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A new approach to the blocking of alloreactive T cell-mediated graft-versus-host disease by in vivo administration of anti-CXCR3 neutralizing antibody
- Source :
- Journal of immunology (Baltimore, Md. : 1950). 181(11)
- Publication Year :
- 2008
-
Abstract
- Chemokines and chemokine receptors play critical roles in directing the migration of alloreactive donor T cells into graft-vs-host disease (GVHD) target organs. However, blockade of GVHD by antagonist Ab against chemokine receptors remains an elusive goal. Using a mouse model of human GVHD, we demonstrate that in vivo administration of anti-CXCR3 Ab for 21 days (long-term), but not for 7 days (short-term), inhibits alloreactive CD8+ T cell-mediated GVHD. During a graft-vs-host reaction, infused donor CD8+ T cells generate two subsets of potent inducers of GVHD: CXCR3+CD8+ and CXCR3−CD8+ T cells. Compared with CXCR3+CD8+ T cells, CXCR3−CD8+ T cells produce less granzyme B, Fas ligand, IFN-γ, and TNF-α. Interestingly, stimulation with either dendritic cells or IL-2 induces a dynamic conversion between CXCR3+CD8+ and CXCR3−CD8+ T cells. Short-term anti-CXCR3 Ab treatment inhibits only CXCR3+CD8+ T cell-mediated GVHD, but not the disease induced by CXCR3−CD8+ T cells. Prolonged in vivo administration of anti-CXCR3 Ab significantly reduces the infiltration of alloreactive CD8+ T cells into GVHD target organs and inhibits GVHD mediated by either CXCR3+CD8+ or CXCR3−CD8+ T cells. Thus, we have established a novel and effective approach with the potential to give rise to new clinical methods for preventing and treating GVHD after allogeneic hematopoietic stem cell transplantation.
- Subjects :
- Fas Ligand Protein
Receptors, CXCR3
Time Factors
T cell
Immunology
Graft vs Host Disease
chemical and pharmacologic phenomena
Biology
CD8-Positive T-Lymphocytes
CXCR3
Granzymes
Interleukin 21
Interferon-gamma
Mice
stomatognathic system
immune system diseases
medicine
Immunology and Allergy
Cytotoxic T cell
Animals
Humans
Transplantation, Homologous
Tumor Necrosis Factor-alpha
Hematopoietic Stem Cell Transplantation
Antibodies, Monoclonal
hemic and immune systems
medicine.disease
Granzyme B
stomatognathic diseases
Disease Models, Animal
Graft-versus-host disease
medicine.anatomical_structure
Granzyme
Cancer research
biology.protein
CD8
Subjects
Details
- ISSN :
- 15506606
- Volume :
- 181
- Issue :
- 11
- Database :
- OpenAIRE
- Journal :
- Journal of immunology (Baltimore, Md. : 1950)
- Accession number :
- edsair.doi.dedup.....f9d7a58160b12790910335bc4fea40a6