IL-15 Is Required for Sustained Lymphopenia-Driven Proliferation and Accumulation of CD8 T Cells

Sandau, Michelle M.; Winstead, Colleen J.; Jameson, Stephen C.

doi:10.4049/jimmunol.179.1.120

Cited by 55 publications

(49 citation statements)

References 35 publications

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“…Indeed, IL-7, produced by stromal cells, is required for homeostatic expansion of naive and memory CD4 and CD8 T cells and is critical for their survival (36). IL-15 drives Ag-independent homeostatic memory CD8 + abT cell proliferation (36,37). IL-7 and IL-15 are also required for gdT cell homeostatic expansion (38).…”

Section: Discussionmentioning

confidence: 99%

Increased Plasma-Immune Cytokines throughout the High-Dose Melphalan-Induced Lymphodepletion in Patients with Multiple Myeloma: A Window for Adoptive Immunotherapy

Condomines

Veyrune²,

Larroque³

et al. 2009

The Journal of Immunology

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High-dose melphalan (HDM) followed by autologous stem cell transplantation (ASCT) is a standard treatment for patients with multiple myeloma. However, lymphocyte reconstitution is impaired after HDM. Recent work has suggested that the lymphopenia period occurring after various immunosuppressive or chemotherapy treatments may provide an interesting opportunity for adoptive antitumor immunotherapy. The objective of this study was to determine an immunotherapy window after HDM and ASCT, evaluating T cell lymphopenia, and measuring circulating immune cytokine concentrations in patients with multiple myeloma. The counts of T cell subpopulations reached a nadir at day 8 post-ASCT (day 10 post-HDM) and recovered by day 30. IL-6, IL-7, and IL-15 plasma levels increased on a median day 8 post-ASCT, respectively, 35-fold, 8-fold, and 10-fold compared with pre-HDM levels (p ≤ 0.05). The increases in IL-7 and IL-15 levels were inversely correlated to the absolute lymphocyte count, unlike monocyte or myeloid counts. Furthermore, we have shown that CD3 T cells present in the ASC graft are activated, die rapidly when they are cultured without cytokine in vitro, and that addition of IL-7 or IL-15 could induce their survival and proliferation. In conclusion, the early lymphodepletion period, occurring 4–11 d post-HDM and ASCT, is associated with an increase of circulating immune cytokines and could be an optimal window to enhance the survival and proliferation of polyclonal T cells present in the ASC autograft and also of specific antimyeloma T cells previously expanded in vitro.

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Section: Discussionmentioning

confidence: 99%

Increased Plasma-Immune Cytokines throughout the High-Dose Melphalan-Induced Lymphodepletion in Patients with Multiple Myeloma: A Window for Adoptive Immunotherapy

Condomines

Veyrune²,

Larroque³

et al. 2009

The Journal of Immunology

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“…Although few studies have investigated the combined use of IL-12 with IL-7 for anti-tumor therapies, there is good rationale for such investigations. IL-12 acts directly on CD8 + T cells to enhance their IL-7 mediated proliferation [46]. Furthermore, IL-7 could stimulate lymphocyte proliferation and was particularly effective at synergizing with IL-2 for the restoration of cytolytic activity of lymphocytes against autologous tumors [47].…”

