Use of an Antibody Against the Soluble Interleukin 2 Receptor Α Subunit Can Modulate the Stability and Biodistribution of Interleukin-2

Kobayashi, Hisataka; Tagaya, Yutaka; Han, Eui-Sik; Kim, Insook; Le, Nhat; Paik, Chang H.; Pastan, Ira; Nelson, David L.; Waldmann, Thomas A.; Carrasquillo, Jorge A.

doi:10.1006/cyto.1999.0509

Cited by 16 publications

(13 citation statements)

References 40 publications

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“…This notion deserves consideration because the enhancing effect of sIL-15R␣-Fc on IL-15 function was more pronounced in vivo than in vitro. Here, it is notable that binding of certain cytokines to antibodies or soluble receptors can extend cytokine survival in vivo (31)(32)(33)(34)(35)(36). Consistent with this view, binding to sIL-15R␣-Fc did extend the half-life of IL-15 in vivo.…”

Section: Discussionsupporting

confidence: 56%

Converting IL-15 to a superagonist by binding to soluble IL-15Rα

Rubinstein

Kovář

Purton

et al. 2006

Proc. Natl. Acad. Sci. U.S.A.

355

362

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IL-15 is normally not secreted in soluble form (8-10) but is held on the cell surface bound to a unique receptor, IL-15R␣, especially on dendritic cells (11-16). Cell-bound IL-15 then is presented in trans to T cells and NK cells and is recognized by the ␤␥ c receptor on these cells; such recognition maintains cell survival and intermittent proliferation.IL-15R␣ plays a mandatory role in presenting endogenous IL-15. Thus, like IL-15 -/-mice (1), IL-15R␣ -/-mice lack CD122 hi CD8 ϩ cells and NK cells (17), presumably because the IL-15 synthesized in IL-15R␣ -/-mice fails to leave the cytoplasm. Nevertheless, ␤␥ c ϩ cells can proliferate in response to a soluble recombinant form of IL-15 in the absence of IL-15R␣ (18). Moreover, under certain conditions, IL-15R␣ can be inhibitory. Thus, injecting mice with a soluble (s) recombinant form of IL-15R␣ is reported to suppress NK cell proliferation (10) and certain T dependent immune responses in vivo (19)(20)(21)(22), and adding sIL-15R␣ in vitro can block the response of cell lines to . Despite these findings, there are other reports that sIL-15R␣ (26), and also a soluble sushi domain of IL-15R␣ (27), can enhance IL-15 responses of human cell lines.In this paper, we investigated whether sIL-15R␣ can alter the response of normal mouse T cells to IL-15. As discussed below, IL-15 responses of CD8 ϩ T cells and NK cells are improved considerably by association with sIL-15R␣, both in vitro and in vivo. Results Stimulation by IL-15͞IL-15R␣ Complexes in Vitro.To examine whether the stimulatory function of soluble IL-15 is altered by binding to sIL-15R␣, purified MP CD44 hi CD122 hi CD8 ϩ cells were cultured in vitro with mouse IL-15 Ϯ mouse sIL-15R␣ covalently linked to the Fc portion of human IgG1 (sIL-15R␣-Fc). For IL-15 alone, half-maximal responses required Ϸ30 ng͞ml and responses were negligible with Ͻ10 ng͞ml (Fig. 1A and B). Here, the notable finding was that supplementing a low concentration of IL-15, e.g., 5 ng͞ml, with sIL-15R␣-Fc led to strong proliferative responses of MP CD8 ϩ cells as measured either by carboxyf luorescein diacetate succinimidyl ester (CFSE) dilution (Fig. 1 A) or by [ 3 H]thymidine incorporation (Fig. 1B). No proliferation occurred with sIL-15R␣-Fc alone (Fig. 1B), and the addition of sIL-15R␣-Fc failed to alter the response of MP CD8 ϩ cells to a different cytokine, IL-2 (data not shown). With IL-15, sIL-15R␣-Fc did not appear to act by enhancing the half-life of IL-15 in vitro (Fig. 6, which is published as supporting information on the PNAS web site).With a limiting concentration of cytokine, IL-15 responses were improved generally by 6-to 9-fold by the addition of sIL-15R␣-Fc. Adding sIL-15R␣-Fc also considerably improved the IL-15 response of CD122 hi NK cells (Fig. 1C) but was relatively ineffective on MP (CD44 hi ) CD4 ϩ cells, which express intermediate levels of CD122 (Fig. 1C). Unexpectedly, sIL-15R␣-Fc plus IL-15 led to significant proliferation of typical naïve CD44 lo CD122 lo CD8 ϩ cells, although only with high concentrations o...

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Section: Discussionsupporting

confidence: 56%

Converting IL-15 to a superagonist by binding to soluble IL-15Rα

Rubinstein

Kovář

Purton

et al. 2006

Proc. Natl. Acad. Sci. U.S.A.

355

362

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“…5 g of human cytokines into mice (27). As described, IL-2 and IL-7 levels declined to undetectable levels by 48 h after the injection (28). However, the serum levels of IL-15 showed different kinetics.…”

Section: Il-15r␣-positive Cells Can Provide a Persistent Il-15 Reservmentioning

confidence: 65%

“…The clearance of IL-15 has two phases. In the first rapid clearance phase, IL-15 behaves like other cytokines (28), but detectable levels of IL-15 remain in circulation or in association with select tissues for more than a week after a bolus injection. This retention of IL-15 is mediated by IL-15R␣, because IL-15 disappears from IL-15R␣ Ϫ/Ϫ mice without retention.…”

Section: Discussionmentioning

confidence: 99%

The IL-15/IL-15Rα on cell surfaces enables sustained IL-15 activity and contributes to the long survival of CD8 memory T cells

Sato

Patel

Waldmann

et al. 2007

Proc. Natl. Acad. Sci. U.S.A.

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134

138

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“…Competitive binding studies indicate that sCD25 binds IL-2 with low affinity [124], although in vivo functional properties remain to be elucidated. The half-life of sCD25 is about 40 min in the circulation [125], and it has been suggested that sCD25 inhibits bioactive IL-2 [126][127][128]. Kobayashi et al [125] have evaluated the extent of the protection from degradation conferred by sCD25 on IL-2.…”

Section: Non-regulatory T Cells and T1dmentioning

confidence: 99%