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Maternal dendritic cells influence fetal allograft response following murine in-utero hematopoietic stem cell transplantation

BACKGROUND: Intrauterine hematopoietic stem cell transplantation (IUT), potentially curative in congenital haematological disease, is often inhibited by deleterious immune responses to donor cells resulting in subtherapeutic donor cell chimerism (DCC). Microchimerism of maternal immune cells (MMc) t...

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Autores principales: Kandasamy, Karthikeyan, Johana, Nuryanti Binti, Tan, Lay Geok, Tan, Yvonne, Yeo, Julie Su Li, Yusof, Nur Nazneen Binte, Li, Zhihui, Koh, Jiayu, Ginhoux, Florent, Chan, Jerry K. Y., Choolani, Mahesh, Mattar, Citra N. Z.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: BioMed Central 2023
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10206581/
https://www.ncbi.nlm.nih.gov/pubmed/37226255
http://dx.doi.org/10.1186/s13287-023-03366-9
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author Kandasamy, Karthikeyan
Johana, Nuryanti Binti
Tan, Lay Geok
Tan, Yvonne
Yeo, Julie Su Li
Yusof, Nur Nazneen Binte
Li, Zhihui
Koh, Jiayu
Ginhoux, Florent
Chan, Jerry K. Y.
Choolani, Mahesh
Mattar, Citra N. Z.
author_facet Kandasamy, Karthikeyan
Johana, Nuryanti Binti
Tan, Lay Geok
Tan, Yvonne
Yeo, Julie Su Li
Yusof, Nur Nazneen Binte
Li, Zhihui
Koh, Jiayu
Ginhoux, Florent
Chan, Jerry K. Y.
Choolani, Mahesh
Mattar, Citra N. Z.
author_sort Kandasamy, Karthikeyan
collection PubMed
description BACKGROUND: Intrauterine hematopoietic stem cell transplantation (IUT), potentially curative in congenital haematological disease, is often inhibited by deleterious immune responses to donor cells resulting in subtherapeutic donor cell chimerism (DCC). Microchimerism of maternal immune cells (MMc) trafficked into transplanted recipients across the placenta may directly influence donor-specific alloresponsiveness, limiting DCC. We hypothesized that dendritic cells (DC) among trafficked MMc influence the development of tolerogenic or immunogenic responses towards donor cells, and investigated if maternal DC-depletion reduced recipient alloresponsiveness and enhanced DCC. METHODS: Using transgenic CD11c.DTR (C57BL/6) female mice enabled transient maternal DC-depletion with a single dose of diphtheria toxin (DT). CD11c.DTR females and BALB/c males were cross-mated, producing hybrid pups. IUT was performed at E14 following maternal DT administration 24 h prior. Bone marrow-derived mononuclear cells were transplanted, obtained from semi-allogenic BALB/c (paternal-derived; pIUT), C57BL/6 (maternal-derived; mIUT), or fully allogenic (aIUT) C3H donor mice. Recipient F1 pups were analyzed for DCC, while maternal and IUT-recipient immune cell profile and reactivity were examined via mixed lymphocyte reactivity functional assays. T- and B-cell receptor repertoire diversity in maternal and recipient cells were examined following donor cell exposure. RESULTS: DCC was highest and MMc was lowest following pIUT. In contrast, aIUT recipients had the lowest DCC and the highest MMc. In groups that were not DC-depleted, maternal cells trafficked post-IUT displayed reduced TCR & BCR clonotype diversity, while clonotype diversity was restored when dams were DC-depleted. Additionally, recipients displayed increased expression of regulatory T-cells and immune-inhibitory proteins, with reduced proinflammatory cytokine and donor-specific antibody production. DC-depletion did not impact initial donor chimerism. Postnatal transplantation without immunosuppression of paternal donor cells did not increase DCC in pIUT recipients; however there were no donor-specific antibody production or immune cell changes. CONCLUSIONS: Though maternal DC depletion did not improve DCC, we show for the first time that MMc influences donor-specific alloresponsiveness, possibly by expanding alloreactive clonotypes, and depleting maternal DC promotes and maintains acquired tolerance to donor cells independent of DCC, presenting a novel approach to enhancing donor cell tolerance following IUT. This may have value when planning repeat HSC transplantations to treat haemoglobinopathies. SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1186/s13287-023-03366-9.
