At times, MRI was performed in combination with [18F]fluorodeoxyglucose (FDG) positron emission tomography (PET) scans to assess glucose metabolism [17,21,48], [11C]SCH 23 390 for D1 receptor binding and [123I]iodobenzamide

(IBZM) or [11C]raclopride (RAC) for D2 receptor binding [17,19–21], allowing for the evaluation of the extent of grafted cell survival and functionality. For example, Hauser et al. reported that putaminal glucose metabolism and D1 receptor binding did not decrease as usually expected with disease progression, AZD2281 mw although this was not observed in the caudate nucleus. The authors suggested that this was likely due to the small amount of tissue implanted [17]. However, they also reported a decrease in D2 receptor binding in the putamen and caudate nucleus, presumably due to the selective survival of transplanted neurones or to differences in the time-course or capacity for expression of these receptors [17]. Gaura et al. reported that at 30 months after transplantation,

brain glucose metabolism was either increased or stable in all parts of the striatum when compared with images obtained immediately after surgery. Small regions corresponding to the grafts, as identified by MRI, showed a higher metabolic activity compared with the host striatum. Cortical and striatal hypometabolism was ameliorated in three patients R788 solubility dmso 2 years after transplantation, which correlated with functional improvement [49]. However, at the 6-year post-transplantation follow-up, glucose metabolism had decreased again [50]. Two patients in whom no increase in metabolic activity had been detected at 2 years [48] continued to deteriorate clinically and, accordingly, MRI did not indicate improvements at 6 years after surgery [50]. Reuter et al. reported Cell press increased D2 receptor binding at 6 months in one transplanted patient, which slightly

declined afterwards but stayed at levels higher than baseline, whereas another patient did not exhibit any improvement on imaging [20]. Imaging techniques have also been of crucial importance in identifying potential complications and irregularities, although graft complication or unusual grafting patterns remain anecdotal. One single case, which had taken part in a phase II trial conducted by the Institut National de la Santé et de la Recherche Médicale (INSERM), was diagnosed with encephalitis and displayed striatal glucose hypometabolism, which were interpreted by the authors as signs of graft rejection. These were identified at 14 months after grafting when the patient had become ill after being taken off a 9-month regime of immunosuppressive drugs [51].

V.S), and

the Netherlands Organization for Scientific Research (NWO-ALW to A.V.S). The authors thank: Carmel Daunt and Mariam Sofi for technical assistance; Errin Johnson (Sir William Dunn School of Pathology, University of Oxford) for scanning EM, Josh Lorimer, Aaron Moldrich, and Gabriela Panoschi for animal care; David Vremec and Ken Shortman for the gift of antibodies, staff of Monash Micro Imaging for assistance with in vivo DC imaging experiments, Gabrielle Belz for the gift of OT-I Ly5.1 mice, and Drs Michel Nussenzweig and Wolfgang Weninger for the gift of CD11c-YFP mice. The authors declare no financial or commercial conflict of interest. As a service to our authors and readers, this journal provides supporting information supplied by the authors. Such Tanespimycin manufacturer materials are peer reviewed and may be re-organized for online delivery, but are not copy-edited or typeset. Technical support issues arising from supporting information (other than missing files) should be addressed to the authors. Figure S1. Splenocyte distribution is normal in both naïve and immunized CD37−/−mice. FACS analyses of the major splenocyte and T lymphocyte populations in WT and CD37−/− mice that were (A) naïve, (B) 10 days post-immunization and (C) 14 days post-immunization with B16-OVA. The frequencies of NK cells (CD3−NK1.1+),

