall survival. © The Author(s) 2012.


Parker R.,Institute Pasteur Paris | Dutrieux J.,Institute Pasteur Paris | Beq S.,Institute Pasteur Paris | Beq S.,Cytheris SA | And 11 more authors.
Blood | Year: 2010

Interferon-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. © 2010 by The American Society of Hematology.


Fabre-Mersseman V.,Institute Cochin | Fabre-Mersseman V.,French Institute of Health and Medical Research | Fabre-Mersseman V.,French National Center for Scientific Research | Fabre-Mersseman V.,University of Paris Descartes | And 20 more authors.
AIDS | Year: 2011

Objective: The contribution of naive CD4+T cells to the pool of HIV-infected cells remains poorly described. This study aimed at evaluating HIV infection in naive T-cell subsets in viremic and HAART-treated patients, together with various parameters implicated in naive T-cell homeostasis, in order to better understand infection in these subsets. DESIGN AND METHODS:: HIV provirus was quantified in various FACS-sorted CD4/CD8 T-cell subsets [recent thymic emigrants (RTEs), non-RTE naives and memory T cells] purified from peripheral blood cells of untreated viremic and HAART-treated aviremic HIV-infected patients. HIV proviral DNA was quantified using a highly sensitive real-time PCR assay allowing detection of one HIV copy in 10 cells. Intrathymic precursor T-cell proliferation and circulating T-cell cycling were, respectively, evaluated through measurement of the sj/βTREC ratio (signal joint T-Cell Receptor Excision Circle frequency divided by DβJβTREC frequency) and Ki-67 expression. Plasma interleukin (IL)-7 concentrations were measured by ELISA. Results: RTEs and non-RTEs were equally HIV infected. Altogether, naive CD4 T cells represented 0.24%-60% of the infected cells. In contrast, HIV DNA was undetectable in naive CD8 T cells. RTE infection rate directly correlated with IL-7 plasma levels (r = 0.607, P = 0.0035) but was independent from plasma viral load, peripheral T-cell cycling and intrathymic precursor T-cell proliferation. Conclusion: We demonstrated that RTEs are effectively HIV infected. The similar infection rate observed in RTEs and other naive T cells, its relationship with plasma IL-7 levels, together with the lack of correlation between RTE infection and either thymic or peripheral proliferation, strongly suggests that RTE infection occurs either late during thymopoiesis or early on during their extrathymic maturation. © 2011 Wolters Kluwer Health - Lippincott Williams & Wilkins.


Alstadhaug K.B.,Nordland Hospital Trust | Alstadhaug K.B.,University of Tromsø | Croughs T.,Cytheris SA | Henriksen S.,University of Tromsø | And 4 more authors.
JAMA Neurology | Year: 2014

IMPORTANCE: No reliable treatment options are known for progressive multifocal leukoencephalopathy with underlying immunodeficiency. We describe successful compassionate use of recombinant human interleukin 7 in a patient with idiopathic CD4+ T-cell lymphocytopenia. OBSERVATIONS: After the diagnoses of progressive multifocal leukoencephalopathy and idiopathic CD4 + T-cell lymphocytopenia were established, a 61-year-old man was treated with recombinant human interleukin 7 on November 1, 2012. Except for an episode of epilepsia partialis continua on January 16, 2013, a gradual clinical improvement was observed until March. Abnormalities shown on magnetic resonance imaging regressed; JC virus DNA in plasma, likely originating from the brain based on sequencing data, cleared; and increases in peripheral CD4+ T cells and JC virus intrathecal antibodies were observed. One year after treatment, the CD4+ T-cell count returned to baseline and the clinical improvement waned, possibly due to the patient's complex epilepsy. On the latest evaluation on January 14, 2014, the patient's condition was unchanged, with no signs of ongoing central nervous system infection. CONCLUSIONS AND RELEVANCE: The present case argues strongly for proof of the treatment concept. However, deeper insight into the JC virus and its pathogenesis and the immune response during central nervous system infection as well as further clinical studies are needed before recombinant human interleukin 7 can be recommended for the treatment of other cases of immunodeficiency and progressive multifocal leukoencephalopathy. Copyright 2014 American Medical Association. All rights reserved.


