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1.  Interleukin-7 Ameliorates Immune Dysfunction and Improves Survival in a 2-Hit Model of Fungal Sepsis 
The Journal of Infectious Diseases  2012;206(4):606-616.
Background. Secondary hospital-acquired fungal infections are common in critically-ill patients and mortality remains high despite antimicrobial therapy. Interleukin-7 (IL-7) is a potent immunotherapeutic agent that improves host immunity and has shown efficacy in bacterial and viral models of infection. This study examined the ability of IL-7, which is currently in multiple clinical trials (including hepatitis and human immunodeficiency virus), to improve survival in a clinically relevant 2-hit model of fungal sepsis.
Methods. Mice underwent cecal ligation and puncture to induce peritonitis. Four days later, surviving mice had intravenous injection with Candida albicans. Following Candida infection, mice were treated with IL-7 or saline control. The effect of IL-7 on host immunity and survival was recorded.
Results. IL-7 ameliorated the loss of immune effector cells and increased lymphocyte functions, including activation, proliferation, expression of adhesion molecules, and interferon-γ production. These beneficial effects of IL-7 were associated with an increase in global immunity as reflected by an enhanced delayed type hypersensitivity response and a 1.7-fold improvement in survival.
Conclusions. The present findings showing that IL-7 improves survival in fungal sepsis, together with its previously reported efficacy in bacterial and viral infectious models, further supports its use as a novel immunotherapeutic in sepsis.
PMCID: PMC3491749  PMID: 22693226
2.  Measuring Copper and Zinc Superoxide Dismutase from Spinal Cord Tissue using Electrospray Mass Spectrometry 
Analytical biochemistry  2011;415(1):52-58.
Metals are key cofactors for many proteins, yet quantifying the metals bound to specific proteins is a persistent challenge in vivo. We have developed a rapid and sensitive method using electrospray ionization mass spectrometry to measure Cu,Zn superoxide dismutase (SOD1) directly from the spinal cord of SOD1-overexpressing transgenic rats. Metal dyshomeostasis has been implicated in motor neuron death in amyotrophic lateral sclerosis (ALS). Using the assay, SOD1 was directly measured from 100 μg of spinal cord, allowing for anatomical quantitation of apo, metal-deficient, and holo SOD1. SOD1 was bound on a C4 ZipTip® that served as a disposable column, removing interference by physiological salts and lipids. SOD1 was eluted with 30% acetonitrile plus 100 μM formic acid to provide sufficient hydrogen ions to ionize the protein without dislodging metals. SOD1 was quantified by including bovine SOD1 as an internal standard. SOD1 could be measured in subpicomole amounts and resolved to within two Daltons of the predicted parent mass. The methods can be adapted to quantify modifications to other proteins in vivo that can be resolved by mass spectrometry.
PMCID: PMC3118564  PMID: 21453670
Metals; Superoxide dismutase; Amyotrophic Lateral Sclerosis; Mass Spectrometry; Copper; Zinc
3.  Effects of Recombinant Human Interleukin 7 on T-Cell Recovery and Thymic Output in HIV-Infected Patients Receiving Antiretroviral Therapy: Results of a Phase I/IIa Randomized, Placebo-Controlled, Multicenter Study 
Interleukin 7 induces a well-tolerated, dose-dependent, and sustained increase of CD4 T cells in human immunodeficiency virus-infected individuals treated with antiretroviral therapy, through an expansion of peripheral T cells that do not express activation markers, and increases thymic output in some patients.
Background. The immune deficiency of human immunodeficiency virus (HIV) infection is not fully corrected with ARV therapy. Interleukin-7 (IL-7) can boost CD4 T-cell counts, but optimal dosing and mechanisms of cellular increases need to be defined.
Methods. We performed a randomized placebo-controlled dose escalation (10, 20 and 30 µg/kg) trial of 3 weekly doses of recombinant human IL-7 (rhIL-7) in ARV-treated HIV-infected persons with CD4 T-cell counts between 101 and 400 cells/µL and plasma HIV levels <50 copies/mL. Toxicity, activity and the impact of rhIL-7 on immune reconstitution were monitored.
