Selective Reconstitution by GM-CSF of the Immune Response in Human Immunosuppressed Cells

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2002
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Xu, Jian
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Selektive Wiederherstellung der Immunantwort in humanem immunsupprimiertem Blut durch GM-CSF
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Abstract
Background: Since infection remains the major complication of immunosuppressive therapy in organ transplantation, reconstitution of the innate immunity against infections, without activation of the acquired immune response, in order to prevent graft rejection, is a clinically desirable status in transplant recipients. This study investigates the reconstitution potential of GM-CSF in immunosuppressed blood from liver transplant patients.

Methods: In vitro and ex vivo immunosuppressed whole blood or PBMC from 10 healthy donors and from 10 liver transplant patients, whose blood was drawn post liver transplantation, was stimulated with LPS or Con A after incubation with GM-CSF. ELISA, RPA, Western-blot and gene array were used to compare ex vivo the cytokine release, mRNA, protein expression and the gene expression profile, altered by GM-CSF under immunosuppression.

Results: GM-CSF restored TNF mRNA and protein expression to the stimulated non-suppression control levels, without inducing IL-2 production and T-cell proliferation in immunosuppressed blood in vitro and ex vivo. In contrast, GM-CSF did not restore the expression of IL-1beta mRNA and protein, but rather enhanced the release of IL-1 receptor antagonist. In contrast to GM-CSF, exogenous IL-1beta restored an IL-2-independent Con A-stimulated proliferation of immunosuppressed lymphocytes to the Con A stimulated control levels, characterized by down-regulation of p27kip1 and up-regulation of Cdk2 and Jab1. This might explain why GM-CSF does not reactivate the lymphocyte response under immunosuppression. Furthermore, gene expression profiling indicated that many genes encoding for the innate immune response were essentially completely restored, while important markers for LPS-responses of lymphocytes were not restored.

Conclusions: The selective restoration of innate immune defense suggests a therapeutic potential of GM-CSF in fighting against infections upon organ transplantation.
Summary in another language
Hintergrund: Infektionen bleiben die Hauptkomplikation der immunsuppressiven Therapie bei Organtransplantationen. Aus klinischer Sicht ist es daher wünschenswert, das angeborene Immunsystem für die Abwehr bakterieller Infektionen in den Transplantat-Empfängern wiederherzustellen, ohne jedoch die spezifische Immunantwort, welche zur Transplantat-Abstoßung führen kann, zu aktivieren. Untersucht diese Arbeit das Potential von GM-CSF zur Wiederherstellung der Immunantwort in immunsupprimiertem Blut.

Methoden: In vitro oder ex vivo supprimiertes Vollblut/PBMC von 10 Gesunden oder von 10 Lebertransplantat-Patienten wurde als klinisches Ausgangsmaterial verwendet. Anschließend (LPS/Con A Modell) wurde die Wirkungen von GM-CSF auf die Zytokin-Freisetzung (gemessen im ELISA), die mRNA (mit RPA) und das Genexpressionsprofil (mit Gene Array Technik) sowie die Proteinexpression (mit Western Blotting) untersucht.

Ergebnisse: GM-CSF stellte nach Stimulation sowohl TNF mRNA als auch TNF-Freisetzung auf die Werte stimulierter Kontrollen wieder her, ohne jedoch die IL-2 Produktion und Lymphozyten-Proliferation in Immunsupprimiertem Blut in vitro und ex vivo zu induzieren. Demgegenüber beeinflußte GM-CSF weder die mRNA- noch die Protein-Expression für IL-1beta. Die Freisetzung von IL-1ra wurde jedoch gegenüber stimulierten Kontrollen mehr als verdoppelt. Im Gegensatz zu GM-CSF induzierte exogenes IL-1beta eine IL-2-unabhängige Proliferation immunsupprimierter Lymphozyten nach Con A-Stimulation, charakterisiert durch eine Regulierung von p27kip1, cdk2 und Jab1. Zusätzlich zeigte das Genexpressions-Profil, daß viele weitere Gene durch GM-CSF in vitro hochreguliert wurden, die für Funktionen des angeborenen Immunsystems kodieren. Im Gegensatz dazu wurden wichtige Marker einer LPS-Antwort von Lymphozyten nicht wiederhergestellt.

Schlussfolgerung: GM-CSF ist von therapeutischer Bedeutung, um Patienten nach einer Lebertransplantation resistenter gegenüber Infektionen zu machen.
Subject (DDC)
570 Biosciences, Biology
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Infection,Immunosuppression,Transplantation
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ISO 690XU, Jian, 2002. Selective Reconstitution by GM-CSF of the Immune Response in Human Immunosuppressed Cells [Dissertation]. Konstanz: University of Konstanz
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@phdthesis{Xu2002Selec-8261,
  year={2002},
  title={Selective Reconstitution by GM-CSF of the Immune Response in Human Immunosuppressed Cells},
  author={Xu, Jian},
  address={Konstanz},
  school={Universität Konstanz}
}
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