Cargando…
Donor-Derived Regulatory Dendritic Cell Infusion Maintains Donor-Reactive CD4(+)CTLA4(hi) T Cells in Non-Human Primate Renal Allograft Recipients Treated with CD28 Co-Stimulation Blockade
Donor-derived regulatory dendritic cell (DCreg) infusion before transplantation, significantly prolongs renal allograft survival in non-human primates. This is associated with enhanced expression of the immunoregulatory molecules cytotoxic T-lymphocyte-associated antigen (Ag) 4 (CTLA4) and programme...
Autores principales: | , , , , |
---|---|
Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Frontiers Media S.A.
2018
|
Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5827543/ https://www.ncbi.nlm.nih.gov/pubmed/29520267 http://dx.doi.org/10.3389/fimmu.2018.00250 |
_version_ | 1783302492890595328 |
---|---|
author | Ezzelarab, Mohamed B. Lu, Lien Shufesky, William F. Morelli, Adrian E. Thomson, Angus W. |
author_facet | Ezzelarab, Mohamed B. Lu, Lien Shufesky, William F. Morelli, Adrian E. Thomson, Angus W. |
author_sort | Ezzelarab, Mohamed B. |
collection | PubMed |
description | Donor-derived regulatory dendritic cell (DCreg) infusion before transplantation, significantly prolongs renal allograft survival in non-human primates. This is associated with enhanced expression of the immunoregulatory molecules cytotoxic T-lymphocyte-associated antigen (Ag) 4 (CTLA4) and programmed cell death protein 1 (PD1) by host donor-reactive T cells. In rodents and humans, CD28 co-stimulatory pathway blockade with the fusion protein CTLA4:Ig (CTLA4Ig) is associated with reduced differentiation and development of regulatory T cells (Treg). We hypothesized that upregulation of CTLA4 by donor-reactive CD4(+) T cells in DCreg-infused recipients treated with CTLA4Ig, might be associated with higher incidences of donor-reactive CD4(+) T cells with a Treg phenotype. In normal rhesus monkeys, allo-stimulated CD4(+)CTLA4(hi), but not CD4(+)CTLA4(med/lo) T cells exhibited a regulatory phenotype, irrespective of PD1 expression. CTLA4Ig significantly reduced the incidence of CD4(+)CTLA4(hi), but not CD4(+)CTLA4(med/lo) T cells following allo-stimulation, associated with a significant reduction in the CD4(+)CTLA4(hi)/CD4(+)CTLA4(med/lo) T cell ratio. In CTLA4Ig-treated renal allograft recipient monkeys, there was a marked reduction in circulating donor-reactive CD4(+)CTLA4(hi) T cells. In contrast, in CTLA4Ig-treated monkeys with DCreg infusion, no such reduction was observed. In parallel, the donor-reactive CD4(+)CTLA4(hi)/CD4(+)CTLA4(med/lo) T cell ratio was reduced significantly in graft recipients without DCreg infusion, but increased in those given DCreg. These observations suggest that pre-transplant DCreg infusion promotes and maintains donor-reactive CD4(+)CTLA4(hi) T cells with a regulatory phenotype after transplantation, even in the presence of CD28 co-stimulation blockade. |
format | Online Article Text |
id | pubmed-5827543 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2018 |
publisher | Frontiers Media S.A. |
record_format | MEDLINE/PubMed |
spelling | pubmed-58275432018-03-08 Donor-Derived Regulatory Dendritic Cell Infusion Maintains Donor-Reactive CD4(+)CTLA4(hi) T Cells in Non-Human Primate Renal Allograft Recipients Treated with CD28 Co-Stimulation Blockade Ezzelarab, Mohamed B. Lu, Lien Shufesky, William F. Morelli, Adrian E. Thomson, Angus W. Front Immunol Immunology Donor-derived regulatory dendritic cell (DCreg) infusion before transplantation, significantly prolongs renal allograft survival in non-human primates. This is associated with enhanced expression of the immunoregulatory molecules cytotoxic T-lymphocyte-associated antigen (Ag) 4 (CTLA4) and programmed cell death protein 1 (PD1) by host donor-reactive T cells. In rodents and humans, CD28 co-stimulatory pathway blockade with the fusion protein CTLA4:Ig (CTLA4Ig) is associated with reduced differentiation and development of regulatory T cells (Treg). We hypothesized that upregulation of CTLA4 by donor-reactive CD4(+) T cells in DCreg-infused