Abstract 4952: Transplant Vasculopathy Response in CCR2 and NDST-1 Deficient Mice Aortic Transplant Model After Viral Anti-Inflammatory Chemokine Modulating Protein, M-T7, Treatment
Background: Transplant vasculopathy impedes long-term organ transplant survival. Chemokines direct inflammatory cell migration, through binding to glycosaminoglycans (GAGs) on the surface of endothelial cells and in connective tissues. Chemokines bind GAGs via the C terminus and receptors via the N terminus. Both chemokine receptor and chemokine GAG interactions are important to inflammatory responses. Chemokines and chemokine receptors have been demonstrated to have important roles in transplant rejection. The relative roles of receptor and GAG interaction in transplant vasculopathy are not defined. Myxoma viral chemokine modulating protein (CMP) M-T7 interrupts C terminal GAG binding of C, CC and CXC chemokines. In prior work M-T7 reduced transplant vasculopathy in aortic and renal transplant models. We examine here the effects of CCR2 and GAG deficiency as well as M-T7 treatment in CCR2 and heparan sulfate (HS-GAG) deficient mouse aortic allograft transplant models.
CCR2−/− or CCR2+/+ donor Balb/C aorta was transplanted to C57BL/6 recipients
HS-GAG+/+ and HS-GAG−/− aorta was transplanted to Balb/C.
WT to CCR2−/− or NDST-1−/− reverse aortic transplant was also examined.
All aortic transplant group were assessed with and without M-T7 treatment. Plaque growth and macrophage/T cell invasion were measured at 28 days.
Plaque growth was significantly decreased in both CCR2−/− and HS-GAG−/− transplants when compared to CCR2 +/+ (P = .021) or HS-GAG+/+ (P = .032), respectively. Immunostaining demonstrated reduced CD3 T-cell and macrophage invasion.
Plaque was reduced in WT HS-GAG+/+ when compared to WT Balb/C aortic transplant (P = .306).
Reverse Transplant of WT C57Bl/6 or Balb/C donor aorta to CCR2−/− or HS-GAG−/− mice, respectively, did not reduce plaque growth.
M-T7 treatment reduced plaque growth in both CCR2+/+ (P < .047) and CCR2−/− (P = .017) aortic transplant, but had reduced inhibitory activity in HS-GAG−/− aortic transplants when compared to HS-GAG+/+.
Heparan sulfate GAG is an important mediator in transplant vasculopathy development.
Interruption of chemokine: GAG binding provides a new therapeutic target for prevention of transplant vasculopathy.