Section: Il-7/il-12mentioning

confidence: 99%

Immunotherapy of cancer by IL-12-based cytokine combinations

Weiss

Subleski

Wigginton

et al. 2007

Expert Opinion on Biological Therapy

198

118

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Cancer is a multi-faceted disease comprising complex interactions between neoplastic and normal cells. Over the past decade, there has been considerable progress in defining the molecular, cellular and environmental contributions to the pathophysiology of tumor development. Despite these advances, the conventional treatment of patients still generally involves surgery, radiotherapy and/ or chemotherapy and the clinical outcome for many of these efforts remains unsatisfactory. Recent studies have highlighted the feasibility of using immunotherapeutic approaches that seek to enhance host immune responses to developing tumors. These strategies include immunomodulatory cytokines, with tumor necrosis factor (TNF) alpha, type I or type II Interferons (IFNs), Interleukins (IL)-2, IL-12, IL-15 and IL-18 being among the most potent inducers of anti-tumor activity in a variety of pre-clinical studies. More recently, some exciting new cytokines have been characterized, such as IL-21, IL-23, IL-27, and their immunomodulatory and anti-tumor effects in vitro and in vivo suggest that they may have considerable promise for future immunotherapy protocols. The promise of cytokine therapy does indeed derive from the identification of these novel cytokines, but even more fundamentally, the field is greatly benefiting from the ever-expanding amount of preclinical data that convincingly demonstrate synergistic and/or novel biological effects that may be achieved through the use of several combinations of cytokines with complementary immunestimulating capabilities. One cytokine in particular, IL-12, holds considerable promise by virtue of the fact that it plays a central role in regulating both innate and adaptive immune responses, can by itself induce potent anti-cancer effects, and synergizes with several other cytokines for increased immunoregulatory and anti-tumor activities. This review will discuss the anti-tumor activity of IL-12, with a special emphasis on its ability to synergize with other cytokines for enhancement of immune effector cell populations and regulation of host-tumor cell interactions and the overall tumor microenvironment.

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“…9 Memory CD8 T cells and natural killer (NK) cells express the highest levels of IL-2/15Rb chain, making these cells particularly responsive to IL-15. 7,[10][11][12] High systemic levels of IL-7 or IL-15 have been associated with aGVHD development after MA transplantation. [13][14][15][16] Only one study has investigated RIC allo-SCT, but conditioning was preceded by intensive induction chemotherapy, 17 resulting in IL-7 levels twice as great as after MA conditioning.…”

Section: Introductionmentioning

confidence: 99%

Plasma levels of IL-7 and IL-15 after reduced intensity conditioned allo-SCT and relationship to acute GVHD

Thiant

Labalette

Trauet

et al. 2010

Bone Marrow Transplant

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To assess the impact of homeostatic expansion on the occurrence of acute GVHD after reduced intensity conditioning (RIC) transplantation, systemic levels of IL-7 and IL-15 and expression of their specific receptor chains were prospectively investigated in 45 fully HLAmatched allograft recipients. IL-7 and IL-15 levels peaked at four-to fivefold over pre-conditioning values. IL-7 levels were inversely correlated to absolute T-cell counts. Peak IL-15 levels positively correlated to concurrent CRP levels, but normalized earlier than IL-7. These results indicate that the kinetic course of IL-7 depends mainly on initiation of T-cell recovery, while IL-15 depends more on peri-transplant inflammation after RIC. Longer duration of the rise in IL-7 levels was associated with preservation of a normal CD4/CD8 ratio. In all, 16 (35%) patients developed grade 2-4 acute GVHD at a median of 42 days post graft, preceded by higher IL-7 levels and more downregulation of IL-7 receptor a chain on CD4 þ T cells than in patients without acute GVHD, suggesting enhanced homeostatic expansion. In multivariate analysis, IL-7 level measured on day þ 30 was the foremost predictive factor for grade 2-4 acute GVHD (P ¼ 0.002). Measurement of IL-7 level after RIC transplantation might help predict risk of subsequent acute GvHD.

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IL-15 Is Required for Sustained Lymphopenia-Driven Proliferation and Accumulation of CD8 T Cells

Cited by 55 publications

References 35 publications

Increased Plasma-Immune Cytokines throughout the High-Dose Melphalan-Induced Lymphodepletion in Patients with Multiple Myeloma: A Window for Adoptive Immunotherapy

Increased Plasma-Immune Cytokines throughout the High-Dose Melphalan-Induced Lymphodepletion in Patients with Multiple Myeloma: A Window for Adoptive Immunotherapy

Immunotherapy of cancer by IL-12-based cytokine combinations

Plasma levels of IL-7 and IL-15 after reduced intensity conditioned allo-SCT and relationship to acute GVHD

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