Results. Doses of rhIL-7 up to 20 µg/kg were well tolerated. CD4 increases of predominantly naive and central memory T cells were brisk (averaging 323 cells/µL at 12 weeks) and durable (up to 1 year). Increased cell cycling and transient increased bcl-2 expression were noted. Expanded cells did not have the characteristics of regulatory or activated T cells. Transient low-level HIV viremia was seen in 6 of 26 treated patients; modest increases in total levels of intracellular HIV DNA were proportional to CD4 T-cell expansions. IL-7 seemed to increase thymic output and tended to improve the T-cell receptor (TCR) repertoire in persons with low TCR diversity.
Conclusions. Three weekly doses of rhIL-7 at 20 µg/kg are well tolerated and lead to a dose-dependent CD4 T-cell increase and the broadening of TCR diversity in some subjects. These data suggest that this rhIL-7 dose could be advanced in future rhIL-7 clinical studies.
Clinical Trials Registration NCT0047732.
PMCID: PMC3381639  PMID: 22550117
4.  Treatment with IL-7 Prevents the Decline of Circulating CD4+ T Cells during the Acute Phase of SIV Infection in Rhesus Macaques 
PLoS Pathogens  2012;8(4):e1002636.
Although treatment with interleukin-7 (IL-7) was shown to transiently expand the naïve and memory T-cell pools in patients with chronic HIV-1 infection receiving antiretroviral therapy (ART), it is uncertain whether a full immunologic reconstitution can be achieved. Moreover, the effects of IL-7 have never been evaluated during acute HIV-1 (or SIV) infection, a critical phase of the disease in which the most dramatic depletion of CD4+ T cells is believed to occur. In the present study, recombinant, fully glycosylated simian IL-7 (50 µg/kg, s.c., once weekly for 7 weeks) was administered to 6 rhesus macaques throughout the acute phase of infection with a pathogenic SIV strain (mac251); 6 animals were infected at the same time and served as untreated controls. Treatment with IL-7 did not cause clinically detectable side effects and, despite the absence of concomitant ART, did not induce significant increases in the levels of SIV replication except at the earliest time point tested (day 4 post-infection). Strikingly, animals treated with IL-7 were protected from the dramatic decline of circulating naïve and memory CD4+ T cells that occurred in untreated animals. Treatment with IL-7 induced only transient T-cell proliferation, but it was associated with sustained increase in the expression of the anti-apoptotic protein Bcl-2 on both CD4+ and CD8+ T cells, persistent expansion of all circulating CD8+ T-cell subsets, and development of earlier and stronger SIV Tat-specific T-cell responses. However, the beneficial effects of IL-7 were not sustained after treatment interruption. These data demonstrate that IL-7 administration is effective in protecting the CD4+ T-cell pool during the acute phase of SIV infection in macaques, providing a rationale for the clinical evaluation of this cytokine in patients with acute HIV-1 infection.
Author Summary
The development of highly effective cocktails of antiretroviral drugs has had a major impact on the survival and quality of life of individuals with HIV-1 infection. Yet, current protocols often fail to fully restore the immunologic function, a limitation that has prompted the clinical evaluation of immune-reconstitution agents, such as IL-7, as adjuvant therapies. To date, however, IL-7 has been tested exclusively in patients with chronic HIV-1 infection, while it appears that the immune system is irreparably damaged during acute primary infection, within the first few weeks after encountering the virus. We used a macaque model to show that treatment with IL-7 has beneficial effects if implemented during the acute phase of infection with SIV, the simian AIDS virus. Early administration of IL-7 was safe and effectively protected CD4+ T cells, the primary target cells for the virus, from the marked decline that typically occurs during acute SIV infection. Furthermore, IL-7 boosted the development of antiviral immune responses. Thus, IL-7 might be an effective adjuvant therapy in acute HIV-1 infection, which can protect the pool of CD4+ T cells before it is irreversibly compromised by the action of the virus.
PMCID: PMC3325214  PMID: 22511868
5.  Interleukin-7 and immune reconstitution in cancer patients: a new paradigm for dramatically increasing overall survival 
Targeted Oncology  2012;7(1):55-68.
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.
