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Immunoglobulin-Like Transcript 3-Fc Suppresses T-Cell Responses to Allogeneic Human Islet Transplants in hu-NOD/SCID Mice

OBJECTIVE—The aim of our study was to explore the immunomodulatory activity of soluble immunoglobulin (Ig)-like transcript (ILT) 3-Fc in pancreatic islet transplantation and to determine its mechanism of action. RESEARCH DESIGN AND METHODS—NOD/SCID mice in which diabetes was induced by streptozotoci...

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Autores principales: Vlad, George, D'Agati, Vivette D., Zhang, Qing-Yin, Liu, Zhuoru, Ho, Eric K., Mohanakumar, Thalachallour, Hardy, Mark A., Cortesini, Raffaello, Suciu-Foca, Nicole
Formato: Texto
Lenguaje:English
Publicado: American Diabetes Association 2008
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2453624/
https://www.ncbi.nlm.nih.gov/pubmed/18420485
http://dx.doi.org/10.2337/db08-0054
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author Vlad, George
D'Agati, Vivette D.
Zhang, Qing-Yin
Liu, Zhuoru
Ho, Eric K.
Mohanakumar, Thalachallour
Hardy, Mark A.
Cortesini, Raffaello
Suciu-Foca, Nicole
author_facet Vlad, George
D'Agati, Vivette D.
Zhang, Qing-Yin
Liu, Zhuoru
Ho, Eric K.
Mohanakumar, Thalachallour
Hardy, Mark A.
Cortesini, Raffaello
Suciu-Foca, Nicole
author_sort Vlad, George
collection PubMed
description OBJECTIVE—The aim of our study was to explore the immunomodulatory activity of soluble immunoglobulin (Ig)-like transcript (ILT) 3-Fc in pancreatic islet transplantation and to determine its mechanism of action. RESEARCH DESIGN AND METHODS—NOD/SCID mice in which diabetes was induced by streptozotocin injection were transplanted with human pancreatic islet cells. Mice in which the transplant restored euglycemia were humanized with allogeneic peripheral blood mononuclear cells and treated with ILT3-Fc or control human IgG or left untreated. The blood glucose level was monitored twice a week, and rejection was diagnosed after two consecutive readings >350 mg/dl. Tolerated and rejected grafts were studied histologically and by immunostaining for human T-cells and insulin production. CD4 and CD8 T-cells from the spleen were studied for suppressor activity, expression of cytokines, and CD40L. RESULTS—Although human T-cell engraftment was similar in all groups, ILT3-Fc–treated mice tolerated the islets for the entire period of observation (91 days), whereas control mice rejected the graft within 7 weeks (P < 0.0001). ILT3-Fc treatment suppressed the expression of cytokines and CD40L and induced the differentiation of human CD8(+) T suppressor cells that inhibited Th alloreactivity against graft HLA antigens. T-cells allostimulated in vitro in the presence of ILT3-Fc inhibited CD40L-induced upregulation of CD40 in human pancreatic islet cells. Histochemical studies showed dramatic differences between human pancreatic islets from tolerant, ILT3-Fc–treated mice and control recipients rejecting the grafts. CONCLUSIONS—The data indicated that ILT3-Fc is a potent immunoregulatory agent that suppressed islet allograft rejection in humanized NOD/SCID mice.
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spelling pubmed-24536242009-07-01 Immunoglobulin-Like Transcript 3-Fc Suppresses T-Cell Responses to Allogeneic Human Islet Transplants in hu-NOD/SCID Mice Vlad, George D'Agati, Vivette D. Zhang, Qing-Yin Liu, Zhuoru Ho, Eric K. Mohanakumar, Thalachallour Hardy, Mark A. Cortesini, Raffaello Suciu-Foca, Nicole Diabetes Immunology and Transplantation OBJECTIVE—The aim of our study was to explore the immunomodulatory activity of soluble immunoglobulin (Ig)-like transcript (ILT) 3-Fc in pancreatic islet transplantation and to determine its mechanism of action. RESEARCH DESIGN AND METHODS—NOD/SCID mice in which diabetes was induced by streptozotocin injection were transplanted with human pancreatic islet cells. Mice in which the transplant restored euglycemia were humanized with allogeneic peripheral blood mononuclear cells and treated with ILT3-Fc or control human IgG or left untreated. The blood glucose level was monitored twice a week, and rejection was diagnosed after two consecutive readings >350 mg/dl. Tolerated and rejected grafts were studied histologically and by immunostaining for human T-cells and insulin production. CD4 and CD8 T-cells from the spleen were studied for suppressor activity, expression of cytokines, and CD40L. RESULTS—Although human T-cell engraftment was similar in all groups, ILT3-Fc–treated mice tolerated the islets for the entire period of observation (91 days), whereas control mice rejected the graft within 7 weeks (P < 0.0001). ILT3-Fc treatment suppressed the expression of cytokines and CD40L and induced the differentiation of human CD8(+) T suppressor cells that inhibited Th alloreactivity against graft HLA antigens. T-cells allostimulated in vitro in the presence of ILT3-Fc inhibited CD40L-induced upregulation of CD40 in human pancreatic islet cells. Histochemical studies showed dramatic differences between human pancreatic islets from tolerant, ILT3-Fc–treated mice and control recipients rejecting the grafts. CONCLUSIONS—The data indicated that ILT3-Fc is a potent immunoregulatory agent that suppressed islet allograft rejection in humanized NOD/SCID mice. American Diabetes Association 2008-07 /pmc/articles/PMC2453624/ /pubmed/18420485 http://dx.doi.org/10.2337/db08-0054 Text en Copyright © 2008, American Diabetes Association https://creativecommons.org/licenses/by-nc-nd/3.0/Readers may use this article as long as the work is properly cited, the use is educational and not for profit, and the work is not altered. See http://creativecommons.org/licenses/by-nc-nd/3.0/ for details.
spellingShingle Immunology and Transplantation
Vlad, George
D'Agati, Vivette D.
Zhang, Qing-Yin
Liu, Zhuoru
Ho, Eric K.
Mohanakumar, Thalachallour
Hardy, Mark A.
Cortesini, Raffaello
Suciu-Foca, Nicole
Immunoglobulin-Like Transcript 3-Fc Suppresses T-Cell Responses to Allogeneic Human Islet Transplants in hu-NOD/SCID Mice
title Immunoglobulin-Like Transcript 3-Fc Suppresses T-Cell Responses to Allogeneic Human Islet Transplants in hu-NOD/SCID Mice
title_full Immunoglobulin-Like Transcript 3-Fc Suppresses T-Cell Responses to Allogeneic Human Islet Transplants in hu-NOD/SCID Mice
title_fullStr Immunoglobulin-Like Transcript 3-Fc Suppresses T-Cell Responses to Allogeneic Human Islet Transplants in hu-NOD/SCID Mice
title_full_unstemmed Immunoglobulin-Like Transcript 3-Fc Suppresses T-Cell Responses to Allogeneic Human Islet Transplants in hu-NOD/SCID Mice
title_short Immunoglobulin-Like Transcript 3-Fc Suppresses T-Cell Responses to Allogeneic Human Islet Transplants in hu-NOD/SCID Mice
title_sort immunoglobulin-like transcript 3-fc suppresses t-cell responses to allogeneic human islet transplants in hu-nod/scid mice
topic Immunology and Transplantation
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2453624/
https://www.ncbi.nlm.nih.gov/pubmed/18420485
http://dx.doi.org/10.2337/db08-0054
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