Document Detail


Lymphotoxin-beta receptor blockade induces inflammation and fibrosis in tolerized cardiac allografts.
MedLine Citation:
PMID:  22594431     Owner:  NLM     Status:  MEDLINE    
Abstract/OtherAbstract:
The lymphotoxin system (LT) regulates interactions between lymphocytes and stromal cells to maintain lymphoid microenvironmental homeostasis. Soluble LT beta-receptor-Ig (LTβRIg) blocks lymphocyte LTα1β2-stromal cell LTβR signaling. In a murine cardiac allograft model, LTbRIg treatment reversed the tolerance induced by anti-CD40L antibody leading to graft inflammation and fibrosis. LTβRIg treatment decreased PD-L1 expression by blood endothelial cells, and decreased VCAM-1 while increasing CXCL1, CXCL2, CXCL12, CCL5, CCL21 and IL-6 expression in fibroblastic reticular cells. In secondary lymphoid organs these effects caused T- and B cell zone disruption, loss of CD35(+) follicular dendritic cells and abnormal recruitment of CD11b(+) Ly6G(+) neutrophils. These disruptions correlated with increased numbers of CD8(+) T cells and CD11b(+) Ly6G(+) neutrophils, and decreased numbers of CD4(+) T cells and Foxp3(+) regulatory T cells in the grafts. Depleting neutrophils or blocking neutrophil-attracting chemokines restored normal histology in lymph node, spleen and grafts. Taken together, LTβRIg treatment altered stromal subset, particularly fibroblastic reticular cell, production of cytokines and chemokines, resulting in changes in neutrophil recruitment in spleen, lymph node and grafts, and inflammation and fibrosis associated with decreased Foxp3(+) regulatory T cells and increased CD8(+) T cell infiltration of grafts.
Authors:
Y Nakayama; J S Bromberg
Publication Detail:
Type:  Journal Article; Research Support, N.I.H., Extramural     Date:  2012-05-17
Journal Detail:
Title:  American journal of transplantation : official journal of the American Society of Transplantation and the American Society of Transplant Surgeons     Volume:  12     ISSN:  1600-6143     ISO Abbreviation:  Am. J. Transplant.     Publication Date:  2012 Sep 
Date Detail:
Created Date:  2012-08-28     Completed Date:  2013-01-14     Revised Date:  2013-09-03    
Medline Journal Info:
Nlm Unique ID:  100968638     Medline TA:  Am J Transplant     Country:  United States    
Other Details:
Languages:  eng     Pagination:  2322-34     Citation Subset:  IM    
Copyright Information:
© Copyright 2012 The American Society of Transplantation and the American Society of Transplant Surgeons.
Affiliation:
Center for Vascular and Inflammatory Diseases, University of Maryland, Baltimore, MD, USA.
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MeSH Terms
Descriptor/Qualifier:
Animals
Chemokines / metabolism
Fibrosis / etiology*
Heart Transplantation*
Immunoglobulins / immunology
Immunohistochemistry
Inflammation / etiology*
Lymphotoxin beta Receptor / antagonists & inhibitors*,  immunology
Mice
Mice, Inbred BALB C
Mice, Inbred C57BL
Neutrophils / immunology
Grant Support
ID/Acronym/Agency:
D RO1 AI41428/AI/NIAID NIH HHS; R01 AI041428-15/AI/NIAID NIH HHS; R01 AI062765/AI/NIAID NIH HHS; R01 AI062765-09/AI/NIAID NIH HHS; R01 AI072039/AI/NIAID NIH HHS; R01 AI072039-05/AI/NIAID NIH HHS
Chemical
Reg. No./Substance:
0/Chemokines; 0/Immunoglobulins; 0/Lymphotoxin beta Receptor
Comments/Corrections

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