PMCID: PMC3304058  PMID: 22383042
IL-7; Immunotherapy; Cancer; Immune reconstitution
6.  Increased CD4+ T cell levels during IL-7 administration of ART treated SIV+ macaques are not dependent on strong proliferative responses 
CD4+ T cell depletion is a fundamental component of HIV infection and AIDS pathogenesis, and is not always reversed following anti-retroviral therapy (ART). Here the SIV-infected Rhesus macaque model was utilized to assess recombinant simian IL-7 in its glycosylated form (rsIL-7gly) to enhance regeneration of CD4+ T cells, particularly the crucial central memory (CM) compartment, post ART. We assessed the impact of rsIL-7gly administration as single injections and as a cluster of three doses. Irrespective of the dosing strategy utilized, the rsIL-7gly administration transiently increased proliferation of both CM and naïve cells, in both CD4+ and CD8+ subsets without increasing SIV levels in the blood. Administration of rsIL-7gly at intervals of 4-6 weeks maximized the proliferative response to therapy, but resulted in only transient increases in peripheral blood T cell counts. However, more frequent rsIL-7gly ‘clustered’ dosing (weekly × 3, with 2 weeks 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 bromodeoxy-uridine (BrDU) label among memory T cells in the blood when compared to macaques treated with ART alone, consistent with enhanced cell survival. These results indicate that dosing intervals have a major impact on the response to rsIL-7gly in SIV+ ART treated RM, and that optimum dosing strategies may be ones that induce CD4+ T cell proliferation initially and provide increased CD4+ T cell survival.
PMCID: PMC3050806  PMID: 20622118
7.  Interleukin-7 (IL-7) Treatment Accelerates Neutrophil Recruitment through γδ T-Cell IL-17 Production in a Murine Model of Sepsis ▿  
Infection and Immunity  2010;78(11):4714-4722.
The sepsis syndrome represents an improper immune response to infection and is associated with unacceptably high rates of mortality and morbidity. The interactions between T cells and the innate immune system while combating sepsis are poorly understood. In this report, we observed that treatment with the potent, antiapoptotic cytokine interleukin-7 (IL-7) accelerated neutrophil recruitment and improved bacterial clearance. We first determined that T cells were necessary for the previously observed IL-7-mediated enhanced survival. Next, IL-7 increased Bcl-2 expression in T cells isolated from septic mice as early as 3 h following treatment. This treatment resulted in increased gamma interferon (IFN-γ) and IP-10 production within the septic peritoneum together with local and systemic increases of IL-17 in IL-7-treated mice. We further demonstrate that the increase in IL-17 was largely due to increased recruitment and production by γδ T cells, which express CXCR3. Consistent with increased IL-17 production, IL-7 treatment increased CXCL1/KC production, neutrophil recruitment, and bacterial clearance. Significantly, end-organ tissue injury was not significantly different between vehicle- and IL-7-treated mice. Collectively, these data illustrate that IL-7 can mediate the cross talk between Th1 and Th17 lymphocytes during sepsis such that neutrophil recruitment and bacterial clearance is improved while early tissue injury is not increased. All together, these observations may underlay novel potential therapeutic targets to improve the host immune response to sepsis.
PMCID: PMC2976361  PMID: 20823197
8.  Phase I study of recombinant human interleukin-7 administration in subjects with refractory malignancy 
Interleukin-7 has critical and non redundant roles in T-cell development, hematopoiesis and post developmental immune functions as a prototypic homeostatic cytokine. Based on a large body of pre-clinical evidence, it may have multiple therapeutic applications in immunodeficiency states, either physiologic (immuno-senescence), pathologic (HIV) or iatrogenic (post-chemotherapy and post-hematopoietic stem cell transplant) and may have roles in immune reconstitution or enhancement of immunotherapy. We report here on the toxicity and biological activity of recombinant human IL-7 (rhIL-7) in humans.
Subjects with incurable malignancy received rhIL-7 subcutaneously every other day for two weeks, in a phase I, inter-patient dose escalation study (3, 10, 30 & 60 μg/Kg/dose). The objectives were safety and dose-limiting toxicity determination, identification of a range of biologically active doses and characterization of biological and, possibly, anti-tumor effects.
Mild to moderate constitutional symptoms, reversible spleen and lymph node enlargement and marked increase in peripheral CD3+, CD4+, CD8+ lymphocytes were seen in a dose dependent and age independent manner in all subjects receiving 10 μg/Kg/dose or more, resulting in a rejuvenated circulating T cell profile, resembling that seen earlier in life. In some subjects, rhIL-7 induced in the bone marrow a marked, transient polyclonal proliferation of pre B cells showing a spectrum of maturation as well as an increase in circulating transitional B-cells.