T-cells (CD3+), B cells (CD19+), DC (CD11c+MHC-II+), Granulocytes (F4/80−Gr1+) and Macrophages Buparlisib chemical structure (F4/80+CD11c−) are expressed as a percentage relative www.selleck.co.jp/products/Gemcitabine(Gemzar).html to the total

number of viable cells (left axis). The frequencies of T-cell subpopulations including NKT (CD3+NK1.1+), Th (CD3+CD4+), Tc (CD3+CD8+) and T regulatory (CD3+Foxp3+) cells are expressed as a percentage relative to the total number of viable CD3+ T-cells (right axis). Histogram bars represent the mean frequency of the given population +/-SD and significance tested via ANOVA (n = 3–4 mice/group). Figure S2. The Th1-polarizing cytokine IL-12p70 is secreted at normal levels by CD37−/-DC. Purified naïve splenic DC were pooled from four mice/group and cultured with either media alone, 10 ng/mL CpG peptide or 1 ng/mL LPS. All conditions were supplemented with GM-CSF, IL-4 and IFNy. After 24 hours, IL-6, TNFa, IL-10 and IL-12p70 secretion was quantified in supernatants via flow cytometric bead array. Histogram bars represent the average cytokine concentration from three independent experiments + SEM and significance tested via ANOVA (n = 3 experiments/group). (B) BMDC maturation was assessed by flow cytometric analysis of surface CD80, CD86 and MHC Class II upregulation post LPS activation (1 ng/mL). “
“The establishment of immune tolerance and prevention of chronic rejection remain major goals in clinical transplantation. In bone marrow (BM) transplantation, T cells and NK cells play important roles for graft rejection. In addition, graft-versus-host-disease (GVHD) remains a major obstacle for BM transplantation.

Kidney function remained stable in patients treated with valsartan combined with probucol or valsartan alone. However, the long-term effect needs further investigation. We are deeply grateful to all the patients who donated blood. This work was supported by grants from Guangzhou people’s livelihood science and technology major projects of Guangdong (2012Y2-00028); Guangdong science and technology plan (2012B031800016). Clinical Trial Registration: A Study of the Antioxidant Probucol Combined

With Valsartan in Patients With IgA Nephropathy (NCT00426348). “
“Date written: June 2007 Final submission: October 2008 No recommendations possible based on Level I or II evidence (Suggestions are based on Level III and IV evidence) A formal psychosocial assessment should be a mandatory Sirolimus supplier part of the pre-transplant workup process. Living kidney donors should undergo psychosocial assessment and have access to psychosocial care before and after the transplant surgery. Living kidney

donor transplantation leads to better outcomes for the transplant recipient; however, there is increasing concern about the safety and wellbeing of live kidney donors.1 Live donors are not only at risk of physical adverse events including infection and loss of renal https://www.selleckchem.com/products/wnt-c59-c59.html function in the remaining kidney but they may also experience psychosocial problems including anxiety, depression, regret and financial hardship.2,3 The psychosocial evaluation of donors (pre- and post-transplant) is widely advocated;4 however, there is a paucity of data on the process and content of psychosocial evaluations. For example, there are Interleukin-2 receptor no set standards regarding who should conduct psychosocial evaluations (physician, psychiatrist, psychologist, medical social worker), whether evaluations should be mandatory, at what stage of the work-up evaluations should be conducted, at what time interval repeat evaluations should be

performed and what criteria need to be met. A limited number of studies and evaluation tools have suggested that the live donor psychosocial evaluation should include an assessment of: the donor’s ability to give informed consent, donor motivation, relationship between donor and recipient, donor/spouse agreement, information needs, mental status, coping and personality style, emotional and behavioural issues that may impact on donation, and social and financial support.4–7 The objective of this guideline is to assess and summarize the evidence on psychosocial care for living donors. Databases searched: MeSH terms and text words for kidney transplantation were combined with MeSH terms and text words for living donors and MeSH terms and text words for social psychology and support. The search was conducted in Medline (1955 to September Week 1, 2006). Date of searches: 9 September 2006.

