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Dissecting Allo-Sensitization After Local Administration of Human Allogeneic Adipose Mesenchymal Stem Cells in Perianal Fistulas of Crohn's Disease Patients
Adipose mesenchymal stem cells (ASC) are considered minimally immunogenic. This is due to the low expression of human leukocyte antigens I (HLA-I), lack of HLA-II expression and low expression of co-stimulatory molecules such as CD40 and CD80. The low rate of observed immunological rejection as well...
Autores principales: | , , , , , , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Frontiers Media S.A.
2019
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6587893/ https://www.ncbi.nlm.nih.gov/pubmed/31258526 http://dx.doi.org/10.3389/fimmu.2019.01244 |
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author | Avivar-Valderas, Alvaro Martín-Martín, Cristina Ramírez, Cristina Del Río, Borja Menta, Ramón Mancheño-Corvo, Pablo Ortiz-Virumbrales, Maitane Herrero-Méndez, Ángel Panés, Julián García-Olmo, Damián Castañer, José Luís Palacios, Itziar Lombardo, Eleuterio Dalemans, Wilfried DelaRosa, Olga |
author_facet | Avivar-Valderas, Alvaro Martín-Martín, Cristina Ramírez, Cristina Del Río, Borja Menta, Ramón Mancheño-Corvo, Pablo Ortiz-Virumbrales, Maitane Herrero-Méndez, Ángel Panés, Julián García-Olmo, Damián Castañer, José Luís Palacios, Itziar Lombardo, Eleuterio Dalemans, Wilfried DelaRosa, Olga |
author_sort | Avivar-Valderas, Alvaro |
collection | PubMed |
description | Adipose mesenchymal stem cells (ASC) are considered minimally immunogenic. This is due to the low expression of human leukocyte antigens I (HLA-I), lack of HLA-II expression and low expression of co-stimulatory molecules such as CD40 and CD80. The low rate of observed immunological rejection as well as the immunomodulatory qualities, position ASC as a promising cell-based therapy for the treatment of a variety of inflammatory indications. Yet, few studies have addressed relevant aspects of immunogenicity such as ASC donor-to-patient HLA histocompatibility or assessment of immune response triggered by ASC administration, particularly in the cases of presensitization. The present study aims to assess allo-immune responses in a cohort of Crohn's disease patients administered with allogeneic ASC (darvadstrocel formerly Cx601) for the treatment of complex perianal fistulas. We identified donor-specific antibodies (DSA) generation in a proportion of patients and observed that patients showing preexisting immunity were prone to generating DSA after allogeneic therapy. Noteworthy, naïve patients generating DSA at week 12 (W12) showed a significant reduction in DSA titer at week 52 (W52), whereas DSA titer was reduced in pre-sensitized patients only with no specificities against the donor administered. Remarkably, we did not observe any correlation of DSA generation with ASC therapeutic efficacy. In vitro complement-dependent cytotoxicity (CDC) studies have revealed limited cytotoxic levels based upon HLA-I expression and binding capacity even in pro-inflammatory conditions. We sought to identify CDC coping mechanisms contributing to the limited cytotoxic killing observed in ASC in vitro. We found that ASC express membrane-bound complement regulatory proteins (mCRPs) CD55, CD46, and CD59 at basal levels, with CD46 more actively expressed in pro-inflammatory conditions. We demonstrated that CD46 is a main driver of CDC signaling; its depletion significantly enhances sensitivity of ASC to CDC. In summary, despite relatively high clearance, DSA generation may represent a major challenge for allogeneic cell therapy management. Sensitization may be a significant concern when evaluating re-treatment or multi-donor trials. It is still unknown whether DSA generation could potentially be the consequence of donor-to-patient interaction and, therefore, subsequently link to efficacy or biological activity. Lastly, we propose that CDC modulators such as CD46 could be used to ultimately link CDC specificity with allogeneic cell therapy efficacy. |
format | Online Article Text |
id | pubmed-6587893 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2019 |
publisher | Frontiers Media S.A. |
record_format | MEDLINE/PubMed |