This study demonstrates rhIL-7's potent biologic activity in humans, over a well tolerated dose range and allows further exploration of its possible therapeutic applications.
PMCID: PMC2808195  PMID: 20068111
immune reconstitution; immune enhancement; immunotherapy; vaccine; cancer vaccine
9.  IL-7 Promotes T Cell Viability, Trafficking, and Functionality and Improves Survival in Sepsis 
Sepsis is a highly lethal disorder characterized by widespread apoptosis-induced depletion of immune cells and the development of a profound immunosuppressive state. IL-7 is a potent antiapoptotic cytokine that enhances immune effector cell function and is essential for lymphocyte survival. In this study, recombinant human IL-7 (rhIL-7) efficacy and potential mechanisms of action were tested in a murine peritonitis model. Studies at two independent laboratories showed that rhIL-7 markedly improved host survival, blocked apoptosis of CD4 and CD8 T cells, restored IFN-γ production, and improved immune effector cell recruitment to the infected site. Importantly, rhIL-7 also prevented a hallmark of sepsis (i.e., the loss of delayed-type hypersensitivity), which is an IFN-γ– and T cell-dependent response. Mechanistically, rhIL-7 significantly increased the expression of the leukocyte adhesion markers LFA-1 and VLA-4, consistent with its ability to improve leukocyte function and trafficking to the infectious focus. rhIL-7 also increased the expression of CD8. The potent antiapoptotic effect of rhIL-7 was due to increased Bcl-2, as well as to a dramatic decrease in sepsis-induced PUMA, a heretofore unreported effect of IL-7. If additional animal studies support its efficacy in sepsis and if current clinical trials continue to confirm its safety in diverse settings, rhIL-7 should be strongly considered for clinical trials in sepsis.
PMCID: PMC2914630  PMID: 20200277
10.  Enhanced T cell recovery in HIV-1–infected adults through IL-7 treatment 
HIV infection results in CD4+ T cell deficiency, but efficient combination antiretroviral therapy (c-ART) restores T cells and decreases morbidity and mortality. However, immune restoration by c-ART remains variable, and prolonged T cell deficiency remains in a substantial proportion of patients. In a prospective open-label phase I/IIa trial, we evaluated the safety and efficacy of administration of the T cell regulator IL-7. The trial included 13 c-ART–treated HIV-infected patients whose CD4+ cell counts were between 100 and 400 cells/μl and plasma HIV RNA levels were less than 50 copies/ml. Patients received a total of 8 subcutaneous injections of 2 different doses of recombinant human IL-7 (rhIL-7; 3 or 10 μg/kg) 3 times per week over a 16-day period. rhIL-7 was well tolerated and induced a sustained increase of naive and central memory CD4+ and CD8+ T cells. In the highest dose group, 4 patients experienced transient increases in viral replication. However, functional assays showed that the expanded T cells responded to HIV antigen by producing IFN-γ and/or IL-2. In conclusion, in lymphopenic HIV-infected patients, rhIL-7 therapy induced substantial functional and quantitative changes in T cells for 48 weeks. Therefore, patients may benefit from intermittent therapy with IL-7 in combination with c-ART.
PMCID: PMC2662568  PMID: 19287090
11.  Administration of rhIL-7 in humans increases in vivo TCR repertoire diversity by preferential expansion of naive T cell subsets 
The Journal of Experimental Medicine  2008;205(7):1701-1714.
Interleukin-7 (IL-7) is a homeostatic cytokine for resting T cells with increasing serum and tissue levels during T cell depletion. In preclinical studies, IL-7 therapy exerts marked stimulating effects on T cell immune reconstitution in mice and primates. First-in-human clinical studies of recombinant human IL-7 (rhIL-7) provided the opportunity to investigate the effects of IL-7 therapy on lymphocytes in vivo. rhIL-7 induced in vivo T cell cycling, bcl-2 up-regulation, and a sustained increase in peripheral blood CD4+ and CD8+ T cells. This T cell expansion caused a significant broadening of circulating T cell receptor (TCR) repertoire diversity independent of the subjects' age as naive T cells, including recent thymic emigrants (RTEs), expanded preferentially, whereas the proportions of regulatory T (T reg) cells and senescent CD8+ effectors diminished. The resulting composition of the circulating T cell pool more closely resembled that seen earlier in life. This profile, distinctive among cytokines under clinical development, suggests that rhIL-7 therapy could enhance and broaden immune responses, particularly in individuals with limited naive T cells and diminished TCR repertoire diversity, as occurs after physiological (age), pathological (human immunodeficiency virus), or iatrogenic (chemotherapy) lymphocyte depletion.