PMNs, 2 × 104 cells/ml in PBS+/+, were incubated with increasing concentrations (1 μM–0·1 nM) of the FPR2/ALX agonists (15-epi-LXA4 or compound 43) or CysTL1 antagonists (montelukast Atezolizumab purchase or MK-571) for 30 min at 37°C or vehicle (DMSO < 0·1%) in 96-well plates. Human recombinant IL-8 (100 nM) was added to the wells and incubated for 4 h. After covering the bottom of the plate with the adhesive non-translucid paper, the caspase 3/7 reagent was added

and incubated for 30 min. Caspase 3/7 activity was measured by luminometry using a Luminoskan Ascent (Thermo Labsystems, Bar Hill, Cambridge, UK). Caspase inhibitor I (5 μM) was used as a control of apoptosis inhibition and staurosporine (1 μg/ml) as a control of apoptosis induction. In order to avoid LPS contamination, fresh buffers were prepared using sterile and filtered solutions on the same day of the apoptosis assay. PMNs at 1 × 106 cells/ml in PBS+/+ were incubated with the FPR2/ALX agonists (15-epi-LXA4 and compound 43) and CysTL1 antagonists (montelukast and MK-571) (100 nM) for 30 min at 37°C or vehicle (DMSO < 0·1%) in 24-well plates. Human recombinant IL-8 (100 nM) was added to the wells and incubated for 4 h. After incubation cells were transferred to a clean FACS tube and washed with PBS (×2). Briefly, cells were resuspended with ×1 binding buffer (500 μl) and 5 μl www.selleckchem.com/products/Maraviroc.html of annexin V-FITC (Sigma, Saint

Louis, MO, USA) and 10 μl of propidium iodide were added. Cells were incubated

at room temperature for 10 min and fluorescence was measured immediately by flow cytometry using a FACSCanto (BD Biosciences, Franklin Lakes, NJ, USA). Dose–response curves were set up in duplicate. Half maximal inhibitory concentration (IC50) and Half maximal effective concentration (EC50) calculations Selleck Fludarabine were performed using the four-parameter logistic (4PL) non-linear regression [log (inhibitor) versus response with variable slope equation] using GraphPad Prism software. IC50 values are reported as geometric mean (GeoMean) ± standard error of the mean. Values for chemotaxis and apoptosis assessment were analysed by Student’s t-test. In order to study the signalling pathway triggered by activation of FPR2/ALX and CysLT1 by each reference compound, cAMP and GTPγ binding assays in FPR2/ALX recombinant cells and membranes and binding and calcium flux assays in CysLT1 recombinant cells were performed. IC50 and percentage of inhibition of the reference compounds in agonist and antagonist mode in FPR2/ALX and CysLT1 are shown in Table 1 and Fig. 2, respectively. 15-Epi-LXA4 was inactive (0% of inhibition at 100 μM) in either GTPγ binding or cAMP assays in both agonist or antagonist mode in FPR2/ALX-expressing cells (Table 1 and Fig. 2a). Calcium release was not increased after stimulation of FPR2/ALX recombinant cells by 15-epi-LXA4 (data not shown).

Next, we examined cells lacking TLR adaptors (MyD88/MAL/TRIF/TRAM) and we found that MyD88, but none of the other adaptors, was absolutely required for RNA-or DNA-induced IL-12p70 production (Fig. 3B). Since an involvement of the IRF1 transcription factor in TLR7-dependent responses to bacterial RNA has been previously demonstrated [29], we tested whether a similar dependency also applied to IL-12p70 responses induced by fungal RNA or DNA. Figure 3C shows that this was indeed the case, since nucleic acid-induced IL-12p70 production was

