Home About us Contact
|
Home About us Contact | ||
|
|
||
Vivo Depletion (vivo + depletion)
Selected AbstractsDepletion of tumor-induced Treg prior to reconstitution rescues enhanced priming of tumor-specific, therapeutic effector T cells in lymphopenic hostsEUROPEAN JOURNAL OF IMMUNOLOGY, Issue 11 2009Christian H. Poehlein Abstract We reported previously that vaccination of reconstituted, lymphopenic mice resulted in a higher frequency of tumor-specific effector T cells with therapeutic activity than vaccination of normal mice. Here, we show that lymphopenic mice reconstituted with spleen cells from tumor-bearing mice (TBM), a situation that resembles the clinical condition, failed to generate tumor-specific T cells with therapeutic efficacy. However, depletion of CD25+ Treg from the spleen cells of TBM restored tumor-specific priming and therapeutic efficacy. Adding back TBM CD25+ Treg to CD25, naïve and TBM donor T cells prior to reconstitution confirmed their suppressive role. CD25+ Treg from TBM prevented priming of tumor-specific T cells since subsequent depletion of CD4+ T cells did not restore therapeutic efficacy. This effect may not be antigen-specific as three histologically distinct tumors generated CD25+ Treg that could suppress the T-cell immune response to a melanoma vaccine. Importantly, since ex vivo depletion of CD25+ Treg from TBM spleen cells prior to reconstitution and vaccination fully restored the generation of therapeutic effector T cells, even in animals with established tumor burden, we have initiated a translational clinical trial of this strategy in patients with metastatic melanoma. [source] Therapy-induced antitumor vaccination by targeting tumor necrosis factor-, to tumor vessels in combination with melphalanEUROPEAN JOURNAL OF IMMUNOLOGY, Issue 12 2007Lorenzo Mortara Abstract Treatment of tumor-bearing mice with mouse (m)TNF-,, targeted to tumor vasculature by the anti-ED-B fibronectin domain antibody L19(scFv) and combined with melphalan, induces a therapeutic immune response. Upon treatment, a highly efficient priming of CD4+ T cells and consequent activation and maturation of CD8+ CTL effectors is generated, as demonstrated by in vivo depletion and adoptive cell transfer experiments. Immunohistochemical analysis of the tumor tissue demonstrated massive infiltration of CD4+ and CD8+ T cells 6,days after treatment and much earlier in the anamnestic response to tumor challenge in cured mice. In fact, the curative treatment with L19mTNF-, and melphalan resulted in long-lasting antitumor immune memory, accompanied by a mixed Th1/Th2-type response and significant in vitro tumor-specific cytolytic activity. Finally, the combined treatment reduced the percentage and absolute number of CD4+CD25+ regulatory T cells in the tumor-draining lymph nodes of mice responding to therapy, and this was associated with the establishment of protective immunity. These findings pave the way for alternative therapeutic strategies based on the targeted delivery of biological and pharmacological cytotoxic compounds that not only kill most of the tumor cells but, more importantly, trigger an effective and long-lasting antitumor adaptive immune response. [source] In vivo overexpression of CTLA-4 suppresses lymphoproliferative diseases and thymic negative selectionEUROPEAN JOURNAL OF IMMUNOLOGY, Issue 2 2005Shigekazu Takahashi Abstract Cytotoxic T,lymphocyte antigen-4 (CTLA-4) induces major inhibitory signals for T,cell activation. From analyses of TCR-transgenic (Tg) CTLA-4-deficient mice, it has been believed that CTLA-4 does not affect thymocyte development. To focus upon the in vivo function of CTLA-4 in thymocyte development from a different aspect, we have established Tg mice expressing either full-length CTLA-4 (FL-Tg) or a mutant CTLA-4 lacking the cytoplasmic region (truncated, TR-Tg), and analyzed thymocyte development. TR-T,cells express much higher CTLA-4 on the cell surface than FL-T,cells, in which most CTLA-4 was localized in intracellular vesicles. While CTLA-4,/, mice exhibit lymphoproliferative disease, neither of the Tg mice with CTLA-4,/, background developed the disorder. Although the development of thymocytes appeared normal in both Tg mice, in vivo depletion of double-positive thymocytes by injection of anti-CD3 Ab as well as the elimination of minor lymphocyte-stimulating antigen-reactive thymocytes were impaired in FL-Tg mice but not in TR-Tg mice. Functionally, cross-linking of CTLA-4 on thymocytes from FL-Tg mice, but not from TR-Tg mice, inhibited proliferation. These results reveal a potential role of CTLA-4, through its cytoplasmic domain, in the negative selection of thymocytes and in the prevention of lymphoproliferative disease. [source] A novel role for polyamines in adult neurogenesis in rodent brainEUROPEAN JOURNAL OF NEUROSCIENCE, Issue 2 2004Jordane Malaterre Abstract Although neurogenesis in the adult is known to be regulated by various internal cues such as hormones, growth factors and cell-adherence molecules, downstream elements underlying their action at the cellular level still remain unclear. We previously showed in an insect model that polyamines (putrescine, spermidine and spermine) play specific roles in adult brain neurogenesis. Here, we demonstrate their involvement in the regulation of secondary neurogenesis in the rodent brain. Using neurosphere assays, we show that putrescine addition stimulates neural progenitor proliferation. Furthermore, in vivo depletion of putrescine by specific and irreversible inhibition of ornithine