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T cell growth factor [keywords]
- Dose-finding/phase II trial: bevacizumab, immunotherapy, and chemotherapy (BIC) in metastatic renal cell cancer (mRCC). Antitumor effects and variations of circulating T regulatory cells (Treg). [JOURNAL ARTICLE]
- Target Oncol 2014 Sep 19.
The aim of this study was to explore the efficacy and toxicities of a combined regimen of bevacizumab plus immunotherapy and chemotherapy (BIC) and the circulating T regulatory cells (Treg) in metastatic renal cell cancer (mRCC). Nephrectomized mRCC patients were enrolled into a multicenter single-arm dose-finding study with five escalated dose levels of chemotherapy with intravenous gemcitabine and 5-fluorouracil associated with fixed intravenous doses of bevacizumab, subcutaneous low doses of interleukin-2, and interferon-α-2a. An expanded cohort (phase II study) was treated at the recommended dose for additional safety and efficacy information according to minimax Simon two-stage design. Blood samples for Treg were collected and evaluated by fluorescence-activated cell sorting (FACS) analysis on cycle 1. Fifty-one patients were entered to receive one of five dose levels. Median age was 58 years (male 67 %, pretreated 49 %): 15 patients were low risk according to Memorial Sloan-Kettering Cancer Center (MSKCC) criteria, while 27 and nine were respectively intermediate- and high-risk patients. More frequent grade 3 and 4 toxicities included nonfebrile neutropenia, thrombocytopenia, and fever. Among patients evaluable for response (49), 29.5 % had partial response and 37 % stable disease. Overall median time to progression and median overall survival were 8.8 and 22.67 months, respectively. We observed a rapid increase in the percentage of Treg after immunotherapy and a reduction after bevacizumab only in patient who obtained a partial response or stable disease. The BIC was feasible, well tolerated, and shown interesting activity. Further studies are needed to explore if Treg could have a role in clinical response in mRCC treated with bevacizumab.
- Successful treatment with Ipilimumab and Interleukin-2 in two patients with metastatic melanoma and systemic autoimmune disease. [JOURNAL ARTICLE]
- Cancer Immunol Immunother 2014 Sep 17.
Two patients were treated with immunotherapy for metastatic malignant melanoma (MM) despite suffering from systemic autoimmune disease, i.e., ulcerative colitis (UC) and Behcets disease (BD), respectively. Both patients benefitted from the treatment. The patient with UC achieved partial remission of all measurable parameters after treatment with Ipilimumab, while the patient with BD achieved a complete remission of MM after treatment with Interleukin-2 (IL-2) and Interferon-α (IFN-α). Moreover, no aggravation of symptoms related to the autoimmune diseases was seen during treatment, in contrast, clinical indications of improvement were observed. These two cases illustrate that the presence of autoimmune disease does not necessarily predict increased autoimmune toxicity in connection with immunotherapy. They also raise the question of whether autoimmune disease should continue to be an absolute exclusion criterion for treatment of MM with immunotherapy. Consequently, given the poor prognosis of refractory MM, immunotherapies need to be taken into consideration even in cases of autoimmune comorbidity due to the potential long-term benefit that these therapies offer to MM patients.
- Immune Changes and Dysphoric Moods Across the Postpartum. [JOURNAL ARTICLE]
- Am J Reprod Immunol 2014 Sep 17.