severely reduced in cells lacking IRF1, but not IRF3 or IRF7 (Fig. 3C). Although the involvement Ibrutinib ic50 of TLR9 and MyD88 in fungal DNA-induced IL-12 secretion was previously documented [26-28], the role of the IRF family of transcription factors in such response was not studied. Collectively, these data suggest that IRF1 is targeted by both TLR7 and TLR9 in a MyD88-dependent fashion after recognition of fungal RNA and DNA, respectively, leading to IL-12p70 induction. In further studies, we examined signaling requirements for RNA-induced TNF-α and IL-23 production. In these experiments, we used, as a control stimulus, depleted zymosan, which in previous experiments selectively induced these cytokines, but not IL-12p70 (Fig. 1). TLR7 and MyD88 were essential for the production of either IL-23 (Supporting Information Fig. 1) or TNF-α (Supporting Information Fig. 2) following RNA stimulation. In contrast,

none of the TLRs or the TLR adaptors examined,

including MyD88, were required for depleted zymosan-induced IL-23 or TNF-α release. Rather, the latter responses were largely buy Deforolimus dectin-1-dependent (Supporting Information Fig. 1 and 2). Moreover, neither IRF1, IRF3, or IRF7 were required for TNF-α or IL-23 production in response to RNA, DNA, or zymosan. Thus, IL-23 and TNF-α induction by C. albicans RNA required BCKDHB TLR7 and MyD88, but not IRF1. Since the data presented above indicated that TLR7 was absolutely required for RNA-induced responses, it was of interest to assess the relative contribution of this receptor in the context of whole organism stimulation. Live C. albicans was not used, since it was previously found to produce significant cell toxicity in BMDCs, even at very low multiplicities of infection or in the presence of high-dose fluconazole [22]. In contrast, the closely related [30] model yeast S. cerevisiae, which is also an opportunistic pathogen [31, 32], was devoid of any cell toxicity [22]. After observing that live S. cerevisiae potently induced IL-12p70, IL-23, and TNF-α in a dose-dependent fashion, we assessed the signaling requirements for these responses using BMDCs lacking specific signaling factors (Fig. 4). Both TLR7 and TLR9, but not dectin-1, were at least partially required for IL-12p70 responses to whole organisms. Moreover, cells lacking the TLR adaptor MyD88 or the transcription factor IRF1 were totally unable to produce IL-12p70 in response to yeast (Fig. 4).

Th2-biased OVA-specific DO11.10 cells were transferred into

BALB/c mice, and these mice were challenged i.n. with either OVA or OVA-IC. Twenty-four selleck hours after the last challenge, the mice that had received OVA-IC not only had significantly increased total cell counts in the BALF, as compared to PBS or anti-OVA IgG treated mice, but these mice also presented with significantly increased total cell numbers, as compared to OVA challenged mice (Fig. 4A). These differences resulted mainly from increased eosinophil counts, as mice challenged with OVA-IC had more than three times higher eosinophil counts in the BALF, as compared to OVA challenged mice. Eosinophilia was negligible in PBS and anti-OVA IgG-treated mice (Fig. 4B). Importantly, control animals not receiving Th2-biased DO11.10 cells but challenged three times with OVA-IC showed no peribronchial/perivascular inflammation and their BALF of was devoid of eosionophils (data not shown), suggesting that no other FcγR-expressing inflammatory cells independently (e.g. macrophages) caused eosinophila and inflammation. In line with the cellular data, lung function confirmed the severe airway selleck kinase inhibitor hypersensitivity reaction in mice treated with OVA (Fig. 4C).

Because provocation was terminated for ethical reasons once the animals had reached an ED200RL, the lung function did not quantify a further impairment when mice were challenged with OVA-IC. However, the mice treated with OVA-IC revealed a

