IL-7/anti-IL-7 mAb complexes restore T cell development and induce homeostatic T Cell expansion without lymphopenia.

IL-7, a member of the common gamma-chain family of cytokines, is essential for B and T lymphocyte development and homeostasis of mature T cell subsets. Thus, naive and memory T cells are both dependent on IL-7 for survival and homeostatic proliferation under lymphopenic conditions. In line with prior findings with IL-2, we show in this study that the biological activity of IL-7 in vivo is greatly increased by association with anti-IL-7 mAb. Under in vivo conditions, IL-7/mAb complexes displayed 50- to 100-fold higher activity than free IL-7 and induced massive expansion of pre-B cells. IL-7/mAb complexes also increased thymopoiesis in normal mice and restored thymopoeisis in IL-7-deficient mice. For mature T cells, IL-7/mAb complexes induced marked homeostatic proliferation of both naive and memory CD4(+) and CD8(+) cell subsets even under normal T cell-replete conditions. Finally, IL-7/mAb complexes were able to enhance the magnitude of the primary response of Ag-specific naive CD8(+) cells. The strong stimulatory activity of IL-7/mAb complexes could be useful for treatment of immunodeficiency and cancer.

Harmonisation of short-term in vitro culture for the expansion of antigen-specific CD8(+) T cells with detection by ELISPOT and HLA-multimer staining.

Ex vivo ELISPOT and multimer staining are well-established tests for the assessment of antigen-specific T cells. Many laboratories are now using a period of in vitro stimulation (IVS) to enhance detection. Here, we report the findings of a multi-centre panel organised by the Association for Cancer Immunotherapy Immunoguiding Program to investigate the impact of IVS protocols on the detection of antigen-specific T cells of varying ex vivo frequency. Five centres performed ELISPOT and multimer staining on centrally prepared PBMCs from 3 donors, both ex vivo and following IVS. A harmonised IVS protocol was designed based on the best-performing protocol(s), which was then evaluated in a second phase on 2 donors by 6 centres. All centres were able to reliably detect antigen-specific T cells of high/intermediate frequency both ex vivo (Phase I) and post-IVS (Phase I and II). The highest frequencies of antigen-specific T cells ex vivo were mirrored in the frequencies following IVS and in the detection rates. However, antigen-specific T cells of a low/undetectable frequency ex vivo were not reproducibly detected post-IVS. Harmonisation of the IVS protocol reduced the inter-laboratory variation observed for ELISPOT and multimer analyses by approximately 20 %. We further demonstrate that results from ELISPOT and multimer staining correlated after (P < 0.0001 and R (2) = 0.5113), but not before IVS. In summary, IVS was shown to be a reproducible method that benefitted from method harmonisation.

Fibroblastic reticular cells from lymph nodes attenuate T cell expansion by producing nitric oxide.

Adaptive immune responses are initiated when T cells encounter antigen on dendritic cells (DC) in T zones of secondary lymphoid organs. T zones contain a 3-dimensional scaffold of fibroblastic reticular cells (FRC) but currently it is unclear how FRC influence T cell activation. Here we report that FRC lines and ex vivo FRC inhibit T cell proliferation but not differentiation. FRC share this feature with fibroblasts from non-lymphoid tissues as well as mesenchymal stromal cells. We identified FRC as strong source of nitric oxide (NO) thereby directly dampening T cell expansion as well as reducing the T cell priming capacity of DC. The expression of inducible nitric oxide synthase (iNOS) was up-regulated in a subset of FRC by both DC-signals as well as interferon-γ produced by primed CD8+ T cells. Importantly, iNOS expression was induced during viral infection in vivo in both LN FRC and DC. As a consequence, the primary T cell response was found to be exaggerated in Inos(-/-) mice. Our findings highlight that in addition to their established positive roles in T cell responses FRC and DC cooperate in a negative feedback loop to attenuate T cell expansion during acute inflammation.

Expansion of gamma delta+ T cells in BALB/c mice infected with Leishmania major is dependent upon Th2-type CD4+ T cells.

