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In vivo IL-12/IL-23p40 neutralization blocks Th1/Th17 response after allogeneic hematopoietic cell transplantation

T-helper 1 and T-helper 17 lymphocytes mediate acute graft-versus-host disease (GvHD). Interleukin 12 is critical for T-helper 1 differentiation and interleukin 23 for T-helper 17 maintenance. Interleukin 12 and 23 are heterodimeric cytokines that share the p40 subunit (IL-12/IL-23p40). In a randomi...

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Autores principales: Pidala, Joseph, Beato, Francisca, Kim, Jongphil, Betts, Brian, Jim, Heather, Sagatys, Elizabeth, Levine, John E., Ferrara, James L.M., Ozbek, Umut, Ayala, Ernesto, Davila, Marco, Fernandez, Hugo F., Field, Teresa, Kharfan-Dabaja, Mohamed A., Khaira, Divis, Khimani, Farhad, Locke, Frederick L., Mishra, Asmita, Nieder, Michael, Nishihori, Taiga, Perez, Lia, Riches, Marcie, Anasetti, Claudio
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Ferrata Storti Foundation 2018
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5830373/
https://www.ncbi.nlm.nih.gov/pubmed/29242294
http://dx.doi.org/10.3324/haematol.2017.171199
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author Pidala, Joseph
Beato, Francisca
Kim, Jongphil
Betts, Brian
Jim, Heather
Sagatys, Elizabeth
Levine, John E.
Ferrara, James L.M.
Ozbek, Umut
Ayala, Ernesto
Davila, Marco
Fernandez, Hugo F.
Field, Teresa
Kharfan-Dabaja, Mohamed A.
Khaira, Divis
Khimani, Farhad
Locke, Frederick L.
Mishra, Asmita
Nieder, Michael
Nishihori, Taiga
Perez, Lia
Riches, Marcie
Anasetti, Claudio
author_facet Pidala, Joseph
Beato, Francisca
Kim, Jongphil
Betts, Brian
Jim, Heather
Sagatys, Elizabeth
Levine, John E.
Ferrara, James L.M.
Ozbek, Umut
Ayala, Ernesto
Davila, Marco
Fernandez, Hugo F.
Field, Teresa
Kharfan-Dabaja, Mohamed A.
Khaira, Divis
Khimani, Farhad
Locke, Frederick L.
Mishra, Asmita
Nieder, Michael
Nishihori, Taiga
Perez, Lia
Riches, Marcie
Anasetti, Claudio
author_sort Pidala, Joseph
collection PubMed
description T-helper 1 and T-helper 17 lymphocytes mediate acute graft-versus-host disease (GvHD). Interleukin 12 is critical for T-helper 1 differentiation and interleukin 23 for T-helper 17 maintenance. Interleukin 12 and 23 are heterodimeric cytokines that share the p40 subunit (IL-12/IL-23p40). In a randomized, blinded, placebo-controlled trial, we examined the biological impact and clinical outcomes following IL-12/IL-23p40 neutralization using ustekinumab. Thirty patients received peripheral blood mobilized hematopoietic cell transplantation (HCT) from HLA-matched sibling or unrelated donors, received sirolimus plus tacrolimus as GvHD prophylaxis, and were randomized to ustekinumab versus placebo with 1:1 allocation after stratification by donor type. The primary end point of the trial was the mean percentage (%) T-regulatory (Treg) cells on day 30 post HCT. Ustekinumab was delivered by subcutaneous injection on day −1 and day +20 after transplantation. On day 30 post transplant, no significant difference in % Treg was observed. Ustekinumab suppressed serum IL-12/IL-23p40 levels. Host-reactive donor alloresponse at days 30 and 90 after transplantation was polarized with significant reduction in IL-17 and IFN-α production and increase in IL-4. No toxicity attributed to ustekinumab was observed. Overall survival and National Institute of Health moderate/severe chronic GvHD-free, relapse-free survival were significantly improved among ustekinumab-treated patients. No significant improvements were observed in acute or chronic GvHD, relapse, or non-relapse mortality. These data provide first evidence that IL-12/IL-23p40 neutralization can polarize donor anti-host alloresponse in vivo and provide initial clinical efficacy evidence to be tested in subsequent trials. (Trial registered at clinicaltrials.gov identifier: 01713400.)
