Therapeutic effect of CXCR3-expressing regulatory T cells on liver, lung and intestinal damages in a murine acute GVHD model.
Adoptive transfer of CD4+CD25+ regulatory T cells has been shown to have therapeutic effects in experimental graft-vs-host disease (GVHD) models. Chemokines play an important role in the recruitment of alloreactive donor T cells into target organs during GVHD. In this study, we investigated the effectiveness of targeted delivery of CD4+CD25+ regulatory T cells via a transfected chemokine receptor on reduction of organ damage during acute GVHD. High levels of expression of Th1-associated chemokines (CXCL9, CXCL10 and CXCL11) and their receptor CXCR3 were observed in the liver, lung and intestine of GVHD-induced recipient mice. Recipient mice that had undergone transfer of CD4+CD25+Foxp3+ CXCR3-transfected T cells (CXCR3-Treg cells) showed significant amelioration of GVHD changes in the liver, lung and intestine in comparison with recipient mice that had received CD4+CD25+Foxp3+ T cells (Treg cells) or naturally occurring CD4+CD25+ regulatory T cells. This was due to more pronounced migration of CXCR3-Treg cells and their localization for a longer time in Th1-associated chemokine-expressing organs, resulting in stronger suppressive activity. We succeeded in preparing chemokine receptor-expressing Treg cells and demonstrated their ability to ameliorate disease progression upon accumulation in target organs. This method may provide a new therapeutic approach for organ damage in acute GVHD.
Hasegawa
H
H
Department of Bioregulatory Medicine, Ehime University Graduate School of Medicine, Ehime, Japan. hitoshih@m.ehime-u.ac.jp
Inoue
A
A
Kohno
M
M
Lei
J
J
Miyazaki
T
T
Yoshie
O
O
Nose
M
M
Yasukawa
M
M
D019264:Adoptive Transfer / Q000379:methods*; D000818:Animals; D016026:Bone Marrow Transplantation; D005260:Female; D051858:Forkhead Transcription Factors / Q000032:analysis / Q000235:genetics; D015316:Genetic Therapy / Q000379:methods*; D005822:Genetic Vectors / Q000008:administration & dosage; D006086:Graft vs Host Disease / Q000276:immunology / Q000473:pathology / Q000628:therapy*; D007422:Intestines / Q000276:immunology / Q000473:pathology; D008099:Liver / Q000276:immunology / Q000473:pathology; D008168:Lung / Q000276:immunology / Q000473:pathology; D051379:Mice; D008810:Mice, Inbred C57BL; D008811:Mice, Inbred DBA; D023421:Models, Animal; D054367:Receptors, CXCR3 / Q000032:analysis / Q000235:genetics / Q000378:metabolism*; D012190:Retroviridae / Q000235:genetics; D050378:T-Lymphocytes, Regulatory / Q000276:immunology*
D051858:Forkhead Transcription Factors; C498833:Foxp3 protein, mouse; D054367:Receptors, CXCR3