recipients treated with CTLA4Ig, might be associated with higher incidences of donor-reactive CD4(+) T cells with a Treg phenotype. In normal rhesus monkeys, allo-stimulated CD4(+)CTLA4(hi), but not CD4(+)CTLA4(med/lo) T cells exhibited a regulatory phenotype, irrespective of PD1 expression. CTLA4Ig significantly reduced the incidence of CD4(+)CTLA4(hi), but not CD4(+)CTLA4(med/lo) T cells following allo-stimulation, associated with a significant reduction in the CD4(+)CTLA4(hi)/CD4(+)CTLA4(med/lo) T cell ratio. In CTLA4Ig-treated renal allograft recipient monkeys, there was a marked reduction in circulating donor-reactive CD4(+)CTLA4(hi) T cells. In contrast, in CTLA4Ig-treated monkeys with DCreg infusion, no such reduction was observed. In parallel, the donor-reactive CD4(+)CTLA4(hi)/CD4(+)CTLA4(med/lo) T cell ratio was reduced significantly in graft recipients without DCreg infusion, but increased in those given DCreg. These observations suggest that pre-transplant DCreg infusion promotes and maintains donor-reactive CD4(+)CTLA4(hi) T cells with a regulatory phenotype after transplantation, even in the presence of CD28 co-stimulation blockade. Frontiers Media S.A. 2018-02-19 /pmc/articles/PMC5827543/ /pubmed/29520267 http://dx.doi.org/10.3389/fimmu.2018.00250 Text en Copyright © 2018 Ezzelarab, Lu, Shufesky, Morelli and Thomson. http://creativecommons.org/licenses/by/4.0/ This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms. |
spellingShingle | Immunology Ezzelarab, Mohamed B. Lu, Lien Shufesky, William F. Morelli, Adrian E. Thomson, Angus W. Donor-Derived Regulatory Dendritic Cell Infusion Maintains Donor-Reactive CD4(+)CTLA4(hi) T Cells in Non-Human Primate Renal Allograft Recipients Treated with CD28 Co-Stimulation Blockade |
title | Donor-Derived Regulatory Dendritic Cell Infusion Maintains Donor-Reactive CD4(+)CTLA4(hi) T Cells in Non-Human Primate Renal Allograft Recipients Treated with CD28 Co-Stimulation Blockade |
title_full | Donor-Derived Regulatory Dendritic Cell Infusion Maintains Donor-Reactive CD4(+)CTLA4(hi) T Cells in Non-Human Primate Renal Allograft Recipients Treated with CD28 Co-Stimulation Blockade |
title_fullStr | Donor-Derived Regulatory Dendritic Cell Infusion Maintains Donor-Reactive CD4(+)CTLA4(hi) T Cells in Non-Human Primate Renal Allograft Recipients Treated with CD28 Co-Stimulation Blockade |
title_full_unstemmed | Donor-Derived Regulatory Dendritic Cell Infusion Maintains Donor-Reactive CD4(+)CTLA4(hi) T Cells in Non-Human Primate Renal Allograft Recipients Treated with CD28 Co-Stimulation Blockade |
title_short | Donor-Derived Regulatory Dendritic Cell Infusion Maintains Donor-Reactive CD4(+)CTLA4(hi) T Cells in Non-Human Primate Renal Allograft Recipients Treated with CD28 Co-Stimulation Blockade |
title_sort | donor-derived regulatory dendritic cell infusion maintains donor-reactive cd4(+)ctla4(hi) t cells in non-human primate renal allograft recipients treated with cd28 co-stimulation blockade |
topic | Immunology |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5827543/ https://www.ncbi.nlm.nih.gov/pubmed/29520267 http://dx.doi.org/10.3389/fimmu.2018.00250 |
work_keys_str_mv | AT ezzelarabmohamedb donorderivedregulatorydendriticcellinfusionmaintainsdonorreactivecd4ctla4hitcellsinnonhumanprimaterenalallograftrecipientstreatedwithcd28costimulationblockade AT lulien donorderivedregulatorydendriticcellinfusionmaintainsdonorreactivecd4ctla4hitcellsinnonhumanprimaterenalallograftrecipientstreatedwithcd28costimulationblockade AT shufeskywilliamf donorderivedregulatorydendriticcellinfusionmaintainsdonorreactivecd4ctla4hitcellsinnonhumanprimaterenalallograftrecipientstreatedwithcd28costimulationblockade AT morelliadriane donorderivedregulatorydendriticcellinfusionmaintainsdonorreactivecd4ctla4hitcellsinnonhumanprimaterenalallograftrecipientstreatedwithcd28costimulationblockade AT thomsonangusw donorderivedregulatorydendriticcellinfusionmaintainsdonorreactivecd4ctla4hitcellsinnonhumanprimaterenalallograftrecipientstreatedwithcd28costimulationblockade |