Interleukin-15 enhances immune reconstitution after allogeneic bone marrow transplantation

Department of Medicine, Memorial Sloan-Kettering Cancer Center, New York, NY 10021, USA.
Blood (Impact Factor: 10.45). 02/2005; 105(2):865-73. DOI: 10.1182/blood-2003-09-3344
Source: PubMed


Interleukin-15 (IL-15) is a gamma-common cytokine that plays an important role in the development, survival, and proliferation of natural killer (NK), NK T, and CD8+ T-cells. We administered IL-15 to recipients of an allogeneic bone marrow transplantation (allo BMT) to determine its effects on immune reconstitution. Posttransplantation IL-15 administration significantly increased donor-derived CD8+ T (mostly CD122(+)CD44(+)CD8+ T-cells), NK, and NK T-cells at day +28 in young and old recipients of allo BMT. This was associated with enhanced T-cell and NK-cell function. IL-15 stimulated homeostatic proliferation of donor CD8+ T-cells in recipients of carboxyfluorescein diacetate succinimidyl ester-labeled donor T-cell infusions. Posttransplantation IL-15 administration also resulted in a decrease in apoptotic CD8+ T-cells, an increase in Bcl-2-expressing CD8+ T-cells, and an increase in the fraction of Ki67+ proliferative NK and CD8+ T-cells in recipients of allo BMT. IL-15 did not exacerbate graft-versus-host disease (GVHD) in recipients of T-cell-depleted BMT but could aggravate GVHD in some cases in recipients of a T-cell-repleted BMT. Finally, we found that IL-15 administration could enhance graft-versus-leukemia activity. In conclusion, IL-15 can be administered safely to recipients of a T-cell-depleted allo BMT to enhance CD8+ T, NK, and NK T-cell reconstitution.

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    • "IL-15 has been shown to improve immune reconstitution after allo-HCT in animals [105]. Deregulation of endogenous IL-15 expression or administration of exogenous IL-15 can increase acute GVHD lethality in the presence of donor-derived allogeneic T cells [105] [106]. Moreover, acute GVHD lethality significantly decreased in the absence of donor-derived IL-15 expression, although donor T-cell reconstitution and GVT effects were maintained [107]. "
    Dataset: 0007CSCR

    Full-text · Dataset · Sep 2014
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    • "Distinct from IL-2, IL-15 is mainly produced by monocytes with wide tissue distribution and prevents activation induced cell death [9]. IL-15 has been shown to improve immune reconstitution after allogeneic bone marrow transplantation in animals [10] and enhance in vitro T cell survival and effector function after human autologous stem cell transplant [11]. Recent reports, however, incriminate IL-15 as playing a critical role in allogeneic GVHD [12] [13]. "
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    ABSTRACT: Interleukin(IL)-15 is a promising immunotherapeutic agent for immune reconstitution following stem cell transplantation. To investigate whether IL-15 would aggravate graft-versus-host disease (GVHD) in the setting of unrelated umbilical cord blood (CB) transplantation, we examined the effect of IL-15 on activation marker expression, proliferation and cytokine production of CB in a one-way mixed lymphocyte culture (MLC) assay. We found that IL-15 differentially enhanced CD69 and CD25 expression on CB T cells following allo-stimulation. The maximum degree of allo-specific CB proliferation was achieved on Day 6. IL-15 down-regulated the CB alloreactive proliferative response on Days 4, 6, and 8, with preferentially enhanced autologous proliferation. Exogenous IL-15 further enhanced CB TNF-alpha and IL-10 production in both autologous and allogeneic MLC 6 days after allopriming. Thus, IL-15 was effective in enhancing activation marker expression and cytokine production during CB alloreactivity, but failed to enhance allospecific proliferation. Further studies would be needed to study the role of IL-15 on GVHD in the setting of CB transplantation.
    Preview · Article · Sep 2006 · Transplant Immunology
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    ABSTRACT: Hematopoietic stem cell transplantation (HSCT) is associated with a period of immune incompetence that particularly affects the T cell lineage. Strategies to enhance T cell reconstitution could significantly improve the survival of HSCT recipients by decreasing the incidence of fatal infectious complications and by enhancing graft-versus-tumor activity. In recent years, a variety of promising strategies have been established in preclinical models to improve T cell recovery in particular after allogeneic T cell-depleted HSCT, without aggravating graft-versus-host disease while preserving or even improving graft-versus-tumor activity. These therapies include treatment with keratinocyte growth factor (KGF), growth hormone (GH), LHRH agonists, interleukin 7 (IL-7) and interleukin 15 (IL-15). Thanks to the establishment of Notch-based culture systems, adoptive cellular therapies with T lineage-committed precursor cells have become feasible, since early T cell progenitors can now easily be generated in vitro in large quantities and have been proven to be very effective in enhancing T cell reconstitution and anti-tumor activity after allogeneic T cell-depleted HSCT. The translation of most of these strategies into clinical trials is likely and in some cases Phase I/II studies are already underway.
    Full-text · Article · Jan 2008 · Blood Cells Molecules and Diseases
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