Regulatory T Cell Responses in Participants with Type 1 Diabetes after a Single Dose of Interleukin-2: A Non-Randomised, Open Label, Adaptive Dose-Finding Trial.
<h4>Background</h4>Interleukin-2 (IL-2) has an essential role in the expansion and function of CD4+ regulatory T cells (Tregs). Tregs reduce tissue damage by limiting the immune response following infection and regulate autoreactive CD4+ effector T cells (Teffs) to prevent autoimmune dis...
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2016-10-01
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| Online Access: | https://doi.org/10.1371/journal.pmed.1002139 |
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| author | John A Todd Marina Evangelou Antony J Cutler Marcin L Pekalski Neil M Walker Helen E Stevens Linsey Porter Deborah J Smyth Daniel B Rainbow Ricardo C Ferreira Laura Esposito Kara M D Hunter Kevin Loudon Kathryn Irons Jennie H Yang Charles J M Bell Helen Schuilenburg James Heywood Ben Challis Sankalpa Neupane Pamela Clarke Gillian Coleman Sarah Dawson Donna Goymer Katerina Anselmiova Jane Kennet Judy Brown Sarah L Caddy Jia Lu Jane Greatorex Ian Goodfellow Chris Wallace Tim I Tree Mark Evans Adrian P Mander Simon Bond Linda S Wicker Frank Waldron-Lynch |
| author_facet | John A Todd Marina Evangelou Antony J Cutler Marcin L Pekalski Neil M Walker Helen E Stevens Linsey Porter Deborah J Smyth Daniel B Rainbow Ricardo C Ferreira Laura Esposito Kara M D Hunter Kevin Loudon Kathryn Irons Jennie H Yang Charles J M Bell Helen Schuilenburg James Heywood Ben Challis Sankalpa Neupane Pamela Clarke Gillian Coleman Sarah Dawson Donna Goymer Katerina Anselmiova Jane Kennet Judy Brown Sarah L Caddy Jia Lu Jane Greatorex Ian Goodfellow Chris Wallace Tim I Tree Mark Evans Adrian P Mander Simon Bond Linda S Wicker Frank Waldron-Lynch |
| author_sort | John A Todd |
| collection | DOAJ |
| description | <h4>Background</h4>Interleukin-2 (IL-2) has an essential role in the expansion and function of CD4+ regulatory T cells (Tregs). Tregs reduce tissue damage by limiting the immune response following infection and regulate autoreactive CD4+ effector T cells (Teffs) to prevent autoimmune diseases, such as type 1 diabetes (T1D). Genetic susceptibility to T1D causes alterations in the IL-2 pathway, a finding that supports Tregs as a cellular therapeutic target. Aldesleukin (Proleukin; recombinant human IL-2), which is administered at high doses to activate the immune system in cancer immunotherapy, is now being repositioned to treat inflammatory and autoimmune disorders at lower doses by targeting Tregs.<h4>Methods and findings</h4>To define the aldesleukin dose response for Tregs and to find doses that increase Tregs physiologically for treatment of T1D, a statistical and systematic approach was taken by analysing the pharmacokinetics and pharmacodynamics of single doses of subcutaneous aldesleukin in the Adaptive Study of IL-2 Dose on Regulatory T Cells in Type 1 Diabetes (DILT1D), a single centre, non-randomised, open label, adaptive dose-finding trial with 40 adult participants with recently diagnosed T1D. The primary endpoint was the maximum percentage increase in Tregs (defined as CD3+CD4+CD25highCD127low) from the baseline frequency in each participant measured over the 7 d following treatment. There was an initial learning phase with five pairs of participants, each pair receiving one of five pre-assigned single doses from 0.04 × 106 to 1.5 × 106 IU/m2, in order to model the dose-response curve. Results from each participant were then incorporated into interim statistical modelling to target the two doses most likely to induce 10% and 20% increases in Treg frequencies. Primary analysis of the evaluable population (n = 39) found that the optimal doses of aldesleukin to induce 10% and 20% increases in Tregs were 0.101 × 106 IU/m2 (standard error [SE] = 0.078, 95% CI = -0.052, 0.254) and 0.497 × 106 IU/m2 (SE = 0.092, 95% CI = 0.316, 0.678), respectively. On analysis of secondary outcomes, using a highly sensitive IL-2 assay, the observed plasma concentrations of the drug at 90 min exceeded the hypothetical Treg-specific therapeutic window determined in