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Background
Regulatory T cell (Treg) based immunotherapy is a potential treatment for several immune disorders. By now, this approach proved successful in preclinical animal transplantation and auto-immunity models. In these models the success of Treg based immunotherapy crucially depends on the antigen-specificity of the infused Treg population. For the human setting, information is lacking on how to generate Treg with direct antigen-specificity ex vivo to be used for immunotherapy.Methodology/Principal Findings
Here, we demonstrate that in as little as two stimulation cycles with HLA mismatched allogeneic stimulator cells and T cell growth factors a very high degree of alloantigen-specificity was reached in magnetic bead isolated human CD4posCD25high Treg. Efficient increases in cell numbers were obtained. Primary allogeneic stimulation appeared a prerequisite in the generation of alloantigen-specific Treg, while secondary allogeneic or polyclonal stimulation with anti-CD3 plus anti-CD28 monoclonal antibodies enriched alloantigen-specificity and cell yield to a similar extent.Conclusions/Significance
The ex vivo expansion protocol that we describe will very likely increase the success of clinical Treg-based immunotherapy, and will help to induce tolerance to selected antigens, while minimizing general immune suppression. This approach is of particular interest for recipients of HLA mismatched transplants. 相似文献43.
Kreijveld E Koenen HJ van Cranenbroek B van Rijssen E Joosten I Hilbrands LB 《PloS one》2008,3(7):e2711
Background
Transplant patients would benefit from reduction of immunosuppression providing that graft rejection is prevented. We have evaluated a number of immunological markers in blood of patients in whom tacrolimus was withdrawn after renal transplantation. The alloreactive precursor frequency of CD4+ and CD8+ T cells, the frequency of T cell subsets and the functional capacity of CD4+CD25+FoxP3+ regulatory T cells (Treg) were analyzed before transplantation and before tacrolimus reduction. In a case-control design, the results were compared between patients with (n = 15) and without (n = 28) acute rejection after tacrolimus withdrawal.Principal Findings
Prior to tacrolimus reduction, the ratio between memory CD8+ T cells and Treg was higher in rejectors compared to non-rejectors. Rejectors also had a higher ratio between memory CD4+ T cells and Treg, and ratios <20 were only observed in non-rejectors. Between the time of transplantation and the start of tacrolimus withdrawal, an increase in naive T cell frequencies and a reciprocal decrease of effector T cell percentages was observed in rejectors. The proportion of Treg within the CD4+ T cells decreased after transplantation, but anti-donor regulatory capacity of Treg remained unaltered in rejectors and non-rejectors.Conclusions
Immunological monitoring revealed an association between acute rejection following the withdrawal of tacrolimus and 1) the ratio of memory T cells and Treg prior to the start of tacrolimus reduction, and 2) changes in the distribution of naive, effector and memory T cells over time. Combination of these two biomarkers allowed highly specific identification of patients in whom immunosuppression could be safely reduced. 相似文献44.
Mos van Berlo Marcel Ottens Karel Ch. A. M. Luyben Luuk A. M. van der Wielen 《Journal of chromatography. B, Analytical technologies in the biomedical and life sciences》2000,743(1-2)
As part of an ongoing research effort on aqueous two-phase systems (ATPSs) with volatile salts, this work describes the partitioning behavior of a series of amino acids, namely
-serine, glycine,
-alanine,
-valine,
-methionine,
-isoleucine, and
-phenylalanine, in these systems. The results show that amino acids partition in a similar way in polymer–volatile salt ATPSs and in traditional polymer–salt ATPSs. Increasing amino acid hydrophobicities lead to increasing partition coefficients. Moreover, the common linear relationship between the logarithm of the partition coefficient and the tie line length is observed here as well. Furthermore, the relation between relative partition coefficients and relative hydrophobicities of amino acids in the extraction systems investigated in this work is comparable to that in other extraction systems. 相似文献
45.
Kedar S. Deshpande Tangir Ahamed Joop H. ter Horst Peter J. Jansens Luuk A. M. van der Wielen Marcel Ottens Dr. 《Biotechnology journal》2009,4(9):1266-1277
This paper reviews the basic principles of the recently developed self-interaction chromatography (SIC) technique with regard to protein solution stability and protein crystallization. It gives experimental protocols for both normal-scale and micro-scale SIC experiments and reviews recent developments and current applications of this novel technique in the biopharmaceutical area. This paper aims to be a benchmark in the further proliferation of this highly effective and fast technology for the rational design of stable aqueous formulations of therapeutic proteins and the determination of solution conditions favoring protein crystallization. 相似文献
46.
