Immune reconstitution after autologous peripheral blood progenitor cell transplantation: effect of interleukin-15 on T-cell survival and effector functions


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Article: article from journal or magazin.
Immune reconstitution after autologous peripheral blood progenitor cell transplantation: effect of interleukin-15 on T-cell survival and effector functions
Experimental Hematology
Rutella  S., Pierelli  L., Bonanno  G., Mariotti  A., Sica  S., Sora  F., Chiusolo  P., Scambia  G., Rumi  C., Leone  G.
0301-472X (Print)
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Journal Article
Research Support, Non-U.S. Gov't --- Old month value: Dec
OBJECTIVE: The aim of this study was to evaluate the occurrence of T-cell spontaneous apoptosis (A(spont)) and its modulation in vitro by the interleukin-2 receptor (IL-2R) gamma-chain (gammac)-signaling cytokine IL-15 in patients transplanted with autologous peripheral blood progenitor cells (PBPC) for hematologic malignancies. MATERIALS AND METHODS: Patients were examined on days 30-60, 60-90, and 90-120 after PBPC infusion. Dissipation of mitochondrial transmembrane potential, a hallmark of T-cell apoptosis, has been detected using the fluorescent probe 3,3'-dihexyloxacarbocyanine iodide, after short-term T-cell culture in the absence or presence of exogenous cytokines. Expression of Bcl-2 family members has been studied by flow cytometry and reverse transcriptase polymerase chain reaction. T-cell proliferative responses to recall antigens have been estimated in autologous mixed leukocyte cultures. RESULTS: A(spont) was seen in 45% +/- 6% of CD4(+) and 55% +/- 6% of CD8(+) T cells cultured in the absence of cytokines. Of interest, IL-15 and, to a lesser extent, its structural cousin IL-2 counteracted T-cell A(spont) by inhibiting the processing of caspase-3 and up-regulating Bcl-2 mRNA and protein levels. Cell division tracking confirmed that IL-15 did not rescue T cells from A(spont) by promoting proliferation but rather acted as a genuine survival factor. Addition of a gammac-blocking antibody to cytokine-conditioned cultures abrogated both apoptosis inhibition and Bcl-2 induction by IL-15, suggesting involvement of the IL-2Rgammac signal transduction pathway. Whereas cytokine-unprimed posttransplant T cells mounted inadequate responses to recall antigens, T cells conditioned with IL-15 expanded vigorously, indicating restoration of antigen-specific proliferation. CONCLUSIONS: T cells recovering after autologous PBPC transplantation are highly susceptible to spontaneous apoptosis in vitro. This phenomenon can be counteracted by the gammac-signaling cytokine IL-15. These findings suggest that IL-15 might be a promising immunomodulating agent to improve postgrafting T-cell function.
Actins/genetics Adult Antigens, CD/analysis Apoptosis/drug effects/immunology Cell Survival/*physiology Cytokines/pharmacology Female Hematologic Neoplasms/immunology/*therapy Hematopoietic Stem Cell Transplantation Humans Immunophenotyping Interleukin-15/*pharmacology Interleukin-2/pharmacology Male Middle Aged Proto-Oncogene Proteins/genetics *Proto-Oncogene Proteins c-bcl-2 Reverse Transcriptase Polymerase Chain Reaction Signal Transduction T-Lymphocytes/*immunology/pathology Transplantation, Autologous/immunology bcl-2-Associated X Protein
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28/01/2008 9:33
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20/08/2019 14:42
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