Immune Modulation with Interleukin-21 (original) (raw)
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Cancer Immunology, Immunotherapy, 2008
Purpose Human interleukin-21 (IL-21) is a class I cytokine previously reported in clinical studies on immune responsive cancers. Here we report the eVects of systemic IL-21 therapy on the immune system in two phase 1 trials with this novel cytokine. Experimental design Recombinant IL-21 was administered by intravenous bolus injection at dose levels from 1 to 100 g/kg using two planned treatment regimens: thrice weekly for 6 weeks (3/week); or once daily for Wve consecutive days followed by nine dose-free days (5 + 9). The following biomarkers were studied in peripheral blood mononuclear cells (PBMC) during treatment: phosphorylation of STAT3, alterations in the composition of leukocyte subsets, ex vivo cytotoxicity, expression of eVector molecules in enriched CD8 + T cells and CD56 + NK cells by quantitative RT-PCR, and gene array proWling of CD8 + T cells. Results EVects of IL-21 were observed at all dose levels. In the 5 + 9 regimen IL-21 induced a dose dependent decrease in circulating NK cells and T cells followed by a return to baseline in resting periods. In both CD8 + T cells and CD56 + NK cells we found up-regulation of perforin and granzyme B mRNA. In addition, full transcriptome analysis of CD8 + T cells displayed changes in several transcripts associated with increased cell cycle progression, cellular motility, and immune activation. Finally, cytotoxicity assays showed that IL-21 enhanced the ability of NK cells to kill sensitive targets ex vivo. Conclusions IL-21 was biologically active at all dose levels administered with evidence of in vivo NK cell and CD8 + T cell activation.
Interleukin-21: a modulator of lymphoid proliferation, apoptosis and differentiation
Nature Reviews Immunology, 2005
The interleukin-21 (IL-21)-IL-21-receptor system was discovered in 2000. It was immediately of great interest because of the homology of IL-21 to IL-2, IL-4 and IL-15, and of the IL-21-receptor subunit IL-21R to the beta-subunit of the IL-2 receptor, and because the IL-21 receptor also contains the common cytokine-receptor gamma-chain, the protein that is mutated in X-linked severe combined immunodeficiency. As we discuss, IL-21 has pleiotropic actions, from augmenting the proliferation of T cells and driving the differentiation of B cells into memory cells and terminally differentiated plasma cells to augmenting the activity of natural killer cells. Moreover, it has antitumour activity and might have a role in the development of autoimmunity, so these findings have implications for the treatment of cancer and autoimmune diseases.
Clinical Cancer Research, 2008
Purpose: Interleukin 21 (IL-21) is a promising new cytokine, which is undergoing clinical testing as an anticancer agent. Although IL-21 provides potent stimulation of CD8+ T cells, it has also been suggested that IL-21 is immunosuppressive by counteracting the maturation of dendritic cells. The dissociation of these two opposing effects may enhance the utility of IL-21 as an immunotherapeutic. In this study, we used a cell-based artificial antigen-presenting cell (aAPC) lacking a functional IL-21 receptor (IL-21R) to investigate the immunostimulatory properties of IL-21. Experimental Design: The immunosuppressive activity of IL-21 was studied using human IL-21R+ dendritic cells. Antigen-specific CD8+ T cells stimulated with human cell–based IL-21R-aAPC were used to isolate the T-cell immunostimulatory effects of IL-21. The functional outcomes, including phenotype, cytokine production, proliferation, and cytotoxicity were evaluated. Results: IL-21 limits the immune response by maint...
The Journal of Immunology, 2009
V␥9V␦2 T lymphocytes are a major human ␥␦ T cell subset that react against a wide array of tumor cells, through recognition of phosphorylated isoprenoid pathway metabolites called phosphoantigens. Immunotherapeutic protocols targeting V␥9V␦2 T cells have yielded promising, yet limited, signs of antitumor efficacy. To improve these approaches, we analyzed the effects on ␥␦ T cells of IL-21, a cytokine known to enhance proliferation and effector functions of CD8 ؉ T cells and NK cells. IL-21 induced limited division of phosphoantigen-stimulated V␥9V␦2 T cells, but did not modulate their sustained expansion induced by exogenous IL-2. V␥9V␦2 T cells expanded in the presence of IL-21 and IL-2 showed enhanced antitumor cytolytic responses, associated with increased expression of CD56 and several lytic molecules, and increased tumor-induced degranulation capacity. IL-21 plus IL-2-expanded V␥9V␦2 T cells expressed higher levels of inhibitory receptors (e.g., ILT2 and NKG2A) and lower levels of the costimulatory molecule NKG2D. Importantly, these changes were rapidly and reversibly induced after short-term culture with IL-21. Finally, IL-21 irreversibly enhanced the proinflammatory Th1 polarization of expanded V␥9V␦2 T cells when added at the beginning of the culture. These data suggest a new role played by IL-21 in the cytotoxic and Th1 programming of precommitted Ag-stimulated ␥␦ T cells. On a more applied standpoint, IL-21 could be combined to IL-2 to enhance ␥␦ T cell-mediated antitumor responses, and thus represents a promising way to optimize immunotherapies targeting this cell subset.
Biological Functions of Interleukin-21 and Its Role in Inflammation
The Scientific World JOURNAL, 2007
Interleukin-21 (IL-21), the most recently discovered CD132-dependent cytokine, is mainly produced by activated T lymphocytes, particularly the inflammatory Th17subset, and is believed to be a key factor in the transition between innate and acquired immunity. In the last few years, this cytokine has been shown to modulate the functions of T, B, and NK cells, as well as cells of myeloid origin. In addition, it was demonstrated that IL-21 is a potent antitumor agent, making it a promising candidate for the development of therapeutic tools. IL-21 has also been associated with different autoimmune and inflammatory diseases, such as rheumatoid arthritis and inflammatory bowel disease. This review will summarize the biological functions of IL-21 and its potential role in inflammation.
IL-21: a novel IL-2–family lymphokine that modulates B, T, and natural killer cell responses
Journal of Allergy and Clinical Immunology, 2003
IL-21 is a recently described type I cytokine produced by activated CD4 + T cells that profoundly affects the growth, survival, and functional activation of B, T, and natural killer lymphocytes in concert with other cytokines or activating stimuli. Structurally, IL-21 is predicted to display a 4helix-bundle-type fold with significant homology to IL-2, IL-4, and IL-15 and mediates its biologic effects through a novel type I cytokine receptor, IL-21R, in conjunction with the common cytokine receptor γ chain (γc) of the IL-2, IL-4, IL-7, IL-9, and IL-15 receptors. As a new member of the γc-dependent cytokine family, there is significant interest in IL-21, in part because of its potential to provide new insights into the immunologic phenotype caused by γc deficiency. IL-21R knockout mice have been generated that have normal lymphoid cell development yet exhibit impaired production of the immunoglobulin IgG 1 and increased IgE responses after immunization. As expected for cytokines that use γc, recent studies indicate that IL-21 induces Janus kinase 1 (JAK1) and JAK3 activation to initiate signal transduction, but unlike these other γc-dependent cytokines, which predominantly activate signal transducer and activator of transcription 5 (STAT5), IL-21 preferentially activates STAT1 and STAT3. IL-21 potently enhances primary antigen responses and the effector functions of T and natural killer cells and stimulates IFN-γ production alone or in concert with other cytokines. Thus, on the basis of primary structure, receptor composition, and biologic activities, IL-21 is a new IL-2-family cytokine that participates in both innate and adaptive immunity and might be important for the development of a T H 1 immune response. (J Allergy Clin Immunol 2003;112:1033-45.)