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Role of Small Intestine and Gut Microbiome in Plant-Based Oral Tolerance for Hemophilia

Fusion proteins, which consist of factor VIII or factor IX and the transmucosal carrier cholera toxin subunit B, expressed in chloroplasts and bioencapsulated within plant cells, initiate tolerogenic immune responses in the intestine when administered orally. This approach induces regulatory T cells...

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Autores principales: Kumar, Sandeep R. P., Wang, Xiaomei, Avuthu, Nagavardhini, Bertolini, Thais B., Terhorst, Cox, Guda, Chittibabu, Daniell, Henry, Herzog, Roland W.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Frontiers Media S.A. 2020
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7251037/
https://www.ncbi.nlm.nih.gov/pubmed/32508814
http://dx.doi.org/10.3389/fimmu.2020.00844
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author Kumar, Sandeep R. P.
Wang, Xiaomei
Avuthu, Nagavardhini
Bertolini, Thais B.
Terhorst, Cox
Guda, Chittibabu
Daniell, Henry
Herzog, Roland W.
author_facet Kumar, Sandeep R. P.
Wang, Xiaomei
Avuthu, Nagavardhini
Bertolini, Thais B.
Terhorst, Cox
Guda, Chittibabu
Daniell, Henry
Herzog, Roland W.
author_sort Kumar, Sandeep R. P.
collection PubMed
description Fusion proteins, which consist of factor VIII or factor IX and the transmucosal carrier cholera toxin subunit B, expressed in chloroplasts and bioencapsulated within plant cells, initiate tolerogenic immune responses in the intestine when administered orally. This approach induces regulatory T cells (Treg), which suppress inhibitory antibody formation directed at hemophilia proteins induced by intravenous replacement therapy in hemophilia A and B mice. Further analyses of Treg CD4(+) lymphocyte sub-populations in hemophilia B mice reveal a marked increase in the frequency of CD4(+)CD25(−)FoxP3(−)LAP(+) T cells (but not of CD4(+)CD25(+)FoxP3(+) T cells) in the lamina propria of the small but not large intestine. The adoptive transfer of very small numbers of CD4(+)CD25(−)LAP(+) Treg isolated from the spleen of tolerized mice was superior in suppression of antibodies directed against FIX when compared to CD4(+)CD25(+) T cells. Thus, tolerance induction by oral delivery of antigens bioencapsulated in plant cells occurs via the unique immune system of the small intestine, and suppression of antibody formation is primarily carried out by induced latency-associated peptide (LAP) expressing Treg that likely migrate to the spleen. Tolerogenic antigen presentation in the small intestine requires partial enzymatic degradation of plant cell wall by commensal bacteria in order to release the antigen. Microbiome analysis of hemophilia B mice showed marked differences between small and large intestine. Remarkably, bacterial species known to produce a broad spectrum of enzymes involved in degradation of plant cell wall components were found in the small intestine, in particular in the duodenum. These were highly distinct from populations of cell wall degrading bacteria found in the large intestine. Therefore, FIX antigen presentation and Treg induction by the immune system of the small intestine relies on activity of a distinct microbiome that can potentially be augmented to further enhance this approach.
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spelling pubmed-72510372020-06-05 Role of Small Intestine and Gut Microbiome in Plant-Based Oral Tolerance for Hemophilia Kumar, Sandeep R. P. Wang, Xiaomei Avuthu, Nagavardhini Bertolini, Thais B. Terhorst, Cox Guda, Chittibabu Daniell, Henry Herzog, Roland W. Front Immunol Immunology Fusion proteins, which consist of factor VIII or factor IX and the transmucosal carrier cholera toxin subunit B, expressed in chloroplasts and bioencapsulated within plant cells, initiate tolerogenic immune responses in the intestine when administered orally. This approach induces regulatory T cells (Treg), which suppress inhibitory antibody formation directed at hemophilia proteins induced by intravenous replacement therapy in hemophilia A and B mice. Further analyses of Treg CD4(+) lymphocyte sub-populations in hemophilia B mice reveal a marked increase in the frequency of CD4(+)CD25(−)FoxP3(−)LAP(+) T cells (but not of CD4(+)CD25(+)FoxP3(+) T cells) in the lamina propria of the small but not large intestine. The adoptive transfer of very small numbers of CD4(+)CD25(−)LAP(+) Treg isolated from the spleen of tolerized mice was superior in suppression of antibodies directed against FIX when compared to CD4(+)CD25(+) T cells. Thus, tolerance induction by oral delivery of antigens bioencapsulated in plant cells occurs via the unique immune system of the small intestine, and suppression of antibody formation is primarily carried out by induced latency-associated peptide (LAP) expressing Treg that likely migrate to the spleen. Tolerogenic antigen presentation in the small intestine requires partial enzymatic degradation of plant cell wall by commensal bacteria in order to release the antigen. Microbiome analysis of hemophilia B mice showed marked differences between small and large intestine. Remarkably, bacterial species known to produce a broad spectrum of enzymes involved in degradation of plant cell wall components were found in the small intestine, in particular in the duodenum. These were highly distinct from populations of cell wall degrading bacteria found in the large intestine. Therefore, FIX antigen presentation and Treg induction by the immune system of the small intestine relies on activity of a distinct microbiome that can potentially be augmented to further enhance this approach. Frontiers Media S.A. 2020-05-20 /pmc/articles/PMC7251037/ /pubmed/32508814 http://dx.doi.org/10.3389/fimmu.2020.00844 Text en Copyright © 2020 Kumar, Wang, Avuthu, Bertolini, Terhorst, Guda, Daniell and Herzog. 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
Kumar, Sandeep R. P.
Wang, Xiaomei
Avuthu, Nagavardhini
Bertolini, Thais B.
Terhorst, Cox
Guda, Chittibabu
Daniell, Henry
Herzog, Roland W.
Role of Small Intestine and Gut Microbiome in Plant-Based Oral Tolerance for Hemophilia
title Role of Small Intestine and Gut Microbiome in Plant-Based Oral Tolerance for Hemophilia
title_full Role of Small Intestine and Gut Microbiome in Plant-Based Oral Tolerance for Hemophilia
title_fullStr Role of Small Intestine and Gut Microbiome in Plant-Based Oral Tolerance for Hemophilia
title_full_unstemmed Role of Small Intestine and Gut Microbiome in Plant-Based Oral Tolerance for Hemophilia
title_short Role of Small Intestine and Gut Microbiome in Plant-Based Oral Tolerance for Hemophilia
title_sort role of small intestine and gut microbiome in plant-based oral tolerance for hemophilia
topic Immunology
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7251037/
https://www.ncbi.nlm.nih.gov/pubmed/32508814
http://dx.doi.org/10.3389/fimmu.2020.00844
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