Browsing by Author "Lapenna, Antonio"

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    Immunotherapy of immunosenesence; who, how and when?
    (Bentham open, 2012-12-31T00:00:00Z) Govind, Sheila; Lapenna, Antonio; Lang, Pierre-Olivier; Aspinall, Richard
    Major changes in social welfare, economic conditions and medical knowledge over the last 60 years have pro-duced a demographic shift in the population. More individuals are living longer, and in a decade there will be more people over 65 than infants under 5 for the first time in history. Taking the analysis beyond mere numbers reveals that older indi-viduals are now physically more active than their forebears and travel more widely. This provides a greater opportunity for encountering infectious agents which could present a considerable problem. Older individuals are more susceptible to infection and do not respond as well as younger people to vaccination because of an age related decline in immunity, a state which has been termed immunosenesence. This decline is not uniform and some older individuals show a greater de-cline in their immune response than others. In this review we have sought to consider who are the ‘at risk' individuals, how they might best be treated and when.
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    A simple model system enabling human CD34+ cells to undertake differentiation towards T cells
    (PLOS (Public Library of Science), 2013-07-23T00:00:00Z) Lapenna, Antonio; B-Lynch, Christopher; Kapeni, Chrysa; Aspinall, Richard
    Channelling the development of haematopoietic progenitor cells into T lymphocytes is dependent upon a series of extrinsic prompts whose temporal and spatial sequence is critical for a productive outcome. Simple models of human progenitor cells development depend in the main on the use of xenogeneic systems which may provide some limitations to development. Here we provide evidence that a simple model system which utilises both human keratinocyte and fibroblast cell lines arrayed on a synthetic tantalum coated matrix provides a permissive environment for the development of human CD34⁺ haematopoietic cells into mature CD4⁺ or CD8⁺ T lymphocytes in the presence of Interleukin 7 (IL-7), Interleukin 15 (IL-15) and the Fms-like tyrosine kinase 3 ligand (Flt-3L). This system was used to compare the ability of CD34(+) cells to produce mature thymocytes and showed that whilst these cells derived from cord blood were able to productively differentiate into thymocytes the system was not permissive for the development of CD34(+) cells from adult peripheral blood. Our study provides direct evidence for the capacity of human cord blood CD34(+) cells to differentiate along the T lineage in a simple human model system. Productive commitment of the CD34⁺ cells to generate T cells was found to be dependent on a three-dimensional matrix which induced the up-regulation of the Notch delta-like ligand 4 (Dll-4) by epithelial cells.
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    T cells development in vitro : a minimalist approach
    (Cranfield University, 2012-04) Lapenna, Antonio; Aspinall, Richard
    T lymphocytes are considered an essential and advanced component of the immune system, since these cells are able to discriminate self from non-self, start up an immune reaction and further develop into memory cells. However, therapies based on the use of patient derived newly generated T cells reinoculated into humans do not exist. This is due to difficulties in replicating the peculiar conditions required for T cell development in vitro. The systems developed so far are based on the use of animal or unrelated human thymic tissue and therefore they would not be adequate to be used in any clinical application. Having conjectured that human skin cells, rearranged in a threedimensional fashion, would be able to support the development of human T lymphocytes from hematopoietic stem cells, we developed a model consisting of human skin keratinocytes and fibroblasts arrayed on a synthetic matrix so to create a prototype suitable to be translated into the clinic. In this way we were able to induce few hundred cord blood CD34⁺ haematopoietic stem cells to entirely develop into mature CD4⁺ or CD8⁺ T lymphocytes in vitro. However, circulating adult peripheral CD34⁺ precursors failed to survive in the same conditions. Finally we were able to explain our success as consequence of strong induction of the Notch delta ligand Dll-4 by the keratinocytes cultured in the construct. In synthesis, we report here for the first time that skin keratinocytes, in the presence of fibroblasts and reconfigured in a three-dimensional arrangement, are able to induce the differentiation of a minimal amount of cord but not adult blood stem cells into fully differentiated T cells by acting through the Dll-4 Notch signaling pathway in vitro.