Leone A.,Seattle Biomedical Research Institute | Rohankhedkar M.,Oregon Health And Science University | Okoye A.,Oregon Health And Science University | Legasse A.,Oregon Health And Science University | And 8 more authors.
Journal of Immunology | Year: 2010

CD4+ T cell depletion is a fundamental component of HIV infection and AIDS pathogenesis and is not always reversed following antiretroviral therapy (ART). In this study, the SIV-infected rhesus macaque model was used to assess recombinant simian IL-7 in its glycosylated form (rsIL-7gly) to enhance regeneration of CD4+ T cells, particularly the crucial central memory compartment, after ART. We assessed the impact of rsIL-7gly administration as single injections and as a cluster of three doses. Irrespective of the dosing strategy used, the rsIL-7gly administration transiently increased proliferation of both central memory and naive cells, in both CD4+ and CD8+ subsets, without increasing SIV levels in the blood. Administration of rsIL-7gly at intervals of 4-6 wk maximized the proliferative response to therapy but resulted in only transient increases in peripheral blood T cell counts. Although more frequent rsIL-7gly "clustered" dosing (three times weekly with 2 wk of rest and then repeat) induced only an initial proliferative burst by CD4+ T cells, this dosing strategy resulted in sustained increases in peripheral blood CD4+ T cell counts. The clustered rsIL-7gly treatment regimen was shown to increase the half-life of a BrdU label among memory T cells in the blood when compared with that of macaques treated with ART alone, which is consistent with enhanced cell survival. These results indicate that dosing intervals have a major impact on the response to rsIL-7gly in SIV-positive ART-treated rhesus macaques and that optimum dosing strategies may be ones that induce CD4+ T cell proliferation initially and provide increased CD4+ T cell survival.


Ruan S.,Louisiana State University Health Sciences Center | Samuelson D.R.,Louisiana State University Health Sciences Center | Assouline B.,Cytheris SA | Morre M.,Cytheris SA | Shellito J.E.,Louisiana State University Health Sciences Center
Infection and Immunity | Year: 2015

Pneumocystis pneumonia (PCP) is a major cause of morbidity and mortality in patients with HIV infection. CD4+ T lymphocytes are critical for host defense against this infection, but in the absence of CD4+ T lymphocytes, CD8+ T lymphocytes may provide limited host defense. The cytokine interleukin-7 (IL-7) functions to enhance lymphocyte proliferation, survival, and recruitment of immune cells to sites of infection. However, there is little known about the role of IL-7 in PCP or its potential use as an immunotherapeutic agent. We hypothesized that treatment with recombinant human IL-7 (rhIL-7) would augment host defense against Pneumocystis and accelerate pathogen clearance in CD4-depleted mice. Control and CD4-depleted mice were infected with Pneumocystis, and rhIL-7 was administered via intraperitoneal injection. Our studies indicate that endogenous murine IL-7 is part of the normal host response to Pneumocystis murina and that administration of rhIL-7 markedly enhanced clearance of Pneumocystis in CD4-depleted mice. Additionally, we observed increased recruitment of CD8+ T lymphocytes to the lungs and decreased apoptosis of pulmonary CD8+ T lymphocytes in rhIL-7-treated animals compared to those in untreated mice. The antiapoptotic effect of rhIL-7 was associated with increased levels of Bcl-2 protein in T lymphocytes. rhIL-7 immunotherapy in CD4-depleted mice also increased the number of gamma interferon (IFN-γ)-positive CD8+ central memory T lymphocytes in the lungs. We conclude that rhIL-7 has a potent therapeutic effect in the treatment of murine Pneumocystis pneumonia in CD4-depleted mice. This therapeutic effect is mediated through enhanced recruitment of CD8+ T cells and decreased apoptosis of lung T lymphocytes, with a preferential action on central memory CD8+ T lymphocytes. © 2015, American Society for Microbiology.