PMCID: PMC2442646  PMID: 18573906
12.  Polymorphisms of CD14 gene and TLR4 gene are not associated with ulcerative colitis in Chinese patients 
Postgraduate Medical Journal  2005;81(958):526-529.
Background and aims: Toll-like receptor 4 and CD14 are the components of the lipopolysaccharide receptor complex. The aim of this study was to investigate the associations between polymorphisms TLR4 Asp299Gly and CD14 C-260T and Chinese patients with ulcerative colitis (UC).
Methods: Using a polymerase chain reaction based restriction fragment length polymorphism, the study genotyped polymorphisms TLR4 Asp299Gly and CD14 C-260T in 114 patients with UC and 160 healthy controls in the Chinese Han population. Moreover a comparison was made with 170 healthy Dutch white subjects.
Results: No TLR4 Asp299Gly mutation was detected in any patients or healthy controls in the Chinese Han population, which was similar to Japanese subjects, but the mutation occurred in 10% of the Dutch white subjects. There were no significant differences of CD14 genotypes between healthy controls and the patients with UC.
PMCID: PMC1743318  PMID: 16085746
13.  IL-7 Administration to Humans Leads to Expansion of CD8+ and CD4+ Cells but a Relative Decrease of CD4+ T-Regulatory Cells 
Lymphopenia is a serious consequence of HIV infection and the administration of cancer chemotherapeutic agents. Although growth factors can be administered to patients to increase circulating neutrophils, there is no effective method to stimulate CD8+ lymphocyte production in humans, in vivo. This report is the first to describe the administration of recombinant interleukin-7 to humans and demonstrates the ability of this cytokine to mediate selective increases in CD4+ and CD8+ lymphocytes along with a decrease in the percentage of CD4+ T-regulatory cells. These studies suggest an important role for interleukin-7 in the treatment of patients with lymphopenia.
PMCID: PMC1473976  PMID: 16699374
interleukin-7; regulatory T cells; human lymphocytes; lymphopoiesis
14.  Effects of IL-7 on memory CD8+ T cell homeostasis are influenced by the timing of therapy in mice  
The Journal of Clinical Investigation  2008;118(3):1027-1039.
IL-7 is integral to the generation and maintenance of CD8+ T cell memory, and insufficient IL-7 is believed to limit survival and the persistence of memory CD8+ T cells. Here, we show that during the mouse T cell response to lymphocytic choriomeningitis virus, IL-7 enhanced the number of memory CD8+ T cells when its administration was restricted to the contraction phase of the response. Likewise, IL-7 administration during the contraction phase of the mouse T cell response to vaccinia virus or a DNA vaccine potentiated antigen-specific CD8+ memory T cell proliferation and function. Qualitatively, CD8+ T cells from IL-7–treated mice exhibited superior recall responses and improved viral control. IL-7 treatment during the memory phase stimulated a marked increase in the number of memory CD8+ T cells, but the effects were transient. IL-7 therapy during contraction of the secondary CD8+ T cell response also expanded the pool of memory CD8+ T cells. Collectively, our studies show differential effects of IL-7 on memory CD8+ T cell homeostasis and underscore the importance of the timing of IL-7 therapy to effectively improve CD8+ T cell memory and protective immunity. These findings may have implications in the clinical use of IL-7 as an immunotherapeutic agent to bolster vaccine-induced CD8+ T cell memory.
PMCID: PMC2214844  PMID: 18246202
15.  No evidence for involvement of the Toll-like receptor 4 (TLR4) A896G and CD14-C260T polymorphisms in susceptibility to ankylosing spondylitis 
Annals of the Rheumatic Diseases  2005;64(2):235-238.
Objectives: Ankylosing spondylitis (AS) is a multifactorial and polygenic disease. Apart from HLA, other genes very probably play a role in disease susceptibility. Indigenous bacteria of the gastrointestinal flora appear to play a role in the pathogenesis of the disease; therefore, genes controling the innate and acquired immune response are good candidates to study disease susceptibility. CD14 and Toll-like receptor 4 (TLR4) are key receptors for the sensing of bacteria. The CD14 C-260T and TLR4 A896G single nucleotide polymorphims are associated with aberrant signal transduction for bacterial agonists.
