Factors affecting long-term efficacy of T regulatory cell-based therapy in type 1 diabetes.

BACKGROUND: Recent studies suggest that immunotherapy using T regulatory cells (Tregs) prolongs remission in type 1 diabetes (T1DM). Here, we report factors that possibly affect the efficacy of this treatment. METHODS: The metabolic and immune background of 12 children with recently diagnosed T1DM, as well as that of untreated subjects, during a 2-year follow-up is presented. Patients were treated with up to 30 × 106/kg b.w. of autologous expanded CD3+CD4+CD25highCD127- Tregs. RESULTS: The disease progressed and all patients were insulin-dependent 2 years after inclusion. The ß-cell function measured by c-peptide levels and the use of insulin were the best preserved in patients treated with two doses of Tregs (3/6 in remission), less so after one dose (1/6 in remission) and the worst in untreated controls (no remissions). Increased levels of Tregs could be seen in peripheral blood after their adoptive transfer together with the shift from naïve CD62L+CD45RA+ to memory CD62L+CD45RA- Tregs. Increasing serum levels of proinflammatory cytokines were found: IL6 increased in all subjects, while IL1 and TNFα increased only in untreated group. Therapeutic Tregs were dependent on IL2, and their survival could be improved by other lymphocytes. CONCLUSIONS: The disease progression was associated with changing proportions of naïve and memory Tregs and slowly increasing proinflammatory activity, which was only partially controlled by the administered Tregs. The therapeutic cells were highly dependent on IL2. We conclude that the therapy should be administered at the earliest to protect the highest possible mass of islets and also to utilize the preserved content of Tregs in the earlier phases of T1DM. Trial registration http://www.controlled-trials.com/ISRCTN06128462 ; registered retrospectively.

Therapy of type 1 diabetes with CD4(+)CD25(high)CD127-regulatory T cells prolongs survival of pancreatic islets - results of one year follow-up.

It is hypothesized that CD4(+)CD25(+)FoxP3(+) regulatory T cells (Tregs) can prevent destruction of pancreatic islets protecting from type 1 diabetes (DM1). Here we present results of one year follow-up of 12 DM1 children treated with autologous expanded ex vivo Tregs. Patients received either a single or double Tregs infusion up to the total dose of 30×10(6)/kg. No severe adverse effects were observed. The treatment did not impair post-immunization antibody responses. Tregs infusion was followed by increase in Tregs number in peripheral blood. Most of the patients responded to the therapy with increase in C-peptide levels (8/12 and 4/6 after the first and the second dose, respectively). Tregs administration resulted also in lower requirement for exogenous insulin (8/12 treated patients versus 2/10 untreated controls in remission) with two children completely insulin independent at one year. Repetitive administration of Tregs is safe and can prolong survival of ß-cells in DM1 (registration: ISRCTN06128462).

Immunological Aspects of Infertility-The Role of KIR Receptors and HLA-C Antigen.

The mechanisms of immune tolerance of a mother against an antigenically foreign fetus without a concomitant loss of defense capabilities against pathogens are the factors underlying the success of a pregnancy. A significant role in human defense is played by killer immunoglobulin-like receptor (KIR) receptors, which regulate the function of the natural killer (NK) cells capable of destroying antigenically foreign cells, virus-infected cells, or tumor-lesioned cells. A special subpopulation of NK cells called uterine NK cells (uNK) is found in the uterus. Disruption of the tolerance process or overactivity of immune-competent cells can lead to immune infertility, a situation in which a woman's immune system attacks her own reproductive cells, making it impossible to conceive or maintain a pregnancy. Since the prominent role of the inflammatory response in infertility, including KIR receptors and NK cells, has been postulated, the process of antigen presentation involving major histocompatibility complex (MHC) molecules (HLA) appears to be crucial for a successful pregnancy. Proper interactions between KIR receptors on female uNK cells and HLA class I molecules, with a predominant role for HLA-C, found on the surface of germ cells, are strategically important during embryo implantation. In addition, maintaining a functional balance between activating and inhibitory KIR receptors is essential for proper placenta formation and embryo implantation in the uterus. A disruption of this balance can lead to complications during pregnancy. The discovery of links between KIR and HLA-C has provided valuable information about the complexity of maternal-fetal immune interactions that determine the success of a pregnancy. The great diversity of maternal KIR and fetal HLA-C ligands is associated with the occurrence of KIR/HLA-C combinations that are more or less favorable for reproductive success.

Whither geographic proximity? Bypassing local R&D units in foreign university collaboration.

MNCs often engage in international research collaborations with foreign universities through one of their central R&D laboratories (at headquarters or elsewhere) even though they operate a local R&D unit close to that university, and hence forego the benefits of geographic proximity and local collaboration. Drawing on the knowledge-based theory of the firm, we hypothesize that the choice between distant and local collaboration systematically relates to the knowledge capabilities of the firms' R&D units, the characteristics of the focal knowledge, and local knowledge leakage risks. Analysis of close to 13,000 research collaborations with foreign universities by the world's major biopharmaceutical firms (1995-2015) confirms that collaboration at distance occurs if this allows the firm to benefit from scale and knowledge diversity advantages, if the central unit has strong basic research capabilities, and if collaboration is in a core research domain of the MNC while rival firms are locally present. Maturity of the focal research domain is associated with local collaboration. Our findings qualify the common arguments in favor of collaboration in proximity and suggest that (distant) central R&D units are important orchestrators of research collaboration with universities around the globe.