T cells belong to either the alpha beta+ or gamma delta+ lineage as defined by their antigen receptor. Although both T-cell subsets have been shown to be involved in the immune response to the parasite Leishmania major, very little is known about possible interactions between these two populations. In this study, using a mouse model of infection with L. major, we showed that expansion of a subset of gamma delta+ T cells in vivo is dependent upon the presence of alpha beta+ CD4+ T cells. Moreover, this effect appears to be mediated via the secretion of lymphokines by CD4+ cells with a T-helper 2 (Th2) functional phenotype. Results showing that activation of Th2-type cells in mice treated with anti-immunoglobulin D antibodies or infected with Nippostrongylus brasiliensis also results in gamma delta+ T-cell expansion suggest that this effect of the Th2-type CD4+ cells is a general phenomenon not restricted to infection with L. major.

Popping expansion and yield responses of popcorn cultivars under different row spacings and plant populations

The objective of this work was to evaluate the agronomic traits and the popping expansion index of three Brazilian popcorn cultivars under different row spacings and plant populations. The trials were performed during two crop seasons, under field conditions. The experimental design used was a randomized complete block, in a split-split plot, with 27 treatments and four replicates. Treatments were represented in a triple factorial arrangement: three row spacings (0.40, 0.60, and 0.80 m), three plant populations (40,000, 60,000, and 80,000 plants per hectare), and three popcorn cultivars (IAC-TC 01, IAC 12, and Zelia). The increase in plant population causes a reduction in the number of grains per ear, lower prolificacy, and grain weight loss. Cultivar grain yield is affected by row spacing and popcorn plant population. Cultivar IAC 12 shows highest grain yield under row spacings of 0.40 and 0.60 m and plant population between 60,000 and 80,000 plants per hectare. The popping expansion index is not affected by row spacing or plant population.

Impulse response recovery of linear systems through weighted cumulant slice

Identifiability of the so-called ω-slice algorithm is proven for ARMA linear systems. Although proofs were developed in the past for the simpler cases of MA and AR models, they were not extendible to general exponential linear systems. The results presented in this paper demonstrate a unique feature of the ω-slice method, which is unbiasedness and consistency when order is overdetermined, regardless of the IIR or FIR nature of the underlying system, and numerical robustness.

System identification using a linear combination of cumulant slices

In this paper we develop a new linear approach to identify the parameters of a moving average (MA) model from the statistics of the output. First, we show that, under some constraints, the impulse response of the system can be expressed as a linear combination of cumulant slices. Then, thisresult is used to obtain a new well-conditioned linear methodto estimate the MA parameters of a non-Gaussian process. Theproposed method presents several important differences withexisting linear approaches. The linear combination of slices usedto compute the MA parameters can be constructed from dif-ferent sets of cumulants of different orders, providing a generalframework where all the statistics can be combined. Further-more, it is not necessary to use second-order statistics (the autocorrelation slice), and therefore the proposed algorithm stillprovides consistent estimates in the presence of colored Gaussian noise. Another advantage of the method is that while mostlinear methods developed so far give totally erroneous estimates if the order is overestimated, the proposed approach doesnot require a previous estimation of the filter order. The simulation results confirm the good numerical conditioning of thealgorithm and the improvement in performance with respect to existing methods.

Managing Subsidiary Integration During Corporate Expansion in Russia

Kansallisten rajojen yli laajentuvat yritykset kohtaavat kasvavia paineita yhtenäistää eri yksiköiden toimintatapoja, prosesseja ja järjestelmiä. Hyvin toteutettuna organisaation sisäinen integrointi voi johtaa tytäryritysten tuottavuuden parantumiseen ja strategisiin mittakaavaetuihin, kun taas huonosti toteutettuna integrointi voi johtaa lisääntyviin konflikteihin ja emoyhtiön kontrollin katoamiseen. Integroinnin kannalta Venäjälle perustettavat tytäryritykset asettavat suuria haasteita. Kasvava ja kehittyvä kansantalous on jatkuvassa muutoksessa kohti edistyneempiä ja tuottavampia toimintamalleja, mutta toisaalta yritystoiminnantaustalla vaikuttaa edelleenkin Neuvostoajan perinnöt, jotka muokkaavat yritysten johtamisrakenteita ja prosesseja. Nämä taustavaikuttajat vaikeuttavat kansainvälisen yrityksen yhtenäistämistä, mutta toisaalta tarjoavat suuria mahdollisuuksia yrityksille, jotka oppivat elämään Venäjän markkinoiden ehdoilla. Tämä tutkimus käyttää apunaan konstruktiivista tutkimustyötä ratkoakseenYIT:n Venäjälle perustettavien yritysten integrointiin liittyviä ongelmia ja mahdollisuuksia. Työn lopputuloksena syntyy oppimiseen pohjautuva integraatiostrategia ja tätä strategiaa tukeva integroinnin johtamisjärjestelmä.