markedly augmented perivascular and peribronchiolar infiltrate of mononuclear cells, thereby providing evidence for more severe pulmonary inflammation (Fig. 4D–F). Taken together, these data suggest that allergen-specific IgG-IC can contribute to enhanced eosinophilia, increased airway inflammation and resulting airway hyperresponsiveness VAV2 when administered i.n. in a Th2 T-cell-dependent murine asthma model. Next, we wished to better define whether or not the increased airway inflammation was a result of enhanced antigen presentation and T-cell proliferation. Therefore, we allowed IC-formation to occur in vivo and examined the resulting T-cell stimulation by DC from lung-draining LN. BALB/c mice were treated i.n. with PBS or anti-OVA IgG (anti-OVA and OVA-IC groups), followed by inhalation of 1% OVA aerosol for 20 min (OVA and OVA-IC groups) on two consecutive days. Twelve hours after the last challenge, lung-draining LN were removed, and DC were isolated and co-cultured with CSFE-labeled DO11.10. As shown in Fig. 5A and B, DC isolated form mice that had received anti-OVA IgG i.n. followed by inhalative challenge with OVA led to a highly significant and at least 100% increase in antigen-specific T-cell stimulation, as compared to DC from mice that were challenged with OVA alone. These data suggest that allergen-specific IgG-IC formation in vivo following allergen inhalation can result in enhanced T-cell proliferation induced by DC in lung-draining LN.

Fumaderm®, a mixture containing DMF as well as other different monoethyl fumarate salts, has been approved for the treatment of psoriasis since the early 1990s, and dermatological experience suggests a favourable safety profile with more than 185 000 patient years. However, PML cases have been reported recently during psoriasis treatment with fumaric esters [125-128], although confounding factors were identified in these cases. Two cases had experienced long-lasting lymphopenia without treatment adaption, as recommended [126, 127]; the other cases had a history of sarcoidosis, cancer, previous mAb (efalizumab) and immunosuppressive (methotrexate) Selleckchem C59 wnt treatment [128]. Tecfidera®, also

with differences regarding galenics, is approved for MS. Thus far, no signal for opportunistic infections such as PML have been reported from the clinical programme or the short post-marketing interval (US) with Tecfidera®. The regular assessment of leuco- and lymphocyte counts is sensible and may serve treatment surveillance. At 1 year of treatment, leuco- and lymphocyte counts decreased by 10–12% and 28–32%

(mean), respectively; 4–5% of patients experienced Carfilzomib research buy total lymphocyte counts below 0·5 × 109 per litre [123, 124]. As in other DMD treatments, regular MRI under DMF therapy will be reasonable for both therapy monitoring and determining effectiveness. Mitoxantrone (MX, Ralenova®/Novantrone®) has been approved for the treatment of secondary progressive and progressive relapsing MS following two placebo-controlled trials [19, 129] and two studies comparing MX or MX in combination with methylprednisolone (MP) to MP alone [130, 131]. Data on MX in primary progressive MS (PPMS) is discouraging [132-134], but has gained relevance in NMO treatment [24, 25]. Although not formally approved, MX has been used in children with aggressive forms of MS [135]. Different treatment SPTLC1 protocols may be an influencing factor for SADR development,

especially in terms of therapy-related acute leukaemia (TRAL) [136]. Whereas an intravenous infusion every 3 months according to the placebo-controlled, double-blind, randomised, multicentre, phase III trial of mitoxantrone in secondary progressive multiple sclerosis (MIMS) protocol [129], including dose adaption according to leucocyte nadir, is used widely in Germany, dose regimens differ substantially and may not include regular dose adaption [137, 138]. Additional differences may comprise pre- or co-treatments [37]. Thus, MP co-treatment has been shown to increase intracellular MX dosage in vitro [139], and may thus increase cellular toxicity. Treatment de-escalation should be considered after 1 year of clinical and paraclinical stability of disease to minimize the risk of at least partially dose-dependent SADRs (e.g. cardiotoxicity).