Les entreprises multinationales s'engagent souvent dans des collaborations de recherche internationales avec des universités étrangères par le biais de l'un de leurs laboratoires centraux de R&D (au siège ou ailleurs) même si elles exploitent une unité de R&D locale, proche de cette université. Elles renoncent ainsi aux avantages de la proximité géographique et de la collaboration locale. Nous appuyant sur la théorie de la firme fondée sur la connaissance, nous développons l'hypothèse que le choix entre les collaborations distantes et locales soit systématiquement lié aux capacités en matière de connaissances des unités de R&D des entreprises, aux caractéristiques des connaissances focales et aux risques de fuites de connaissances locales. L'analyse de près de 13000 collaborations de recherche des principales entreprises biopharmaceutiques (1995-2015) avec des universités étrangères confirme que la collaboration à distance se produira si cela permet à l'entreprise de bénéficier des avantages d'échelle et de diversité des connaissances, si l'unité centrale dispose de solides capacités de recherche fondamentale, et si la collaboration s'inscrit dans un domaine de recherche stratégique des multinationales alors que des entreprises concurrentes sont localement présentes. La maturité du domaine de recherche focal est associée à la collaboration locale. Nos résultats nuancent l'argumentation courante en faveur de la collaboration à proximité, et suggèrent que les unités centrales (et distantes) de R&D soient d'importants orchestrateurs de la collaboration de recherche avec les universités du monde entier.

Las empresas multinacionales con frecuencia participan en colaboraciones de investigación internacionales con universidad extranjeras mediante uno de sus laboratorios de I+D centrales (en la casa matriz o en otra parte) aún cuando operan una unidad de I+D local cerca a esa universidad, y de ahí que proceden los beneficios de la proximidad geográfica y la colaboración local. Basándonos en la teoría de la empresa basada en el conocimiento, planteamos la hipótesis de que la elección entre la colaboración a distancia y la local está sistemáticamente relacionada con las capacidades de conocimiento de las unidades de I+D de las empresas, las características del conocimiento focal y los riesgos de fuga de conocimiento local. Una análisis de cerca de 13.000 colaboraciones de investigación con universidades extranjeras por las empresas biofarmacéuticas más importantes del mundo (1995-2015) confirma que la colaboración a distancia se produce si esto permite a la empresa beneficiarse de las ventajas de escala y de la diversidad de conocimientos, si la unidad central tiene fuertes capacidades de investigación básica, y si la colaboración se produce en un dominio de investigación central de la empresa multinacional mientras que las empresas rivales están presentes a nivel local. La madurez del ámbito de investigación central está asociada a la colaboración local. Nuestros hallazgos habilitan la argumentación común a favor de la colaboración en proximidad y sugieren que las unidades centrales de I+D (distantes) son importantes orquestadoras de la colaboración en investigación con las universidades de todo el mundo.

MNCs frequentemente se envolvem em colaborações de pesquisa internacionais com universidades estrangeiras por meio de um de seus laboratórios centrais de R&D (na sede ou em outro lugar), embora operem uma unidade local de R&D perto dessa universidade e, portanto, renunciam aos benefícios da proximidade geográfica e colaboração local. Com base na teoria baseada no conhecimento da firma, formulamos a hipótese de que a escolha entre colaboração distante e local se relaciona sistematicamente com as capacidades de conhecimento das unidades de R&D das empresas, as características do conhecimento focal e os riscos locais de vazamento de conhecimento. Análise de cerca de 13.000 colaborações de pesquisa com universidades estrangeiras pelas principais empresas biofarmacêuticas do mundo (1995-2015) confirma que a colaboração à distância ocorre se isso permite que a firma se beneficie de vantagens de escala e diversidade de conhecimento, se a unidade central tiver fortes capacidades básicas de pesquisa , e se a colaboração está em um domínio de pesquisa central da MNC enquanto empresas rivais estão localmente presentes. A maturidade do domínio de pesquisa focal está associada à colaboração local. Nossas descobertas qualificam a argumentação comum em favor da colaboração na proximidade e sugerem que as unidades centrais (distantes) de R&D são importantes orquestradoras da colaboração em pesquisa com universidades ao redor do mundo.

Administration of CD4+CD25highCD127- regulatory T cells preserves ß-cell function in type 1 diabetes in children.

OBJECTIVE: Type 1 diabetes is a condition in which pancreatic islets are destroyed by self-reactive T cells. The process is facilitated by deficits in the number and suppressive activity of regulatory T cells (Tregs). Here, we show for the first time that the infusion of autologous Tregs prolongs remission in recently diagnosed type 1 diabetes in children. RESEARCH DESIGN AND METHODS: We have administered Tregs in 10 type 1 diabetic children (aged 8-16 years) within 2 months since diagnosis. In total, 4 patients received 10 × 10(6) Tregs/kg body wt, and the remaining 6 patients received 20 × 10(6) Tregs/kg body wt. The preparation consisted of sorted autologous CD3(+)CD4(+)CD25(high)CD127(-) Tregs expanded under good manufacturing practice conditions. RESULTS: No toxicity of the therapy was noted. A significant increase in the percentage of Tregs in the peripheral blood has been observed since the day of infusion. These patients were followed along with matched type 1 diabetic patients not treated with Tregs. Half a year after type 1 diabetes onset (4-5 months after Tregs infusion), 8 patients treated with Tregs still required <0.5 UI/kg body wt of insulin daily, with 2 patients out of insulin completely, whereas the remission was over in the nontreated group. In addition, plasma C-peptide levels were significantly higher in the treated group as compared with those not treated. CONCLUSIONS: This study shows that the administration of Tregs is safe and tolerable in children with recent-onset type 1 diabetes.