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spelling pubmed-102065812023-05-25 Maternal dendritic cells influence fetal allograft response following murine in-utero hematopoietic stem cell transplantation Kandasamy, Karthikeyan Johana, Nuryanti Binti Tan, Lay Geok Tan, Yvonne Yeo, Julie Su Li Yusof, Nur Nazneen Binte Li, Zhihui Koh, Jiayu Ginhoux, Florent Chan, Jerry K. Y. Choolani, Mahesh Mattar, Citra N. Z. Stem Cell Res Ther Research BACKGROUND: Intrauterine hematopoietic stem cell transplantation (IUT), potentially curative in congenital haematological disease, is often inhibited by deleterious immune responses to donor cells resulting in subtherapeutic donor cell chimerism (DCC). Microchimerism of maternal immune cells (MMc) trafficked into transplanted recipients across the placenta may directly influence donor-specific alloresponsiveness, limiting DCC. We hypothesized that dendritic cells (DC) among trafficked MMc influence the development of tolerogenic or immunogenic responses towards donor cells, and investigated if maternal DC-depletion reduced recipient alloresponsiveness and enhanced DCC. METHODS: Using transgenic CD11c.DTR (C57BL/6) female mice enabled transient maternal DC-depletion with a single dose of diphtheria toxin (DT). CD11c.DTR females and BALB/c males were cross-mated, producing hybrid pups. IUT was performed at E14 following maternal DT administration 24 h prior. Bone marrow-derived mononuclear cells were transplanted, obtained from semi-allogenic BALB/c (paternal-derived; pIUT), C57BL/6 (maternal-derived; mIUT), or fully allogenic (aIUT) C3H donor mice. Recipient F1 pups were analyzed for DCC, while maternal and IUT-recipient immune cell profile and reactivity were examined via mixed lymphocyte reactivity functional assays. T- and B-cell receptor repertoire diversity in maternal and recipient cells were examined following donor cell exposure. RESULTS: DCC was highest and MMc was lowest following pIUT. In contrast, aIUT recipients had the lowest DCC and the highest MMc. In groups that were not DC-depleted, maternal cells trafficked post-IUT displayed reduced TCR & BCR clonotype diversity, while clonotype diversity was restored when dams were DC-depleted. Additionally, recipients displayed increased expression of regulatory T-cells and immune-inhibitory proteins, with reduced proinflammatory cytokine and donor-specific antibody production. DC-depletion did not impact initial donor chimerism. Postnatal transplantation without immunosuppression of paternal donor cells did not increase DCC in pIUT recipients; however there were no donor-specific antibody production or immune cell changes. CONCLUSIONS: Though maternal DC depletion did not improve DCC, we show for the first time that MMc influences donor-specific alloresponsiveness, possibly by expanding alloreactive clonotypes, and depleting maternal DC promotes and maintains acquired tolerance to donor cells independent of DCC, presenting a novel approach to enhancing donor cell tolerance following IUT. This may have value when planning repeat HSC transplantations to treat haemoglobinopathies. SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1186/s13287-023-03366-9. BioMed Central 2023-05-24 /pmc/articles/PMC10206581/ /pubmed/37226255 http://dx.doi.org/10.1186/s13287-023-03366-9 Text en © The Author(s) 2023 https://creativecommons.org/licenses/by/4.0/Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/ (https://creativecommons.org/licenses/by/4.0/) . The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/ (https://creativecommons.org/publicdomain/zero/1.0/) ) applies to the data made available in this article, unless otherwise stated in a credit line to the data.
spellingShingle Research
Kandasamy, Karthikeyan
Johana, Nuryanti Binti
Tan, Lay Geok
Tan, Yvonne
Yeo, Julie Su Li
Yusof, Nur Nazneen Binte
Li, Zhihui
Koh, Jiayu
Ginhoux, Florent
Chan, Jerry K. Y.
Choolani, Mahesh
Mattar, Citra N. Z.
Maternal dendritic cells influence fetal allograft response following murine in-utero hematopoietic stem cell transplantation
title Maternal dendritic cells influence fetal allograft response following murine in-utero hematopoietic stem cell transplantation
title_full Maternal dendritic cells influence fetal allograft response following murine in-utero hematopoietic stem cell transplantation
title_fullStr Maternal dendritic cells influence fetal allograft response following murine in-utero hematopoietic stem cell transplantation
title_full_unstemmed Maternal dendritic cells influence fetal allograft response following murine in-utero hematopoietic stem cell transplantation
title_short Maternal dendritic cells influence fetal allograft response following murine in-utero hematopoietic stem cell transplantation
title_sort maternal dendritic cells influence fetal allograft response following murine in-utero hematopoietic stem cell transplantation
topic Research
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10206581/
https://www.ncbi.nlm.nih.gov/pubmed/37226255
http://dx.doi.org/10.1186/s13287-023-03366-9
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