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Naïve Cells (naive + cell)

Distribution by Scientific Domains

Medical Sciences	80%

Selected Abstracts

Continuous generation of colitogenic CD4+ T cells in persistent colitis

EUROPEAN JOURNAL OF IMMUNOLOGY, Issue 5 2008
Takayuki Tomita
Abstract Inflammatory bowel diseases take chronic courses due to the expansion of colitogenic CD4+ cells. However, it is unclear whether the persistent disease is driven by continuous reactivation of colitogenic memory CD4+ cells to generate effector CD4+ cells or by continuous generation of effector CD4+ cells from naïve cells. To clarify this issue, we performed a series of sequential adoptive transfers of Ly5.2+ and Ly5.1+ CD4+CD45RBhigh cells into RAG-2,/, mice at different time points. We show here that the secondarily transferred CD4+CD45RBhigh cells can be converted to CD4+CD44highCD62L,IL-7R,high effector-memory T cells even in the presence of pre-existing effector-memory CD4+ cells. Although the total cell numbers of CD4+ cells in established colitic mice were consistently equivalent irrespective of the number of primarily transferred cells, the ratio of primarily and secondarily transferred cells was dependent on the ratio of the transferred cell numbers, but not on the order of the transfer. Of note, we found that primarily transferred CD4+ cells produced significantly lower amounts of IFN-, and IL-17 than CD4+ cells arising from secondary transfer. In conclusion, the continuous generation of colitogenic CD4+ cells that compensate for exhausted CD4+ cells may be one of the mechanisms involved in the persistence of colitis. [source]

A novel inducible tyrosine kinase receptor to regulate signal transduction and neurite outgrowth

JOURNAL OF NEUROSCIENCE RESEARCH, Issue 12 2009
Ronald W. Alfa
Abstract Nervous system growth factor gene delivery can promote axonal growth and prevent cell death in animal models of CNS trauma and neurodegenerative diseases. The ability to regulate growth factor expression or signaling pathways downstream from growth factor receptors remains a desirable goal for in vivo gene transfer. To achieve precise pharmacological modulation of neurotrophin activity, we have generated a chimeric trkA receptor (ItrkA) by fusing the entire intracellular domain of the trkA high-affinity NGF receptor to two intracellular, modified FK506 binding domains for the synthetic small molecule dimerization ligand AP20187. Rat PC12 cells were transduced with lentiviral vectors containing ItrkA and green fluorescent protein (GFP; via an internal ribosome entry site). Treatment of ItrkA-expressing PC12 cells with AP20187 induced neurite outgrowth and differentiation in a time- and dose-dependent fashion, with a half-maximal response at a concentration of 1 nM AP20187. Seventy percent of cells responded to AP20187 by day 3. Western blots demonstrated that AP20187 treatment resulted in phosphorylation of Erk1/2 and Akt in ItrkA-transduced PC12 cells but not in nontransduced, naïve cells. Phosphorylation levels were comparable to levels obtained with 50 ng/ml nerve growth factor (NGF). In addition, ItrkA lentiviral transduction of primary E15 dorsal root ganglion neurons significantly increased neurite growth three- to fourfold in the presence of AP20187 compared with control GFP transduced and naïve neurons. These results demonstrate that small ligand-induced dimerization of the intracellular domain of trkA can efficiently simulate the biological activity of NGF and provide a means to regulate intracellular neurotrophin receptor signaling. © 2009 Wiley-Liss, Inc. [source]

Differential Role of Naïve and Memory CD4+ T-Cell Subsets in Primary Alloresponses

AMERICAN JOURNAL OF TRANSPLANTATION, Issue 8 2010
D. Golshayan
The T cell response to major histocompatibility complex (MHC) alloantigens occurs via two main pathways. The direct pathway involves the recognition of intact allogeneic MHC:peptide complexes on donor cells and provokes uniquely high frequencies of responsive T cells. The indirect response results from alloantigens being processed like any other protein antigen and presented as peptide by autologous antigen-presenting cells. The frequencies of T cells with indirect allospecificity are orders of magnitude lower and comparable to other peptide-specific responses. In this study, we explored the contributions of naïve and memory CD4+ T cells to these two pathways. Using an adoptive transfer and skin transplantation model we found that naive and memory CD4+ T cells, both naturally occurring and induced by sensitization with multiple third-party alloantigens, contributed equally to graft rejection when only the direct pathway was operative. In contrast, the indirect response was predominantly mediated by the naïve subset. Elimination of regulatory CD4+CD25+ T cells enabled memory cells to reject grafts through the indirect pathway, but at a much slower tempo than for naïve cells. These findings have implications for better targeting of immunosuppression to inhibit immediate and later forms of alloimmunity. [source]

Investigation of Lymphocyte Depletion and Repopulation Using Alemtuzumab (Campath-1H) in Cynomolgus Monkeys

AMERICAN JOURNAL OF TRANSPLANTATION, Issue 4 2010
D. J. Van Der Windt
As the target CD52 molecule is expressed on erythrocytes of most nonhuman primate strains, using alemtuzumab in these species would cause massive hemolysis. Six cynomolgus monkeys of Indonesian origin, screened by agglutination assay for absence of CD52 on erythrocytes, were administered alemtuzumab in a cumulative dose to a maximum of 60 mg/kg. In two monkeys, mycophenolate mofetil (MMF) was added as maintenance therapy. Complete depletion of T and B lymphocytes (>99.5%) was achieved with 20 mg/kg alemtuzumab and was more profound than in monkeys treated with antithymocyte globulin (n = 5), as quantified by flow cytometry. Repopulation was suppressed by weekly injections of 10 mg/kg. Without MMF, repopulation of CD20+B cells and CD8+T cells was complete within 2 and 3 months, respectively, and repopulation of CD4+T cells was 67% after 1 year. MMF significantly delayed CD4+T-cell repopulation. Among repopulating CD4+ and CD8+ T cells, a phenotypic shift was observed from CD45RAhiCD62Lhi naïve cells toward CD45RAloCD62Llo effector memory cells. In lymph nodes, the depletion of naïve cells was more profound than of memory cells, which may have initiated a proliferation of memory cells. This model offers opportunities to investigate lymphocyte depletion/repopulation phenomena, as well as the efficacy of alemtuzumab in preclinical transplantation models. [source]