decarboxylase, the first key enzyme of the polyamine synthesis pathway, induces a consistent decrease in neural progenitor cell proliferation in the two neurogenic areas, the dentate gyrus and the subventricular zone. The present study reveals common mechanisms underlying birth of new neurons in vertebrate and invertebrate species. [source] Suppression of splenic macrophage Candida albicans phagocytosis following in vivo depletion of natural killer cells in immunocompetent BALB/c mice and T-cell-deficient nude miceFEMS IMMUNOLOGY & MEDICAL MICROBIOLOGY, Issue 3 2002I Algarra Abstract The resistance of mice to systemic infections caused by Candida albicans is associated with activated splenic macrophages. In addition, there is a correlation between natural killer (NK) cell activation and the resistance to systemic candidiasis. The present study was designed to clarify the role of NK cells in the control of splenic macrophage C. albicans phagocytosis by either depleting NK cells (anti-asialo GM1 treatment) or maintaining them in an activated state (tilorone treatment) in both immunocompetent BALB/c mice and T-cell-deficient nude mice. The results of the in vitro phagocytosis assays were analyzed by flow cytometry and demonstrate the pivotal role of NK cells in controlling the capacity of splenic macrophages to phagocytose C. albicans. In summary, these data provide evidence that the NK cells are the main inducers of phagocytic activity of splenic macrophages and that they mediate the protection against C. albicans systemic infection. [source] Splenic marginal zone antigen-presenting cells are critical for the primary allo-immune response to therapeutic factor VIII in hemophilia AJOURNAL OF THROMBOSIS AND HAEMOSTASIS, Issue 11 2009A. NAVARRETE Summary.,Background: Alloimmune responses to intravenously administered protein therapeutics are the most common cause of failure of replacement therapy in patients with defective levels of endogenous proteins. Such a situation is encountered in some patients with hemophilia A, who develop inhibitory anti-factor (F)VIII alloantibodies after administration of FVIII to treat hemorrhages. Objectives: The nature of the secondary lymphoid organs involved in the initiation of immune responses to human therapeutic has not been studied. We therefore investigated this in the case of FVIII, a self-derived exogenous protein therapeutic. Methods: The distribution of intravenously administered FVIII was followed after FVIII-deficient mice were injected with radiolabeled FVIII and using immunohistochemistry. The role of the spleen and antigen-presenting cells (APC) in the onset of the anti-FVIII immune response was analyzed upon splenectomy or treatment of the mice with APC-depleting compounds. Results: FVIII preferentially accumulated in the spleen at the level of metallophilic macrophages in the marginal zone (MZ). Surgical removal of the spleen or selective in vivo depletion of macrophages and CD11c-positive CD8,-negative dendritic cells resulted in a drastic reduction in anti-FVIII immune responses. Conclusions: Using FVIII-deficient mice as a model for patients with hemophilia A, and human pro-coagulant FVIII as a model for immunogenic self-derived protein therapeutics, our results highlight the importance of the spleen and MZ APCs in the initiation of immune responses to protein therapeutics. Identification of the receptors implicated in retention of protein therapeutics in the MZ may pave the way towards novel strategies aimed at reducing their immunogenicity. [source] Depletion of functionally active CD20+ T cells by rituximab treatmentARTHRITIS & RHEUMATISM, Issue 12 2009Esther Wilk Objective Rituximab is a therapeutic anti-CD20 antibody used for in vivo depletion of B cells in proliferative and autoimmune diseases. However, the mechanisms of action are not fully understood, since not all of the therapy-mediated effects can be explained by the depletion of antibody-secreting cells. In addition to B cells, there is also a small population of T cells coexpressing CD20 in all individuals. This study was conducted to examine the phenotype and function of CD3+CD20+ T cells in patients with rheumatoid arthritis (RA) and healthy controls. Methods The phenotype and apoptosis of peripheral blood mononuclear cells from healthy donors and RA patients were examined by 4-color fluorescence-activated cell sorting analyses. Cytokine production was determined by intracellular staining and measurement of cytokines in the supernatants. Proliferation of sorted T cell populations was analyzed using 3H-thymidine uptake assays. Results In healthy individuals, 0.1,6.8% of peripheral blood T cells (mean 1.6%; n = 142) coexpressed CD20, which was not significantly different from that in the peripheral blood of RA patients, in whom 0.4,2.6% of T cells (mean 1.2%; n = 27) were CD20+. During rituximab therapy, the CD20+ T cells along with the B cells were eliminated from the RA peripheral blood. Among the CD20+ T cells, 45% coexpressed CD8 and 55% coexpressed CD4. Polyclonal CD3+CD20+ cells were functionally characterized by constitutive cytokine production (i.e., interleukin-1, and tumor necrosis factor ,), a low proliferative capacity, a high activation state, and enhanced susceptibility to apoptosis. Conclusion These findings suggest that CD20+ T cells represent a terminally differentiated cell type with immune-regulatory and proinflammatory capacities. Depletion of CD20+ T cells may be an additional mechanism by which anti-CD20 therapy functions in patients with RA. [source] | ||||||||||