Methods: The distribution of the CD14 C-260T and TLR4 A896G polymorphisms was studied in genomic DNA from 113 unrelated white Dutch AS patients and 170 ethnically matched healthy controls. The diagnosis of AS was made according to the modified New York criteria. The CD14 C-260T and TLR4 A896G polymorphisms were genotyped by PCR-RFLP methods.
Results: No significant differences were found between patients and controls in the frequencies of the carriership of the less frequent CD14-260T allele (odds ratio 0.65; 95% confidence interval 0.37 to 1.15) or the TLR4 896G allele (1.68; 0.67 to 4.19).
Conclusions: There is no evidence for involvement of the CD14 C-260T or TLR4 A896G polymorphisms in susceptibility to AS. An important role of bacteria and genetic predisposition of the innate immune system in cases of AS cannot be excluded by these findings. Therefore, studies of the surprisingly highly polymorphic candidate genes in this field should be continued.
PMCID: PMC1755347  PMID: 15647432
18.  Prevalence and determinants of Chlamydia trachomatis infections in women from Bogota, Colombia 
Sexually Transmitted Infections  2003;79(6):474-478.
Objectives: Chlamydia trachomatis infection in the cervix and uterus has been hypothesised to be a co-factor for cervical cancer. We performed a cross sectional study in Bogota, Colombia, where cervical cancer rates are high, to determine the prevalence and determinants of C trachomatis infection, and in particular its association with human papillomavirus (HPV).
Methods: 1829 low income sexually active women were interviewed and tested for C trachomatis, using an endogenous plasmid PCR-EIA, and for 37 HPV types, using a general primer GP5+/6+ mediated PCR-EIA.
Results: The overall prevalence of C trachomatis was 5.0%, and it did not differ substantially between women with normal (5.0%) and those with abnormal (5.2%) cervical cytology. Women infected with any HPV type (15.1%) had a slightly increased risk of being simultaneously infected with C trachomatis (adjusted OR 1.3, 95% CI: 0.8 to 2.4). This association was stronger when multiple HPV infections (adjusted OR 2.5, 95% CI: 1.1 to 5.9) were present. No other lifestyle or reproductive characteristics were clearly associated with risk of C trachomatis infection.
Conclusions: HPV infected women, particularly women with multiple HPV infections, are at increased risk of being infected with C trachomatis.
PMCID: PMC1744784  PMID: 14663124
21.  Recombinant Interleukin-7 Induces Proliferation of Naive Macaque CD4+ and CD8+ T Cells In Vivo 
Journal of Virology  2004;78(18):9740-9749.
Interleukin-7 (IL-7) regulates T-cell homeostasis, and its availability is augmented in lymphopenic hosts. Naive CD8+ T cells transferred to lymphopenic mice acquire a memory-like phenotype, raising the possibility that IL-7 is the biological mediator of this effect. Here, we provide direct evidence that IL-7 induces the acquisition of memory-cell markers not only in CD8+ T cells but also in CD4+ T-cell subsets in immune-competent Indian rhesus macaques. The increase of these memory-like populations was dependent on the dose of the cytokine, and these cells were found in the blood as well as secondary lymphoid organs. Memory-like CD4+ and CD8+ T cells acquired the ability to secrete tumor necrosis factor alpha and, to a lesser extent, gamma interferon following stimulation with a cognate antigen. The phenotypic change observed in naive T cells was promptly reversed after discontinuation of IL-7. Importantly, IL-7 induced cycling of both CD4+ and CD8+ central memory and effector memory T cells, demonstrating its contribution to the maintenance of the entire T-cell pool. Thus, IL-7 may be of benefit in the treatment of iatrogenic or virus-induced T-cell depletion.
PMCID: PMC515001  PMID: 15331707
22.  Notice of Redundancy 
PMCID: PMC1744327  PMID: 11463940
23.  Cost effectiveness analysis of a population based screening programme for asymptomatic Chlamydia trachomatis infections in women by means of home obtained urine specimens 
Sexually Transmitted Infections  2001;77(4):276-282.
