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Therapeutic blockade of LIGHT interaction with herpesvirus entry mediator and lymphotoxin β receptor attenuates in vivo cytotoxic allogeneic responses.
- Source :
-
Transplantation [Transplantation] 2014 Dec 15; Vol. 98 (11), pp. 1165-74. - Publication Year :
- 2014
-
Abstract
- Background: Tumor necrosis factor/tumor necrosis factor receptor superfamily members conform a group of molecular interaction pathways of essential relevance during the process of T-cell activation and differentiation toward effector cells and particularly for the maintenance phase of the immune response. Specific blockade of these interacting pathways, such as CD40-CD40L, contributes to modulate the deleterious outcome of allogeneic immune responses. We postulated that antagonizing the interaction of LIGHT expression on activated T cells with its receptors, herpesvirus entry mediator and lymphotoxin β receptor, may decrease T cell-mediated allogeneic responses.<br />Methods: A flow cytometry competition assay was designed to identify anti-LIGHT monoclonal antibodies capable to prevent the interaction of mouse LIGHT with its receptors expressed on transfected cells. An antibody with the desired specificity was evaluated in a short-term in vivo allogeneic cytotoxic assay and tested for its ability to detect endogenous mouse LIGHT.<br />Results: We provide evidence for the first time that in mice, as previously described in humans, LIGHT protein is rapidly and transiently expressed after T-cell activation, and this expression was stronger on CD8 T cells than on CD4 T cells. Two anti-LIGHT antibodies prevented interactions of mouse LIGHT with its two known receptors, herpesvirus entry mediator and lymphotoxin β receptor. In vivo administration of anti-LIGHT antibody (clone 10F12) ameliorated host antidonor short-term cytotoxic response in wild type B6 mice, although to a lesser extent than that observed in LIGHT-deficient mice.<br />Conclusion: The therapeutic targeting of LIGHT may contribute to achieve a better control of cytotoxic responses refractory to current immunosuppressive drugs in transplantation.
- Subjects :
- Animals
Antibodies, Monoclonal immunology
CD4-Positive T-Lymphocytes cytology
CD40 Antigens antagonists & inhibitors
CD40 Ligand antagonists & inhibitors
CD8-Positive T-Lymphocytes cytology
Flow Cytometry
HEK293 Cells
Humans
Lymphocyte Activation
Mice
NIH 3T3 Cells
Protein Binding
Protein Structure, Tertiary
Herpesviridae metabolism
Lymphotoxin beta Receptor metabolism
Tumor Necrosis Factor Ligand Superfamily Member 14 metabolism
Subjects
Details
- Language :
- English
- ISSN :
- 1534-6080
- Volume :
- 98
- Issue :
- 11
- Database :
- MEDLINE
- Journal :
- Transplantation
- Publication Type :
- Academic Journal
- Accession number :
- 25226173
- Full Text :
- https://doi.org/10.1097/TP.0000000000000417