Corjan van den Berg Arjan S. Heeres Luuk A. M. van der Wielen Adrie J. J. Straathof 《Biotechnology and bioengineering》2013,110(1):137-142
The recovery of 1‐butanol from fermentation broth is energy‐intensive since typical concentrations in fermentation broth are below 20 g L?1. To prevent butanol inhibition and high downstream processing costs, we aimed at producing butyl esters instead of 1‐butanol. It is shown that it is possible to perform simultaneously clostridial fermentation, esterification of the formed butanol to butyl butyrate, and extraction of this ester by hexadecane. The very high partition coefficient of butyl butyrate pulls the esterification towards the product side even at fermentation pH and relatively low butanol concentrations. The hexadecane extractant is a model diesel compound and is nontoxic to the cells. If butyl butyrate enriched diesel can directly be used as car fuel, no product recovery is required. A proof‐of‐principle experiment for the one‐pot bio‐ester production from glucose led to 5 g L?1 butyl butyrate in the hexadecane phase. The principle may be extended to a wide range of esters, especially to longer chain ones. Biotechnol. Bioeng. 2013; 110: 137–142. © 2012 Wiley Periodicals, Inc. 相似文献
47.
Dr. Maria C. Cuellar Joseph J. Heijnen Luuk A. M. van der Wielen 《Biotechnology journal》2013,8(6):682-689
Industrial biotechnology is playing an important role in the transition to a bio-based economy. Currently, however, industrial implementation is still modest, despite the advances made in microorganism development. Given that the fuels and commodity chemicals sectors are characterized by tight economic margins, we propose to address overall process design and efficiency at the start of bioprocess development. While current microorganism development is targeted at product formation and product yield, addressing process design at the start of bioprocess development means that microorganism selection can also be extended to other critical targets for process technology and process scale implementation, such as enhancing cell separation or increasing cell robustness at operating conditions that favor the overall process. In this paper we follow this approach for the microbial production of diesel-like biofuels. We review current microbial routes with both oleaginous and engineered microorganisms. For the routes leading to extracellular production, we identify the process conditions for large scale operation. The process conditions identified are finally translated to microorganism development targets. We show that microorganism development should be directed at anaerobic production, increasing robustness at extreme process conditions and tailoring cell surface properties. All the same time, novel process configurations integrating fermentation and product recovery, cell reuse and low-cost technologies for product separation are mandatory. This review provides a state-of-the-art summary of the latest challenges in large-scale production of diesel-like biofuels. 相似文献
48.
Marlous L. Grijsen Ferdinand W. N. M. Wit Suzanne Jurriaans Frank P. Kroon Emile F. Schippers Peter Koopmans Luuk Gras Joep M. A. Lange Jan M. Prins 《PloS one》2014,9(4)
Temporary cART during primary HIV-infection (PHI) did not select for drug resistance mutations after treatment interruption and did not affect the subsequent virological response to long-term cART. Our data demonstrate that fear of drug resistance development is not a valid argument to refrain from temporary early treatment during PHI. 相似文献
49.
Luuk Wieske Esther Witteveen Camiel Verhamme Daniela S. Dettling-Ihnenfeldt Marike van der Schaaf Marcus J. Schultz Ivo N. van Schaik Janneke Horn 《PloS one》2014,9(10)
Introduction
An early diagnosis of Intensive Care Unit–acquired weakness (ICU–AW) using muscle strength assessment is not possible in most critically ill patients. We hypothesized that development of ICU–AW can be predicted reliably two days after ICU admission, using patient characteristics, early available clinical parameters, laboratory results and use of medication as parameters.Methods
Newly admitted ICU patients mechanically ventilated ≥2 days were included in this prospective observational cohort study. Manual muscle strength was measured according to the Medical Research Council (MRC) scale, when patients were awake and attentive. ICU–AW was defined as an average MRC score <4. A prediction model was developed by selecting predictors from an a–priori defined set of candidate predictors, based on known risk factors. Discriminative performance of the prediction model was evaluated, validated internally and compared to the APACHE IV and SOFA score.Results
Of 212 included patients, 103 developed ICU–AW. Highest lactate levels, treatment with any aminoglycoside in the first two days after admission and age were selected as predictors. The area under the receiver operating characteristic curve of the prediction model was 0.71 after internal validation. The new prediction model improved discrimination compared to the APACHE IV and the SOFA score.Conclusion
The new early prediction model for ICU–AW using a set of 3 easily available parameters has fair discriminative performance. This model needs external validation. 相似文献50.
Elena G. Kamburova Hans J. P. M. Koenen Martijn W. F. van den Hoogen Marije C. Baas Irma Joosten Luuk B. Hilbrands 《PloS one》2014,9(11)