Correction of proliferative responses in purine nucleoside phosphorylase (PNP)-deficient T lymphocytes by retroviral-mediated PNP gene transfer and expression

David M. Nelson, Kim A. Butters, M. Louise Markert, Nancy L. Reinsmoen, R S Mc Ivor

Research output: Contribution to journalArticlepeer-review

14 Scopus citations

Abstract

Purine nucleoside phosphorylase (PNP; EC 2.4.2.1) deficiency is associated with a fatal T cell immunodeficiency in children, a candidate condition for gene therapy by introduction of functional PNP sequences into either T lymphocytes or more primitive progenitor cells in the bone marrow. To test the effectiveness of PNP gene transfer in T lymphocytes, a retroviral vector (LmPSN-2) was designed and constructed to express the murine PNP cDNA under transcriptional regulation of the Moloney murine leukemia virus long terminal repeat. LmPSN-2 was first used to mediate gene transfer and expression of electrophoretically distinct murine PNP in normal (PNP-positive) human PBL. Peripheral blood leukocytes were then obtained from a PNP deficient patient and characterized phenotypically. Despite their paucity and general mitogenic unresponsiveness, T lymphocytes from this patient were successfully grown in culture by using anti-CD3 with rIL-2 and then transduced with LmPSN-2. Elevated PNP enzyme activity was observed in the transduced cell population. Mitogenic and allogeneic responses, normally depressed in PNP-deficient patients' cells, were partially corrected in the transduced cell population relative to nontransduced cells. These results suggest the possibility of effecting improved immunologic function in PNP-deficient T lymphoid cells by retroviral-mediated gene transfer as therapy for PNP deficiency.

Original languageEnglish (US)
Pages (from-to)3006-3014
Number of pages9
JournalJournal of Immunology
Volume154
Issue number6
StatePublished - 1995

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