Environmental and T cell-intrinsic factors limit the expansion of neonatal follicular T helper cells but may be circumvented by specific adjuvants.

Follicular Th (T(FH)) cells have emerged as a new Th subset providing help to B cells and supporting their differentiation into long-lived plasma cells or memory B cells. Their differentiation had not yet been investigated following neonatal immunization, which elicits delayed and limited germinal center (GC) responses. We demonstrate that neonatal immunization induces CXCR5(high)PD-1(high) CD4(+) T(FH) cells that exhibit T(FH) features (including Batf, Bcl6, c-Maf, ICOS, and IL-21 expression) and are able to migrate into the GCs. However, neonatal T(FH) cells fail to expand and to acquire a full-blown GC T(FH) phenotype, as reflected by a higher ratio of GC T(FH)/non-GC CD4(+) T cells in immunized adults than neonates (3.8 × 10(-3) versus 2.2 × 10(-3), p = 0.01). Following the adoptive transfer of naive adult OT-II CD4(+) T cells, OT-II T(FH) cells expand in the vaccine-draining lymph nodes of immunized adult but not infant recipients, whereas naive 2-wk-old CD4(+) OT-II cells failed to expand in adult hosts, reflecting the influence of both environmental and T cell-intrinsic factors. Postponing immunization to later in life increases the number of T(FH) cells in a stepwise manner, in direct correlation with the numbers of GC B cells and plasma cells elicited. Remarkably, adjuvantation with CpG oligonucleotides markedly increased GC T(FH) and GC B cell neonatal responses, up to adult levels. To our knowledge, this is the first demonstration that the T(FH) cell development limits early life GC responses and that adjuvants/delivery systems supporting T(FH) differentiation may restore adultlike early life GC B cell responses.

Managing Business Processes in Corporate Expansion

Yrityksen laajentuessa kansainvälisesti, olemassa olevat rutiinit jäävät vanhoiksi ja liiketoimintaprosessien johtaminen muuttuu. Kyseisten prosessien täytyy olla läpinäkyviä ja tietovirtojen hyvin suunniteltuja. Prosessien harmonisointi aiheuttaa haasteita yrityksessä ja konsernin etu tulee ottaa huomioon. Ahlstrom konserni laajentuu merkittävästi kaikilla liiketoiminta-alueillaan ja kansainvälinen laajentuminen vie Ahlstrom Glassfibre Oy:n täysin uuteen tilanteeseen. Liiketoimintaprosessien johtamiseen vaikuttavat konsernin ohjaus, mahdollisuudet muutosten implementoimiseksi, toimintaympäristön tekijät ja järjestelmien muodostama arkkitehtuuri. Tässä tutkimuksessa keskitytään ydinprosessien tietovirtoihin ja työ on tehty Karhulan tehtaalla Suomessa. Johtamismallin luomiseksi vaaditaan yrityksessä ongelmia määrittelevää työskentelyä. Tämä ongelmanmääritys oli työn tärkein tavoite. Ongelma-alueiden tutkimuksen pohjalta muodostettiin ratkaisu, jossa käsiteltiin systemaattisen liiketoimintaprosessien johtamisen mahdollisuuksia ja vaatimuksia. Lopputuloksena voidaan todeta, että suurin painopiste löytyy informaatioteknologian ja liiketoiminnan rajapinnoista. Tähän työhön liittyvät myös prossien harmonisointi ja integrointi.