Burn-Induced Local and Systemic Immune Response: Systematic Review and Meta-Analysis of Animal Studies

Contains fulltext : 284423.pdf (Publisher’s version ) (Open Access

BCG vaccination-induced acquired control of mycobacterial growth differs from growth control preexisting to BCG vaccination

Bacillus Calmette-Guèrin - vaccination induces not only protection in infants and young children against severe forms of tuberculosis, but also against nontuberculosis related all-cause mortality. To delineate different factors influencing mycobacterial growth control, here we first investigate the effects of BCG-vaccination in healthy Dutch adults. About a quarter of individuals already control BCG-growth prior to vaccination, whereas a quarter of the vaccinees acquires the capacity to control BCG upon vaccination. This leaves half of the population incapable to control BCG-growth. Single cell RNA sequencing identifies multiple processes associated with mycobacterial growth control. These data suggest (i) that already controllers employ different mechanisms to control BCG-growth than acquired controllers, and (ii) that half of the individuals fail to develop measurable growth control irrespective of BCG-vaccination. These results shed important new light on the variable immune responses to mycobacteria in humans and may impact on improved vaccination against tuberculosis and other diseases.Immunogenetics and cellular immunology of bacterial infectious disease

Allo-specific immunosuppression by relatory T cells.

Contains fulltext : 19528.pdf (publisher's version ) (Open Access)Transplantation of an allogeneic donor organ results in recipient T cell activation. Under normal circumstances there is a balance between aggressive T cells and suppressive regulatory T cells. In case of transplantation especially the aggressive T cells will divide and initiate rejection. Nowadays, immunosuppressive drugs are used to inhibit T cell expansion, thereby preventing graft rejection. These drugs have many side effects and act in a non-antigen specific way, meaning that also desired T cell responses against pathogens are inhibited. Hence, it is crucial to develop donor specific immuno suppressive modalities. This might be established by therapeutic approaches that shift the balance between aggressive and suppressive regulatory T cell towards donor specific regulatory T cells. In our laboratory we focus on donor specific immunotherapy with ex vivo generated donor (alloantigen)-specific regulatory T cells. In this thesis, ex vivo generation and expansion protocols are described that result in donor antigen-specific regulatory T cells. These cells are of great importance for donor specific immunotherapy in transplantation and offer a route to permanent graft survival without the need for life-long non-specific immunosuppression.KUN Katholieke Universiteit Nijmegen, 12 november 2004Promotor : Pauw, B.E. de Co-promotor : Joosten, I.200 p

Antigen-specific regulatory T-cell subsets in transplantation tolerance regulatory T-cell subset quality reduces the need for quantity.

Contains fulltext : 50679.pdf (publisher's version ) (Closed access)Regulatory T cells (Treg) are critical controllers of the immune response. Disturbed Treg function results in autoimmunity, whereas in transplantation Treg are crucial in graft survival and transplant tolerance. Hence therapeutic modalities that influence Treg numbers or function hold great clinical opportunity. Ahead of us are clinical trails studying in vivo Treg induction protocols and immunotherapy with ex vivo expanded Treg. Here we discuss the preferential use and/or induction of antigen-specific Treg subsets with high suppressive power and migratory capacity as a potential therapeutic tool to prevent solid organ transplantation rejection. Accordingly, ex vivoselection procedures to induce and isolate highly suppressive antigen-specific Treg (subsets) are needed. This subject, as well as the Treg-facilitating potential of immunosuppressive agents, is discussed

CD27/CFSE-based ex vivo selection of highly suppressive alloantigen-specific human regulatory T cells.

Contains fulltext : 47575.pdf (publisher's version ) (Closed access)Naturally occurring CD4(+)CD25(+) regulatory T cells (Treg) are crucial in immunoregulation and have great therapeutic potential for immunotherapy in the prevention of transplant rejection, allergy, and autoimmune diseases. The efficacy of Treg-based immunotherapy critically depends on the Ag specificity of the regulatory T cells. Moreover, the use of Ag-specific Treg as opposed to polyclonal expanded Treg will reduce the total number of Treg necessary for therapy. Hence, it is crucial to develop ex vivo selection procedures that allow selection and expansion of highly potent, Ag-specific Treg. In this study we describe an ex vivo CFSE cell sorter-based isolation method for human alloantigen-specific Treg. To this end, freshly isolated CD4(+)CD25(+) Treg were labeled with CFSE and stimulated with (target) alloantigen and IL-2 plus IL-15 in short-term cultures. The alloantigen-reactive dividing Treg were characterized by low CFSE content and could be subdivided by virtue of CD27 expression. CD27/CFSE cell sorter-based selection of CD27(+) and CD27(-) cells resulted in two highly suppressive Ag-specific Treg subsets. Each subset suppressed naive and Ag-experienced memory T cells, and importantly, CD27(+) Treg also suppressed ongoing T cell responses. Summarizing, the described procedure enables induction, expansion, and especially selection of highly suppressive, Ag-specific Treg subsets, which are crucial in Ag-specific, Treg-based immunotherapy

Stabilizing human regulatory T cells for tolerance inducing immunotherapy

Item does not contain fulltextMany autoimmune diseases develop as a consequence of an altered balance between autoreactive immune cells and suppressive FOXP3+ Treg. Restoring this balance through amplification of Treg represents a promising strategy to treat disease. However, FOXP3+ Treg might become unstable especially under certain inflammatory conditions, and might transform into proinflammatory cytokine-producing cells. The issue of heterogeneity and instability of Treg has caused considerable debate in the field and has important implications for Treg-based immunotherapy. In this review, we discuss how Treg stability is defined and what the molecular mechanisms underlying the maintenance of FOXP3 expression and the regulation of Treg stability are. Also, we elaborate on current strategies used to stabilize human Treg for clinical purposes. This review focuses on human Treg, but considering that cell-intrinsic mechanisms to regulate Treg stability in mice and in humans might be similar, data derived from mice studies are also discussed in this paper

Ex vivo expansion of human CD4+ CD25high regulatory T cells from transplant recipients permits functional analysis of small blood samples.

Contains fulltext : 49881.pdf (publisher's version ) (Closed access)Regulatory T cell (Treg) function is associated with immune tolerance and could serve as a biomarker for optimization of immunosuppressive regimens. This is hampered by the limited number of Treg in the blood circulation; functional Treg analysis requires large volumes of blood or is dependent on indirect analysis. A more attractive strategy is the ex vivo expansion of Treg, provided the original T cell pool remains unaltered. Here, we show that it is possible to ex vivo expand Treg from limited amounts of blood, preserving the original TCR Vbeta repertoire and suppressive capacity. The protocol proved successful in selected renal transplant recipients and leukopenic patients. Sampling of 10-20 ml blood sufficed; Treg numbers increased over 100-fold during the 2-3 week expansion period, easily reaching cell numbers required for functional analysis (>10(6) cells). This protocol will facilitate the monitoring of Treg function in patients in order to address the role of Treg in transplantation tolerance

Immunotherapy with regulary T-cells in transplantation.

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