004; OR: 2.73(1.33–5.29) for DN]. There is no difference in the frequency

between DM and DN subjects. Conclusion: Subjects with T2DM show higher frequency of the 6L-6L leucine repeat in CNDP1 gene compared to non-diabetics. There is no association, however with development of nephropathy. LOH PT1, TOH MPHS2, MOLINA JAD2, VATHSALA A1 1Division of Nephrology, Department of Medicine, National University Hospital. Singapore; 2Health Services and Outcomes Research, National Healthcare Group, Singapore Introduction: Diabetic Nephropathy (DN) is the leading cause of End Stage Renal Disease in Singapore and its incidence is increasing in relation NVP-AUY922 datasheet to increasing prevalence of Type 2 diabetes mellitus (T2DM). While measures to prevent diabetes and its early detection are important, optimal diabetes and blood pressure control, early detection of DN and its early treatment at the primary care setting are crucial to ameliorate the course of DN. We aimed to evaluate the prevalence of DN in a primary care cluster and identify the risk factors for its occurrence in a multi ethnic Asian population. Methods: 57,594 Selleck PF-2341066 T2DM patients on follow-up at the National Healthcare Group Polyclinics with eGFR and at least two urine Albumin/Creatinine Ratio (UACR) measurements were stratified into DN stages:

Normoalbuminuria (NI, UACR <30 mg/g), Microalbuminuria (MI, UACR 30–299 mg/g), Macroalbuminuria (MA, >300 mg/g)

and Renal Impairment TCL (RI, eGFR <60 mL/min/1·73 m2). Risk factors for DN stages were evaluated through multivariate analysis. Results: The study population was 71% Chinese, 56% Female with mean age: 66 years, duration of diabetes of 8 years, HbA1c of 7·5% and Body Mass Index (BMI) of 26·5 kg/m2; 81% has hypertension and 73% were on Angiotensin-Converting-Enzyme-Inhibitor or Angiotensin-Receptor-Blocker. Prevalence of DN, including MI, MA or RI in this primary healthcare cluster was high at 52·5%; 32·1% had MI, 5·3% had MA, while 15·1% had RI. DN prevalence among the ethnic subpopulations was different: 52·2% of Chinese, 60·4% of Malays and 45·3% of Indians had DN respectively, p < 0·0001 (Table 1). After regression analysis, the odds ratio for DN in Malays was 1·42 (95% CI, 1·35–1·51) while in Indians was 0·86 (95%CI, 0·81–0·91). Other independent risk factors for DN prevalence were age, female gender, duration of diabetes and hypertension, HbA1c and BMI (Table 2). While Malays had the shortest duration of diabetes but highest BMI, Indians had the poorest control of diabetes whereas Chinese were older and had the longest duration of hypertension. Conclusion: The high prevalence of DN and its inter-ethnic differences suggest the need for additional measures to optimise the care of T2DM at the primary care setting so as to mitigate its progression.

There was also no significant difference in IL-8 or TNFα responses to 0–3 h RP between infected and co-infected subjects (IL-8 Z: −0·717, P = 0·473, Figure 1a; TNFα Z: −1·050, P = 0·294, Figure 1b). In contrast to the production of IL-8 and TNFα, 0–3 h RP induced significantly elevated quantities of IL-10 by WB cultures in co-infected subjects (median: 327·4 ng/mL, range: 1124·3) compared with uninfected controls (median: 137·5 ng/mL, range: 486·3; Z: −2·063, P = 0·039; Figure 1c).

The median concentration of IL-10 production in response to 0–3 h RP was also higher in WB from infected (i.e. only positive for S. mansoni) participants (median: 190·7 ng/mL, range: 642·4, Figure 1c) compared

