Maternal dendritic cells influence fetal allograft response following murine in-utero hematopoietic stem cell transplantation
Abstract 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...
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BMC
2023-05-01
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Series: | Stem Cell Research & Therapy |
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Online Access: | https://doi.org/10.1186/s13287-023-03366-9 |
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author | Karthikeyan Kandasamy Nuryanti Binti Johana Lay Geok Tan Yvonne Tan Julie Su Li Yeo Nur Nazneen Binte Yusof Zhihui Li Jiayu Koh Florent Ginhoux Jerry K. Y. Chan Mahesh Choolani Citra N. Z. Mattar |
author_facet | Karthikeyan Kandasamy Nuryanti Binti Johana Lay Geok Tan Yvonne Tan Julie Su Li Yeo Nur Nazneen Binte Yusof Zhihui Li Jiayu Koh Florent Ginhoux Jerry K. Y. Chan Mahesh Choolani Citra N. Z. Mattar |
author_sort | Karthikeyan Kandasamy |
collection | DOAJ |
description | Abstract 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. |
first_indexed | 2024-03-13T09:04:05Z |
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id | doaj.art-d7b36631a2c94be8909509e2227f3a5b |
institution | Directory Open Access Journal |
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language | English |
last_indexed | 2024-03-13T09:04:05Z |
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series | Stem Cell Research & Therapy |
spelling | doaj.art-d7b36631a2c94be8909509e2227f3a5b2023-05-28T11:09:58ZengBMCStem Cell Research & Therapy1757-65122023-05-0114111910.1186/s13287-023-03366-9Maternal dendritic cells influence fetal allograft response following murine in-utero hematopoietic stem cell transplantationKarthikeyan Kandasamy0Nuryanti Binti Johana1Lay Geok Tan2Yvonne Tan3Julie Su Li Yeo4Nur Nazneen Binte Yusof5Zhihui Li6Jiayu Koh7Florent Ginhoux8Jerry K. Y. Chan9Mahesh Choolani10Citra N. Z. Mattar11Experimental Fetal Medicine Group, Department of Obstetrics and Gynaecology, Yong Loo Lin School of Medicine, National University of SingaporeReproductive Medicine, KK Women’s and Children’s HospitalExperimental Fetal Medicine Group, Department of Obstetrics and Gynaecology, Yong Loo Lin School of Medicine, National University of SingaporeReproductive Medicine, KK Women’s and Children’s HospitalReproductive Medicine, KK Women’s and Children’s HospitalExperimental Fetal Medicine Group, Department of Obstetrics and Gynaecology, Yong Loo Lin School of Medicine, National University of SingaporeGenome Research Informatics and Data Science Platform, Genome Institute of Singapore, Agency for Science Technology and ResearchGenome Research Informatics and Data Science Platform, Genome Institute of Singapore, Agency for Science Technology and ResearchSingapore Immunology Network (SIgN), Agency for Science, Technology and Research (A*STAR)Experimental Fetal Medicine Group, Department of Obstetrics and Gynaecology, Yong Loo Lin School of Medicine, National University of SingaporeExperimental Fetal Medicine Group, Department of Obstetrics and Gynaecology, Yong Loo Lin School of Medicine, National University of SingaporeExperimental Fetal Medicine Group, Department of Obstetrics and Gynaecology, Yong Loo Lin School of Medicine, National University of SingaporeAbstract 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.https://doi.org/10.1186/s13287-023-03366-9Hematopoietic stem cellsIn-utero transplantationFetal toleranceMaternal microchimerism |
spellingShingle | Karthikeyan Kandasamy Nuryanti Binti Johana Lay Geok Tan Yvonne Tan Julie Su Li Yeo Nur Nazneen Binte Yusof Zhihui Li Jiayu Koh Florent Ginhoux Jerry K. Y. Chan Mahesh Choolani Citra N. Z. Mattar Maternal dendritic cells influence fetal allograft response following murine in-utero hematopoietic stem cell transplantation Stem Cell Research & Therapy Hematopoietic stem cells In-utero transplantation Fetal tolerance Maternal microchimerism |
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 | Hematopoietic stem cells In-utero transplantation Fetal tolerance Maternal microchimerism |
url | https://doi.org/10.1186/s13287-023-03366-9 |
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