Objectives: To evaluate the cost effectiveness of a systematic screening programme for asymptomatic Chlamydia trachomatis infections in a female inner city population. To determine the sensitivity of the cost effectiveness analysis to variation in the probability of developing sequelae.
Methods: A decision tree was constructed to evaluate health effects of the programme, such as averted sequelae of chlamydial infection. Cost effectiveness from a societal perspective was estimated for screening by means of a ligase chain reaction on mailed, home obtained urine specimens, in a population with a C trachomatis test prevalence of 2.9%. An extensive sensitivity analysis was performed for the probability of sequelae, the percentage of preventable pelvic inflammatory disease (PID), and the discount rate.
Results: The estimated net cost of curing one woman, aged 15–40 years, of a C trachomatis infection is US$1210. To prevent one major outcome (PID, tubal factor infertility, ectopic pregnancy, chronic pelvic pain, or neonatal pneumonia), 479 women would have to be screened. The net cost of preventing one major outcome is $15 800. Changing the probability of PID after chlamydial infection from 5% to 25% decreases the net cost per major outcome averted from $28 300 to $6380, a reduction of 78%. Results were less sensitive to variations in estimates for other sequelae. The breakeven prevalence of the programme ranges from 6.4% for the scenario with all probabilities for complications set at the maximum value to a prevalence of 100% for probabilities set at the minimum value.
Conclusions: Systematic screening of all women aged 15–40 years for asymptomatic C trachomatis infections is not cost effective. Although the results of the analyses are sensitive to variation in the assumptions, the costs exceed the benefits, even in the most optimistic scenario.
Key Words: cost effectiveness analysis; Chlamydia trachomatis; screening
PMCID: PMC1744325  PMID: 11463928
24.  Low diagnostic accuracy of selective screening criteria for asymptomatic Chlamydia trachomatis infections in the general population 
Sexually Transmitted Infections  2000;76(5):375-380.
Objectives: To develop and validate selective screening criteria for asymptomatic Chlamydia trachomatis infections in the general population.
Methods: 11 505 people, aged 15–40 years, registered in 16 general practices in Amsterdam were invited to return by mail a home obtained first void urine sample and a questionnaire. Participants were randomly allocated into a development group (75%) or a validation group (25%). C trachomatis infection was determined by the ligase chain reaction. In the development group a set of criteria was identified by means of stepwise logistic regression analysis. The diagnostic accuracy (area under the ROC curve; AUC) and sensitivity, and the corresponding percentage of people selected for screening were calculated. The criteria developed in this study were applied to the validation group.
Results: The prevalence of asymptomatic C trachomatis infections among men was found to be 2.4% (1.7–3.0), and among women 2.8% (2.2–3.4). Screening men, based on Surinam/Antillean origin and painful micturition, yielded an AUC of 0.58 (0.55–0.60). Screening women, based on Surinam/Antillean origin, new sex partner in the previous 2 months, and unmarried/not cohabiting, yielded an AUC of 0.67 (0.65–0.69). Application of the criteria for men to the validation group yielded an AUC of 0.53 (0.48–0.57); by screening 10% of the men, 15% of the cases were detected. The AUC of the criteria for women in the validation group was 0.58 (0.54–0.61); by screening 51% of the women, 63% of the cases were detected.
Conclusion: The prevalence of asymptomatic C trachomatis infections in Amsterdam is less than 3%. No suitable selective screening criteria for the general population could be identified.
Key Words: screening; prevalence; Chlamydia trachomatis
PMCID: PMC1744221  PMID: 11141855
25.  Microorganisms in the aetiology of atherosclerosis 
Journal of Clinical Pathology  2000;53(9):647-654.
Recent publications have suggested that infective pathogens might play an important role in the pathogenesis of atherosclerosis. This review focuses on these microorganisms in the process of atherosclerosis. The results of in vitro studies, animal studies, tissue studies, and serological studies will be summarised, followed by an overall conclusion concerning the strength of the association of the microorganism with the pathogenesis of atherosclerosis. The role of the bacteria Chlamydia pneumoniae and Helicobacter pylori, and the viruses human immunodeficiency virus, coxsackie B virus, cytomegalovirus, Epstein-Barr virus, herpes simplex virus, and measles virus will be discussed.
Key Words: atherosclerosis • Chlamydia pneumoniae • Helicobacter pylori
PMCID: PMC1731245  PMID: 11041053

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