with uninfected controls but this trend did not reach statistical selleck kinase inhibitor significance (Z: −1·504, P = 0·133, Figure 1c). There was also no significant difference in 0–3 h RP-specific IL-10 secretion between the infected and co-infected groups (Z: −0·436, P = 0·451, Selleck Daporinad Figure 1c). The control stimulant zymosan induced levels of IL-10, which did not significantly differ between the three groups (Figure 1c). Further analysis of the 0–3 h RP-specific ratio of IL-10 to TNFα revealed that there was a significant increase in the cytokine ratio in response to 0–3 h RP in co-infected subjects (median: 0·039, range: 0·116; Z: −2·800, P = 0·005, Figure 2) compared with uninfected subjects (median: 0·016, range: 0·139). There was no significant difference between the zymosan-specific IL-10 to TNFα ratio in the different groups. These observations reinforce the theory that 0–3 h RP has ‘regulatory’ activity and promotes IL-10 production compared with pro-inflammatory TNFα in schistosome-infected individuals. As cytokine production is likely to be dependent upon the constituent leucocytes in the WB samples, various leucocyte Ketotifen classes were enumerated as a proportion of the total leucocyte count in the three infection groups

(uninfected n = 11, S. mansoni single infected n = 11 and co-infected n = 17; Figure 3). Eosinophils were the only leucocyte subset that was significantly affected by infection status (Kruskal–Wallis test, χ2 = 8·375, P = 0·015) with a higher percentage of eosinophils in WB from S. mansoni-infected (median: 10·6%, range: 34·2, Z: −2·331, P = 0·020) and co-infected participants (median: 12·0%, range: 43·2, Z: −2·658, P = 0·008) than in WB collected from uninfected participants (median: 4·7%, range: 20·6). There was no significant difference between the percentage of circulating eosinophils in blood collected from infected and co-infected participants (Z: −0·470, P = 0·638).

Furthermore, our studies indicate maternal administration of IL-1 receptor antagonist (IL-1RA) blocked neuronal nitric oxide synthase activation observed in the brain cortex and, we speculate, that this alteration in activation leads to demonstrated decreased neurotoxicity. “
“The cytokine interleukin (IL)-7 is essential for Treg-cell homeostasis. It remains unclear, however, whether IL-7 regulates the homeostatic fitness of T cells quantitatively and, if so, by what mechanisms. We addressed this question by analysing T cells exposed to different levels of IL-7 Vincristine order signalling in vivo. Using TCR transgenic mice that conditionally express IL-7Rα, we show that T-cell longevity

in the absence of survival cues is not a cell-intrinsic property but rather a dynamic Saracatinib ic50 process of which IL-7 signalling is a key regulator. Naïve T cells deficient in IL-7Rα expression underwent rapid cell death within hours of in vitro culture. In contrast, the same T cells from lymphopenic hosts, in which IL-7 is non-limiting, were able to survive in culture independently of growth factors for many days. Surprisingly, different levels of IL-7 signalling in vivo evoked distinct molecular mechanisms to regulate homeostatic fitness. When IL-7 was non-limiting,

increased survival was associated with up-regulation of anti-apoptotic Bcl2 family members. In contrast, in T-cell replete conditions i.e. when IL-7 is limiting, we found evidence that IL-7 regulated T-cell fitness by distinct non-transcriptional mechanisms. Together, these data demonstrate a quantitative aspect to IL-7 signalling dependent on distinct molecular mechanisms. A commonly evoked concept in studies of Chloroambucil lymphocyte homeostasis is that of cellular fitness. Whether a cell lives or dies in a particular context, such as effector cell transition to a memory state,

or survival of recent thymic emigrants entering a replete peripheral compartment, is a function of its relative fitness 1. The cytokine IL-7 plays a fundamental role in homeostasis of the peripheral T-cell compartment 2–4. IL-7 is limiting in replete conditions and is a key determinant of the T-cell compartment size, since total T-cell numbers in mice lacking one or other CD4+ and CD8+ subsets are near-identical to those in mice with both subsets 5–7. Conversely, genetic over-expression of IL-7 8, 9 or its administration in vivo 10 increases T-cell numbers. It is likely, therefore, that IL-7 is a key determinant of homeostatic fitness. Lymphocytes are unlikely to have unfettered access to the multiple environmental cues required for their survival, but rather receive such signals on a sporadic basis. Consistent with this view, chemokines direct T cells to sites of IL-7 production within lymph nodes 11.