Little is known about postpartum immune recovery and relationships of common dysphoric moods, stress, immunology, and endocrinology.Healthy women (n = 72) were followed for six postpartum months with immune and hormone measures and dysphoric moods and stress scales. A panel of cytokines produced in mitogen-stimulated whole blood assays were measured at each time, along with plasma levels of hsC-reactive protein (hsCRP), Interleukin-6 (IL-6), and a panel of hormones.Cellular immunity, measured by production of Interferon-gamma (IFNγ) and (Interleukin-2 (IL-2) from stimulated whole blood culture, was low in the early postpartum with changes by 3 months. Tumor necrosis factor alpha (TNFα) showed a similar pattern. Plasma levels of CRP and Interleukin-6 (IL-6) showed higher levels in the early postpartum. Mood disturbance scores dropped across the postpartum with a change in slope at 3 months. No significant relationships were found between immune, endocrine, and psychosocial measures.Return to normal cellular immune function may take 3-4 months in the postpartum. Some aspects of early immunology (hsCRP and IL-6) probably reflect the latter stage of pregnancy, the stress of birth and the inflammation associated with involution. Dysphoric moods are higher in the early postpartum but are not related to immune factors or hormones.
- Sy35-2dorsal striatal indirect pathway regulates the performance of auditory conditional discrimination. [Journal Article]
- Alcohol Alcohol 2014 Sep.:i30.
The dorsal striatum, which contains the dorsolateral striatum (DLS) and dorsomedial striatum (DMS), is known to be involved in the performance of discrimination learning. The dorsal striatum regulates the basal ganglia circuitry through direct and indirect pathways. However the mechanism by which the striatopallidal pathway regulates the learning processes of discriminative actions remains unclear. To induce selective elimination of the striatopallidal pathway by injecting the recombinant immunotoxin into the DLS or DMS, we used transgenic rats that expressed human interleukin-2 receptor alpha-subunit under the control of dopamine D2 receptor gene promoter. Intrastriatal immunotoxin treatment induced a selective elimination of the striatopallidal neurons while persisting normally the number of other striatal neuronal types. Ablation of the DLS- or DMS-derived striatopallidal pathway transiently impaired the performance of conditional discrimination, showing a marked reduction in the selection accuracy of learned motor responses. In addition, the probability of perseverative errors was significantly increased in the animals lacking the striatopallidal pathway from the DMS, but not from the DLS. Although there is a distinct role in modulating perseverative behavior between the DLS- and DMS-derived striatopallidal pathways, these two pathways are necessary for controlling the accuracy of response selection.
- CD8αα(+) Innate-Type Lymphocytes in the Intestinal Epithelium Mediate Mucosal Immunity. [Journal Article]
- Immunity 2014 Sep 18; 41(3):451-64.
Innate immune responses are critical for mucosal immunity. Here we describe an innate lymphocyte population, iCD8α cells, characterized by expression of CD8α homodimers. iCD8α cells exhibit innate functional characteristics such as the capacity to engulf and kill bacteria. Development of iCD8α cells depends on expression of interleukin-2 receptor γ chain (IL-2Rγc), IL-15, and the major histocompatibility complex (MHC) class Ib protein H2-T3, also known as the thymus leukemia antigen or TL. While lineage tracking experiments indicated that iCD8α cells have a lymphoid origin, their development was independent of the transcriptional suppressor Id2, suggesting that these cells do not belong to the family of innate lymphoid cells. Finally, we identified cells with a similar phenotype in humans, which were profoundly depleted in newborns with necrotizing enterocolitis. These findings suggest a critical role of iCD8α cells in immune responses associated with the intestinal epithelium.
- Interleukin-2 drives immature double negative thymocytes into γδ T cells expressing Foxp3 on a stromal cell line in vitro. [JOURNAL ARTICLE]
- Biochem Biophys Res Commun 2014 Sep 9.
γδ T cells are exported from the thymus as innate-like lymphocytes that can immediately respond to antigens. In the thymus, γδ T cells diverge into functionally distinct lineages. It is not known whether γδ T cells differentiate into regulatory cells that express Foxp3, which is an essential transcription factor for CD4(+) regulatory T cells. In this study, we analyzed CD25(+) immature thymocytes that give rise to both αβ and γδ thymocytes. These precursor cells have the potential to differentiate into Foxp3(+) γδ T cells on a stromal cell line, TSt4-Dll1. Development of Foxp3(+) γδ thymocytes in this culture was dependent on IL-2. IL-2 stimulation induced Id3, Egr1, and Egr3 expression in CD25(+) immature thymocytes, suggesting that it could activate signaling molecules that are downstream of TCR signaling. The induction of Foxp3 in precursor γδ T cells suggested that IL-2 could activate the Foxp3 gene early in thymocyte development.