vitro (0.015-0.24 IU/ml), even at the lowest doses (0.040 × 106 and 0.045 × 106 IU/m2) administered. A rapid decrease in Treg frequency in the circulation was observed at 90 min and at day 1, which was dose dependent (mean decrease 11.6%, SE = 2.3%, range 10.0%-48.2%, n = 37), rebounding at day 2 and increasing to frequencies above baseline over 7 d. Teffs, natural killer cells, and eosinophils also responded, with their frequencies rapidly and dose-dependently decreased in the blood, then returning to, or exceeding, pretreatment levels. Furthermore, there was a dose-dependent down modulation of one of the two signalling subunits of the IL-2 receptor, the β chain (CD122) (mean decrease = 58.0%, SE = 2.8%, range 9.8%-85.5%, n = 33), on Tregs and a reduction in their sensitivity to aldesleukin at 90 min and day 1 and 2 post-treatment. Due to blood volume requirements as well as ethical and practical considerations, the study was limited to adults and to analysis of peripheral blood only.<h4>Conclusions</h4>The DILT1D trial results, most notably the early altered trafficking and desensitisation of Tregs induced by a single ultra-low dose of aldesleukin that resolves within 2-3 d, inform the design of the next trial to determine a repeat dosing regimen aimed at establishing a steady-state Treg frequency increase of 20%-50%, with the eventual goal of preventing T1D.<h4>Trial registration</h4>ISRCTN Registry ISRCTN27852285; ClinicalTrials.gov NCT01827735. |
| format | Article |
| id | doaj-art-ce713b3d60664d62831f35693cfd7b82 |
| institution | Kabale University |
| issn | 1549-1277 1549-1676 |
| language | English |
| publishDate | 2016-10-01 |
| publisher | Public Library of Science (PLoS) |
| record_format | Article |
| series | PLoS Medicine |
| spelling | doaj-art-ce713b3d60664d62831f35693cfd7b822025-08-20T03:44:38ZengPublic Library of Science (PLoS)PLoS Medicine1549-12771549-16762016-10-011310e100213910.1371/journal.pmed.1002139Regulatory T Cell Responses in Participants with Type 1 Diabetes after a Single Dose of Interleukin-2: A Non-Randomised, Open Label, Adaptive Dose-Finding Trial.John A ToddMarina EvangelouAntony J CutlerMarcin L PekalskiNeil M WalkerHelen E StevensLinsey PorterDeborah J SmythDaniel B RainbowRicardo C FerreiraLaura EspositoKara M D HunterKevin LoudonKathryn IronsJennie H YangCharles J M BellHelen SchuilenburgJames HeywoodBen ChallisSankalpa NeupanePamela ClarkeGillian ColemanSarah DawsonDonna GoymerKaterina AnselmiovaJane KennetJudy BrownSarah L CaddyJia LuJane GreatorexIan GoodfellowChris WallaceTim I TreeMark EvansAdrian P ManderSimon BondLinda S WickerFrank Waldron-Lynch<h4>Background</h4>Interleukin-2 (IL-2) has an essential role in the expansion and function of CD4+ regulatory T cells (Tregs). Tregs reduce tissue damage by limiting the immune response following infection and regulate autoreactive CD4+ effector T cells (Teffs) to prevent autoimmune diseases, such as type 1 diabetes (T1D). Genetic susceptibility to T1D causes alterations in the IL-2 pathway, a finding that supports Tregs as a cellular therapeutic target. Aldesleukin (Proleukin; recombinant human IL-2), which is administered at high doses to activate the immune system in cancer immunotherapy, is now being repositioned to treat inflammatory and autoimmune disorders at lower doses by targeting Tregs.<h4>Methods and findings</h4>To define the aldesleukin dose response for Tregs and to find doses that increase Tregs physiologically for treatment of T1D, a statistical and systematic approach was taken by analysing the pharmacokinetics and pharmacodynamics of single doses of subcutaneous aldesleukin in the Adaptive Study of IL-2 Dose on Regulatory T Cells in Type 1 Diabetes (DILT1D), a single centre, non-randomised, open label, adaptive dose-finding trial with 40 adult participants with recently diagnosed T1D. The primary endpoint was the maximum percentage increase in Tregs (defined as CD3+CD4+CD25highCD127low) from the baseline frequency in each participant measured over the 7 d following treatment. There was an initial learning phase with five pairs of participants, each pair receiving one of five pre-assigned single doses from 0.04 × 106 to 1.5 × 106 IU/m2, in order to model the dose-response curve. Results from each participant were then incorporated into interim statistical modelling to target the two doses most likely to induce 10% and 20% increases in Treg frequencies. Primary analysis of the evaluable population (n = 39) found that the optimal doses of aldesleukin to induce 10% and 20% increases in Tregs were 0.101 × 106 IU/m2 (standard error [SE] = 0.078, 95% CI = -0.052, 0.254) and 0.497 × 106 IU/m2 (SE = 0.092, 95% CI = 0.316, 0.678), respectively. On analysis of secondary outcomes, using a highly sensitive IL-2 assay, the observed plasma concentrations of the drug at 90 min exceeded the hypothetical Treg-specific therapeutic window determined in vitro (0.015-0.24 IU/ml), even at the lowest doses (0.040 × 106 and 0.045 × 106 IU/m2) administered. A rapid decrease in Treg frequency in the circulation was observed at 90 min and at day 1, which was dose dependent (mean decrease 11.6%, SE = 2.3%, range 10.0%-48.2%, n = 37), rebounding at day 2 and increasing to frequencies above baseline over 7 d. Teffs, natural killer cells, and eosinophils also responded, with their frequencies rapidly and dose-dependently decreased in the blood, then returning to, or exceeding, pretreatment levels. Furthermore, there was a dose-dependent down modulation of one of the two signalling subunits of the IL-2 receptor, the β chain (CD122) (mean decrease = 58.0%, SE = 2.8%, range 9.8%-85.5%, n = 33), on Tregs and a reduction in their sensitivity to aldesleukin at 90 min and day 1 and 2 post-treatment. Due to blood volume requirements as well as ethical and practical considerations, the study was limited to adults and to analysis of peripheral blood only.<h4>Conclusions</h4>The DILT1D trial results, most notably the early altered trafficking and desensitisation of Tregs induced by a single ultra-low dose of aldesleukin that resolves within 2-3 d, inform the design of the next trial to determine a repeat dosing regimen aimed at establishing a steady-state Treg frequency increase of 20%-50%, with the eventual goal of preventing T1D.<h4>Trial registration</h4>ISRCTN Registry ISRCTN27852285; ClinicalTrials.gov NCT01827735.https://doi.org/10.1371/journal.pmed.1002139 |
| spellingShingle | John A Todd Marina Evangelou Antony J Cutler Marcin L Pekalski Neil M Walker Helen E Stevens Linsey Porter Deborah J Smyth Daniel B Rainbow Ricardo C Ferreira Laura Esposito Kara M D Hunter Kevin Loudon Kathryn Irons Jennie H Yang Charles J M Bell Helen Schuilenburg James Heywood Ben Challis Sankalpa Neupane Pamela Clarke Gillian Coleman Sarah Dawson Donna Goymer Katerina Anselmiova Jane Kennet Judy Brown Sarah L Caddy Jia Lu Jane Greatorex Ian Goodfellow Chris Wallace Tim I Tree Mark Evans Adrian P Mander Simon Bond Linda S Wicker Frank Waldron-Lynch Regulatory T Cell Responses in Participants with Type 1 Diabetes after a Single Dose of Interleukin-2: A Non-Randomised, Open Label, Adaptive Dose-Finding Trial. PLoS Medicine |
| title | Regulatory T Cell Responses in Participants with Type 1 Diabetes after a Single Dose of Interleukin-2: A Non-Randomised, Open Label, Adaptive Dose-Finding Trial. |
| title_full | Regulatory T Cell Responses in Participants with Type 1 Diabetes after a Single Dose of Interleukin-2: A Non-Randomised, Open Label, Adaptive Dose-Finding Trial. |
| title_fullStr | Regulatory T Cell Responses in Participants with Type 1 Diabetes after a Single Dose of Interleukin-2: A Non-Randomised, Open Label, Adaptive Dose-Finding Trial. |
| title_full_unstemmed | Regulatory T Cell Responses in Participants with Type 1 Diabetes after a Single Dose of Interleukin-2: A Non-Randomised, Open Label, Adaptive Dose-Finding Trial. |
| title_short | Regulatory T Cell Responses in Participants with Type 1 Diabetes after a Single Dose of Interleukin-2: A Non-Randomised, Open Label, Adaptive Dose-Finding Trial. |
| title_sort | regulatory t cell responses in participants with type 1 diabetes after a single dose of interleukin 2 a non randomised open label adaptive dose finding trial |
| url | https://doi.org/10.1371/journal.pmed.1002139 |
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