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Transfer of the ADA gene into human ADA-deficient T lymphocytes
reconstitutes specific immune functions
G Ferrari, S Rossini, N Nobili, D Maggioni, A Garofalo, R Giavazzi, F Mavilio and C Bordignon
Department of Biology and Biotechnology, Istituto Scientifico San Raffaele,
Milano, Italy.
Peripheral blood lymphocytes obtained from a patient affected by adenosine
deaminase (ADA) deficiency and severe combined immunodeficiency were
infected with a retroviral vector containing two copies of a human ADA
minigene, and injected into bg/nu/xid (BNX) immunodeficient mice. Six to 10
weeks after injection, human T cells were cloned from the spleens of
recipient animals and analyzed for proliferative potential, T-cell surface
markers, expression of ADA activity, integration of retroviral sequences,
T-cell receptor (TCR) beta gene rearrangement, and specificity of antigen
recognition. Efficient gene transfer and expression restored proliferative
potential in vitro and long-term survival in vivo. All clonable human T
lymphocytes obtained from the spleen of recipient animals had high levels
of vector-derived ADA enzyme activity and showed predominantly the CD4+
phenotype. Retroviral integrations and TCR-beta gene rearrangements
demonstrated the presence of a variety of different clones in the spleens
of recipient mice. Furthermore, the combined analyses of vector integration
and TCR rearrangement provided evidence that a circulating progenitor cell
was transduced by the retroviral vector, giving rise to different and
functional TCRs. Evaluation of antigen-specificity demonstrated both
alloreactive and foreign antigen specific immune responses. These results
suggest that restoration of enzyme activity in human ADA-deficient
peripheral blood T cells by retroviral-mediated ADA gene transfer allows in
vivo survival and reconstitution of specific immune functions. Therefore,
retroviral vector-mediated gene transfer into circulating mononuclear cells
could be successful not only in maintaining the metabolic homeostasis, but
also for the development of a functional immune repertoire. This is a
fundamental prerequisite for the usage of genetically engineered peripheral
blood lymphocytes for somatic cell gene therapy of ADA deficiency.
Volume 80,
Issue 5,
pp. 1120-1124,
09/01/1992
Copyright © 1992 by The American Society of Hematology
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