PubMed | Cytheris SA, University of Basel, University of Tromsø and National Institute of Allergy and Infectious Diseases
Type: Case Reports | Journal: JAMA neurology | Year: 2014

No reliable treatment options are known for progressive multifocal leukoencephalopathy with underlying immunodeficiency. We describe successful compassionate use of recombinant human interleukin 7 in a patient with idiopathic CD4+ T-cell lymphocytopenia.After the diagnoses of progressive multifocal leukoencephalopathy and idiopathic CD4+ T-cell lymphocytopenia were established, a 61-year-old man was treated with recombinant human interleukin 7 on November 1, 2012. Except for an episode of epilepsia partialis continua on January 16, 2013, a gradual clinical improvement was observed until March. Abnormalities shown on magnetic resonance imaging regressed; JC virus DNA in plasma, likely originating from the brain based on sequencing data, cleared; and increases in peripheral CD4+ T cells and JC virus intrathecal antibodies were observed. One year after treatment, the CD4+ T-cell count returned to baseline and the clinical improvement waned, possibly due to the patients complex epilepsy. On the latest evaluation on January 14, 2014, the patients condition was unchanged, with no signs of ongoing central nervous system infection.The present case argues strongly for proof of the treatment concept. However, deeper insight into the JC virus and its pathogenesis and the immune response during central nervous system infection as well as further clinical studies are needed before recombinant human interleukin 7 can be recommended for the treatment of other cases of immunodeficiency and progressive multifocal leukoencephalopathy.


PubMed | Cytheris SA and Louisiana State University Health Sciences Center
Type: Journal Article | Journal: Infection and immunity | Year: 2015

Pneumocystis pneumonia (PCP) is a major cause of morbidity and mortality in patients with HIV infection. CD4(+) T lymphocytes are critical for host defense against this infection, but in the absence of CD4(+) T lymphocytes, CD8(+) T lymphocytes may provide limited host defense. The cytokine interleukin-7 (IL-7) functions to enhance lymphocyte proliferation, survival, and recruitment of immune cells to sites of infection. However, there is little known about the role of IL-7 in PCP or its potential use as an immunotherapeutic agent. We hypothesized that treatment with recombinant human IL-7 (rhIL-7) would augment host defense against Pneumocystis and accelerate pathogen clearance in CD4-depleted mice. Control and CD4-depleted mice were infected with Pneumocystis, and rhIL-7 was administered via intraperitoneal injection. Our studies indicate that endogenous murine IL-7 is part of the normal host response to Pneumocystis murina and that administration of rhIL-7 markedly enhanced clearance of Pneumocystis in CD4-depleted mice. Additionally, we observed increased recruitment of CD8(+) T lymphocytes to the lungs and decreased apoptosis of pulmonary CD8(+) T lymphocytes in rhIL-7-treated animals compared to those in untreated mice. The antiapoptotic effect of rhIL-7 was associated with increased levels of Bcl-2 protein in T lymphocytes. rhIL-7 immunotherapy in CD4-depleted mice also increased the number of gamma interferon (IFN-)-positive CD8(+) central memory T lymphocytes in the lungs. We conclude that rhIL-7 has a potent therapeutic effect in the treatment of murine Pneumocystis pneumonia in CD4-depleted mice. This therapeutic effect is mediated through enhanced recruitment of CD8(+) T cells and decreased apoptosis of lung T lymphocytes, with a preferential action on central memory CD8(+) T lymphocytes.


PubMed | Cytheris S.A.
Type: Journal Article | Journal: Targeted oncology | Year: 2012

Although great effort is being expended in the development of cancer immunotherapies, it is surprising that global lymphopenia and its various dimensions are not being systematically assessed in cancer patients. The incident pathologies associated with various immunosuppressed conditions such as those found in HIV infection have taught us that measuring various T cell populations including CD4 provides the clinician with a reliable measure for gauging the risk of cancer and opportunistic infections. Importantly, recent data emphasize the key link between lymphocyte T cell counts and overall survival in cancer patients receiving chemotherapy. Treatment of immunocompromised patients with interleukin-7 (IL-7), a critical growth and homeostatic factor for T cells, has been shown to produce a compelling profile of T cell reconstitution. The clinical results of this investigational therapy confirm data obtained from numerous preclinical studies and demonstrate the long-term stability of this immune reconstitution, not only on CD4 but also on CD8 T cells, involving recent thymic emigrants as well as naive, memory, and central memory T cells. Furthermore, IL-7 therapy also contributes to restoration of a broadened diversity of the T cell repertoire as well as to migration of these cells to lymph nodes and tissues. All these properties support the initiation of new clinical studies aimed at reconstituting the immune system of cancer patients before or immediately after chemotherapy in order to demonstrate a potentially profound increase in overall survival.

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