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spelling pubmed-58303732018-03-16 In vivo IL-12/IL-23p40 neutralization blocks Th1/Th17 response after allogeneic hematopoietic cell transplantation Pidala, Joseph Beato, Francisca Kim, Jongphil Betts, Brian Jim, Heather Sagatys, Elizabeth Levine, John E. Ferrara, James L.M. Ozbek, Umut Ayala, Ernesto Davila, Marco Fernandez, Hugo F. Field, Teresa Kharfan-Dabaja, Mohamed A. Khaira, Divis Khimani, Farhad Locke, Frederick L. Mishra, Asmita Nieder, Michael Nishihori, Taiga Perez, Lia Riches, Marcie Anasetti, Claudio Haematologica Article T-helper 1 and T-helper 17 lymphocytes mediate acute graft-versus-host disease (GvHD). Interleukin 12 is critical for T-helper 1 differentiation and interleukin 23 for T-helper 17 maintenance. Interleukin 12 and 23 are heterodimeric cytokines that share the p40 subunit (IL-12/IL-23p40). In a randomized, blinded, placebo-controlled trial, we examined the biological impact and clinical outcomes following IL-12/IL-23p40 neutralization using ustekinumab. Thirty patients received peripheral blood mobilized hematopoietic cell transplantation (HCT) from HLA-matched sibling or unrelated donors, received sirolimus plus tacrolimus as GvHD prophylaxis, and were randomized to ustekinumab versus placebo with 1:1 allocation after stratification by donor type. The primary end point of the trial was the mean percentage (%) T-regulatory (Treg) cells on day 30 post HCT. Ustekinumab was delivered by subcutaneous injection on day −1 and day +20 after transplantation. On day 30 post transplant, no significant difference in % Treg was observed. Ustekinumab suppressed serum IL-12/IL-23p40 levels. Host-reactive donor alloresponse at days 30 and 90 after transplantation was polarized with significant reduction in IL-17 and IFN-α production and increase in IL-4. No toxicity attributed to ustekinumab was observed. Overall survival and National Institute of Health moderate/severe chronic GvHD-free, relapse-free survival were significantly improved among ustekinumab-treated patients. No significant improvements were observed in acute or chronic GvHD, relapse, or non-relapse mortality. These data provide first evidence that IL-12/IL-23p40 neutralization can polarize donor anti-host alloresponse in vivo and provide initial clinical efficacy evidence to be tested in subsequent trials. (Trial registered at clinicaltrials.gov identifier: 01713400.) Ferrata Storti Foundation 2018-03 /pmc/articles/PMC5830373/ /pubmed/29242294 http://dx.doi.org/10.3324/haematol.2017.171199 Text en Copyright© 2018 Ferrata Storti Foundation Material published in Haematologica is covered by copyright. All rights are reserved to the Ferrata Storti Foundation. Use of published material is allowed under the following terms and conditions: https://creativecommons.org/licenses/by-nc/4.0/legalcode. Copies of published material are allowed for personal or internal use. Sharing published material for non-commercial purposes is subject to the following conditions: https://creativecommons.org/licenses/by-nc/4.0/legalcode, sect. 3. Reproducing and sharing published material for commercial purposes is not allowed without permission in writing from the publisher.
spellingShingle Article
Pidala, Joseph
Beato, Francisca
Kim, Jongphil
Betts, Brian
Jim, Heather
Sagatys, Elizabeth
Levine, John E.
Ferrara, James L.M.
Ozbek, Umut
Ayala, Ernesto
Davila, Marco
Fernandez, Hugo F.
Field, Teresa
Kharfan-Dabaja, Mohamed A.
Khaira, Divis
Khimani, Farhad
Locke, Frederick L.
Mishra, Asmita
Nieder, Michael
Nishihori, Taiga
Perez, Lia
Riches, Marcie
Anasetti, Claudio
In vivo IL-12/IL-23p40 neutralization blocks Th1/Th17 response after allogeneic hematopoietic cell transplantation
title In vivo IL-12/IL-23p40 neutralization blocks Th1/Th17 response after allogeneic hematopoietic cell transplantation
title_full In vivo IL-12/IL-23p40 neutralization blocks Th1/Th17 response after allogeneic hematopoietic cell transplantation
title_fullStr In vivo IL-12/IL-23p40 neutralization blocks Th1/Th17 response after allogeneic hematopoietic cell transplantation
title_full_unstemmed In vivo IL-12/IL-23p40 neutralization blocks Th1/Th17 response after allogeneic hematopoietic cell transplantation
title_short In vivo IL-12/IL-23p40 neutralization blocks Th1/Th17 response after allogeneic hematopoietic cell transplantation
title_sort in vivo il-12/il-23p40 neutralization blocks th1/th17 response after allogeneic hematopoietic cell transplantation
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5830373/
https://www.ncbi.nlm.nih.gov/pubmed/29242294
http://dx.doi.org/10.3324/haematol.2017.171199
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