- Immunomodulatory role of high-density lipoproteins: impact on immunosenescence. [Journal Article]
- Age (Dordr) 2014 Oct; 36(5):9712.
Natural aging is accompanied by a dysregulation of the host immune response that has well-known clinical consequences but poorly defined underlying causes. It has previously been reported that advancing age is associated with an increase in membrane cholesterol level in T cells. The aim of this study was to investigate whether high-density lipoprotein (HDL) can modulate the age-related accumulation of membrane cholesterol in T cells and impact on their subsequent responsiveness. Our data reveal that cholesterol metabolism, influx, and efflux are altered in T cells with aging, which may in part explain the increase in membrane cholesterol level observed in T cells in elderly individuals. HDL was unable to promote reverse cholesterol transport in T cells from elderly subjects with the same efficiency as was observed in T cells from young subjects besides unchanged ABCA-1 and SR-BI expressions. HDL exhibited a short-acting co-stimulatory effect by enhancing T cell production of interleukin-2 (IL-2). Moreover, HDL from healthy normolipemic individuals exerted differential effects on T cell proliferation that depended on the age of the HDL donor. Finally, HDL modulated TCR/CD28 activation by inducing sustained signaling through pLck, pERK, and pAkt. These data suggest that HDL has immunomodulatory effects on T cells that are influenced by age.
- Population Pharmacokinetics of Daclizumab High-Yield Process in Healthy Volunteers: Integrated Analysis of Intravenous and Subcutaneous, Single- and Multiple-Dose Administration. [JOURNAL ARTICLE]
- Clin Pharmacokinet 2014 Sep 12.
Daclizumab is a humanized monoclonal antibody that blocks the α-subunit of the interleukin-2 receptor with demonstrated benefits in the treatment of multiple sclerosis. The present work aimed to characterize the pharmacokinetics of daclizumab high-yield process (HYP) in healthy volunteers.Three double-blind, randomized, placebo-controlled, phase I studies evaluated the pharmacokinetics of daclizumab HYP in healthy volunteers following single subcutaneous administration (50, 150, or 300 mg), multiple subcutaneous administrations (100 or 200 mg biweekly with a 200 mg loading dose), or single intravenous administration (200 or 400 mg). Measurable serum concentrations (n = 925) from 70 subjects treated with daclizumab HYP in the three studies were analyzed using non-linear mixed-effects modeling.A two-compartment model with a first-order absorption and elimination adequately described daclizumab HYP pharmacokinetics. Daclizumab HYP clearance, inter-compartmental clearance, and central and peripheral volumes of distribution were 10 mL/h, 44 mL/h, 3.89 L, and 2.52 L, respectively, scaled by [bodyweight (kg)/70] with 0.54 and 0.64 exponents for clearance and volume parameters, respectively. Lag-time, mean absorption time, and absolute bioavailability (100-300 mg) for subcutaneous administration were 2 h, 4.6 days, and 84 %, respectively. Bodyweight explained only ~20 % of daclizumab HYP pharmacokinetic variability. With this limited dataset, sex, age, race, or presence of antibodies did not correlate with daclizumab HYP clearance. The estimated effective half-life was 21-25 days. The developed model was robust in bootstrap evaluation and predicted the data adequately in stochastic simulations.Daclizumab HYP is characterized by slow clearance, linear pharmacokinetics (at doses ≥100 mg), high subcutaneous bioavailability, and a half-life suitable for monthly administration.
- Tuberculosis distorts the inhibitory impact of interleukin-10 in HIV infection. [JOURNAL ARTICLE]
- AIDS 2014 Sep 10.
