CXCR3 antagonism impairs the development of donor-reactive, IFN-gamma-producing effectors and prolongs allograft survival.
BACKGROUND
Current immunosuppression regimens are toxic to transplant recipients and, in many cases, acute rejection episodes occur because of escape of donor-reactive lymphocytes from the immunosuppression. T cells are the mediators of acute, cell-mediated graft damage and are hypothesized to use the CXCR3 chemokine axis for migration into the allograft. This study investigates the effect of CXCR3 blockade using a nonpeptide, small molecule inhibitor, AMG1237845, in murine cardiac allograft survival.


METHODS
C57BL/6 (H-2) mice received vascularized cardiac allografts from A/J (H-2) donors and were treated with the CXCR3 antagonist. Histologic and flow cytometric analyses were used to measure infiltration of leukocytes, and quantitative reverse-transcriptase polymerase chain reaction and interferon-gamma ELISPOT assays were used to measure donor-specific reactivity.


RESULTS
CXCR3 antagonism modestly prolonged allograft survival compared with vehicle treatment, but at time-matched intervals posttransplant, neutrophil, CD8, and CD4 T cell infiltration was indistinguishable. Although proliferation of donor-reactive naïve T cells was unaffected by CXCR3 antagonism, the frequency of interferon-gamma-producing cells in the recipient spleen was significantly reduced by AMG1237845 treatment. CXCR3 blockade for 30 days synergized with short-term, low-dose anti-CD154 monoclonal antibodies to prolong survival past 50 days in 75% of grafts and past 80 days in 25% of the cases.


CONCLUSIONS
These results indicate that in synergy with co-stimulation blockade, CXCR3 is a viable therapeutic target to prevent acute graft rejection.
Rosenblum
Joshua M
JM
Department of Pathology, Case Western Reserve University, Cleveland, OH, USA. jmr55@case.edu
Zhang
Qi-Wei
QW
Siu
Gerald
G
Collins
Tassie L
TL
Sullivan
Timothy
T
Dairaghi
Daniel J
DJ
Medina
Julio C
JC
Fairchild
Robert L
RL
D000818:Animals; D006084:Graft Rejection / Q000276:immunology; D006085:Graft Survival / Q000276:immunology*; D016027:Heart Transplantation / Q000276:immunology*; D007166:Immunosuppressive Agents / Q000627:therapeutic use; D007371:Interferon-gamma / Q000276:immunology*; D051379:Mice; D008805:Mice, Inbred A; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D054367:Receptors, CXCR3 / Q000037:antagonists & inhibitors*; D016042:Transplantation, Heterotopic; D014184:Transplantation, Homologous / Q000276:immunology*
C515188:Cxcr3 protein, mouse; D007166:Immunosuppressive Agents; D054367:Receptors, CXCR3; D007371:Interferon-gamma