Prolongation of cardiac and islet allograft survival by a blocking hamster anti-mouse CXCR3 monoclonal antibody.
BACKGROUND
Acute allograft rejection requires a multifaceted immune response involving trafficking of immune cells into the transplant and expression of effector cell functions leading to graft destruction. The chemokine receptor CXCR3 and its ligands, CXCL9, CXCL10 and CXCL11, constitute an important pathway for effector cell recruitment posttransplant. However, analysis of CXCR3 expression and function has been hampered by a general lack of availability of a neutralizing anti-CXCR3 monoclonal antibody (mAb) for use in experimental models.


METHODS
We report the generation, characterization, and use of CXCR3-173, a new hamster mAb specific for mouse CXCR3 that recognizes CXCR3 on cells from wild-type but not CXCR3-/- mice.


RESULTS
Using CXCR3-173 mAb, we demonstrate CXCR3 expression on primary memory phenotype CD4+ and CD8+ T cells, naturally occurring CD4+CD25+ Foxp3+ regulatory T cells, natural killer T cells, and approximately 25% of NK cells. CXCR3-173 blocked chemotaxis in vitro in response to CXCL10 or CXCL11 but not CXCL9. When injected into mice, this mAb significantly prolonged both cardiac and islet allograft survival. When combined with a subtherapeutic regimen of rapamycin, CXCR3-173 mAb induced long-term (>100 day) survival of cardiac and islet allografts. The in vivo effects of CXCR3-173 mAb were not associated with effector lymphocyte depletion.


CONCLUSIONS
These data highlight the utility of CXCR3-173 mAb in developing immunotherapeutic approaches to inhibit transplant rejection and potentially other immune-mediated diseases in murine models.
Uppaluri
Ravindra
R
Department of Otolaryngology, Washington University School of Medicine and John Cochran VA Medical Center, St. Louis, MO, USA.
Sheehan
Kathleen C F
KC
Wang
Liqing
L
Bui
Jack D
JD
Brotman
Joshua J
JJ
Lu
Bao
B
Gerard
Craig
C
Hancock
Wayne W
WW
Schreiber
Robert D
RD
D000818:Animals; D000911:Antibodies, Monoclonal / Q000494:pharmacology*; D015496:CD4-Positive T-Lymphocytes / Q000187:drug effects; D018414:CD8-Positive T-Lymphocytes / Q000187:drug effects; D002460:Cell Line; D002634:Chemotaxis, Leukocyte / Q000187:drug effects; D006224:Cricetinae; D016207:Cytokines / Q000235:genetics / Q000378:metabolism; D004359:Drug Therapy, Combination; D006084:Graft Rejection / Q000276:immunology / Q000473:pathology / Q000517:prevention & control*; D006085:Graft Survival / Q000187:drug effects*; D016027:Heart Transplantation; D007166:Immunosuppressive Agents / Q000494:pharmacology*; D016381:Islets of Langerhans Transplantation; D007694:Killer Cells, Natural / Q000187:drug effects; D016131:Lymphocyte Subsets / Q000187:drug effects* / Q000276:immunology; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D023421:Models, Animal; D012333:RNA, Messenger / Q000378:metabolism; D054367:Receptors, CXCR3 / Q000235:genetics / Q000276:immunology*; D020123:Sirolimus / Q000494:pharmacology; D050378:T-Lymphocytes, Regulatory / Q000187:drug effects; D013997:Time Factors; D014184:Transplantation, Homologous
D000911:Antibodies, Monoclonal; C515188:Cxcr3 protein, mouse; D016207:Cytokines; D007166:Immunosuppressive Agents; D012333:RNA, Messenger; D054367:Receptors, CXCR3; D020123:Sirolimus