This study aimed to assess how Mycobacterium tuberculosis (MTB) coinfection alters the impact of interleukin-10 in chronic HIV infection.We assessed plasma cytokine levels (interleukin-10, interferon-γ, tumor necrosis factor-α, interleukin-2, interleukin-6 and interleukin-13) in 82 individuals presenting with HIV monoinfection, HIV-LTBI (latent MTB infection) coinfection or HIV-TB (active tuberculosis) coinfection. We also assessed the influence of MTB on the functional impact of interleukin-10 receptor alpha (interleukin-10Rα) blockade on HIV and MTB-specific CD4 T cells.Plasma cytokine levels were measured by high sensitivity Luminex. We used an ex-vivo interleukin-10Rα blockade assay to assess if functional enhancement of HIV and MTB-specific CD4 T cells was possible following a 48-h stimulation with HIV gag or pooled ESAT-6 (6 kDa early secretory antigenic target) and CFP-10 (10-kDa culture filtrate protein) peptides. Cell supernatant was collected 48 h after stimulation and the cytokine profile was measured by Luminex.Plasma interleukin-10 levels were elevated in HIV-TB as compared with HIV monoinfection (P < 0.05) and HIV-LTBI (P < 0.05). Plasma interleukin-10 levels correlated to HIV viral load in HIV monoinfection (P = 0.016) and HIV-LTBI (P = 0.042), but not HIV-TB. Ex-vivo blockade of interleukin-10Rα significantly enhanced MTB and HIV-specific CD4 T-cell function in HIV-LTBI individuals but not in HIV-TB individuals.Tuberculosis disrupts the correlation between interleukin-10 and markers of HIV disease progression. In addition, HIV-TB is associated with a more inflammatory cytokine milieu compared with HIV monoinfection. Interestingly, interleukin-10Rα blockade can enhance both HIV and MTB-specific T-cell function in HIV-LTBI, but not in HIV-TB coinfection.
- Human thymus medullary epithelial cells promote regulatory T-cell generation by stimulating interleukin-2 production via ICOS ligand. [Journal Article]
- Cell Death Dis 2014.:e1420.
Natural thymic T regulatory (tTreg) cells maintain tolerance to self-antigen. These cells are generated in the thymus, but how this generation occurs is still controversial. Furthermore, the contribution of thymus epithelial cells to this process is still unclear, especially in humans. Using an exceptional panel of human thymic samples, we demonstrated that medullary thymus epithelial cells (mTECs) promote the generation of tTreg cells and favor their function. These effects were mediated through soluble factors and were mTEC specific since other cell types had no such effect. By evaluating the effects of mTECs on the absolute number of Treg cells and their state of proliferation or cell death, we conclude that mTECs promote the proliferation of newly generated CD25+ cells from CD4+CD25- cells and protect Treg cells from cell death. This observation implicates Bcl-2 and mitochondrial membrane potential changes, indicating that the intrinsic cell death pathway is involved in Treg protection by mTECs. Interestingly, when the mTECs were cultured directly with purified Treg cells, they were able to promote their phenotype but not their expansion, suggesting that CD4+CD25- cells have a role in the expansion process. To explore the mechanisms involved, several neutralizing antibodies were tested. The effects of mTECs on Treg cells were essentially due to interleukin (IL)-2 overproduction by thymus CD4+ T cells. We then searched for a soluble factor produced by mTECs able to increase IL-2 production by CD4+ cells and could identify the inducible T-cell costimulator ligand (ICOSL). Our data strongly suggest a « ménage à trois »: mTEC cells (via ICOSL) induce overproduction of IL-2 by CD25- T cells leading to the expansion of tTreg cells. Altogether, these results demonstrate for the first time a role of mTECs in promoting Treg cell expansion in the human thymus and implicate IL-2 and ICOSL in this process.