spelling | pubmed-65878932019-06-28 Dissecting Allo-Sensitization After Local Administration of Human Allogeneic Adipose Mesenchymal Stem Cells in Perianal Fistulas of Crohn's Disease Patients Avivar-Valderas, Alvaro Martín-Martín, Cristina Ramírez, Cristina Del Río, Borja Menta, Ramón Mancheño-Corvo, Pablo Ortiz-Virumbrales, Maitane Herrero-Méndez, Ángel Panés, Julián García-Olmo, Damián Castañer, José Luís Palacios, Itziar Lombardo, Eleuterio Dalemans, Wilfried DelaRosa, Olga Front Immunol Immunology Adipose mesenchymal stem cells (ASC) are considered minimally immunogenic. This is due to the low expression of human leukocyte antigens I (HLA-I), lack of HLA-II expression and low expression of co-stimulatory molecules such as CD40 and CD80. The low rate of observed immunological rejection as well as the immunomodulatory qualities, position ASC as a promising cell-based therapy for the treatment of a variety of inflammatory indications. Yet, few studies have addressed relevant aspects of immunogenicity such as ASC donor-to-patient HLA histocompatibility or assessment of immune response triggered by ASC administration, particularly in the cases of presensitization. The present study aims to assess allo-immune responses in a cohort of Crohn's disease patients administered with allogeneic ASC (darvadstrocel formerly Cx601) for the treatment of complex perianal fistulas. We identified donor-specific antibodies (DSA) generation in a proportion of patients and observed that patients showing preexisting immunity were prone to generating DSA after allogeneic therapy. Noteworthy, naïve patients generating DSA at week 12 (W12) showed a significant reduction in DSA titer at week 52 (W52), whereas DSA titer was reduced in pre-sensitized patients only with no specificities against the donor administered. Remarkably, we did not observe any correlation of DSA generation with ASC therapeutic efficacy. In vitro complement-dependent cytotoxicity (CDC) studies have revealed limited cytotoxic levels based upon HLA-I expression and binding capacity even in pro-inflammatory conditions. We sought to identify CDC coping mechanisms contributing to the limited cytotoxic killing observed in ASC in vitro. We found that ASC express membrane-bound complement regulatory proteins (mCRPs) CD55, CD46, and CD59 at basal levels, with CD46 more actively expressed in pro-inflammatory conditions. We demonstrated that CD46 is a main driver of CDC signaling; its depletion significantly enhances sensitivity of ASC to CDC. In summary, despite relatively high clearance, DSA generation may represent a major challenge for allogeneic cell therapy management. Sensitization may be a significant concern when evaluating re-treatment or multi-donor trials. It is still unknown whether DSA generation could potentially be the consequence of donor-to-patient interaction and, therefore, subsequently link to efficacy or biological activity. Lastly, we propose that CDC modulators such as CD46 could be used to ultimately link CDC specificity with allogeneic cell therapy efficacy. Frontiers Media S.A. 2019-06-14 /pmc/articles/PMC6587893/ /pubmed/31258526 http://dx.doi.org/10.3389/fimmu.2019.01244 Text en Copyright © 2019 Avivar-Valderas, Martín-Martín, Ramírez, Del Río, Menta, Mancheño-Corvo, Ortiz-Virumbrales, Herrero-Méndez, Panés, García-Olmo, Castañer, Palacios, Lombardo, Dalemans and DelaRosa. 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(s) 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 Avivar-Valderas, Alvaro Martín-Martín, Cristina Ramírez, Cristina Del Río, Borja Menta, Ramón Mancheño-Corvo, Pablo Ortiz-Virumbrales, Maitane Herrero-Méndez, Ángel Panés, Julián García-Olmo, Damián Castañer, José Luís Palacios, Itziar Lombardo, Eleuterio Dalemans, Wilfried DelaRosa, Olga Dissecting Allo-Sensitization After Local Administration of Human Allogeneic Adipose Mesenchymal Stem Cells in Perianal Fistulas of Crohn's Disease Patients |
title | Dissecting Allo-Sensitization After Local Administration of Human Allogeneic Adipose Mesenchymal Stem Cells in Perianal Fistulas of Crohn's Disease Patients |
title_full | Dissecting Allo-Sensitization After Local Administration of Human Allogeneic Adipose Mesenchymal Stem Cells in Perianal Fistulas of Crohn's Disease Patients |
title_fullStr | Dissecting Allo-Sensitization After Local Administration of Human Allogeneic Adipose Mesenchymal Stem Cells in Perianal Fistulas of Crohn's Disease Patients |
title_full_unstemmed | Dissecting Allo-Sensitization After Local Administration of Human Allogeneic Adipose Mesenchymal Stem Cells in Perianal Fistulas of Crohn's Disease Patients |
title_short | Dissecting Allo-Sensitization After Local Administration of Human Allogeneic Adipose Mesenchymal Stem Cells in Perianal Fistulas of Crohn's Disease Patients |
title_sort | dissecting allo-sensitization after local administration of human allogeneic adipose mesenchymal stem cells in perianal fistulas of crohn's disease patients |
topic | Immunology |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6587893/ https://www.ncbi.nlm.nih.gov/pubmed/31258526 http://dx.doi.org/10.3389/fimmu.2019.01244 |
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