Abstract
The role of monocytes/macrophages in antibody-mediated rejection (AMR) remains unclear. We have reported that murine CCR5-/-/CD8-/- recipients produce high titers of donor-specific antibody and reject MHC-mismatched heart allografts. The current studies tested the magnitude of injury and alloimmune responses to grafts deficient in expression of the monocyte chemoattractant MCP-1/CCL2 during AMR. B6.CCR5-/-/CD8-/- recipients rejected MHC-mismatched wild-type A/J allografts with high donor-reactive antibody titers and diffuse C4d deposition in the large vessels and myocardial capillaries, features consistent with AMR. Donor-specific CD4 T cells producing IFN-γ in the recipient spleen were significantly decreased in response to A/J.CCL2-/- vs. A/J allografts and this resulted in decreased donor-reactive antibody production and C4d deposition in allografts in B6. CCR5-/-/CD8-/- recipients at day 7 post-transplant. Consequently, A/J.CCL2-/- allograft survival was slightly but significantly longer than that of A/J allografts (MST: wild-type A/J, day 8 vs. A/J.CCL2-/-, day 10, P < 0.01). Allograft CCL2 deficiency reduced classically activated (M1) macrophage and other inflammatory leukocyte infiltration into the allografts. Strikingly, A/J.CCL2-/- allograft survival was much longer than wild-type A/J allografts in recipients treated with 0.25 mg anti-CD40L mAb at the time of transplant (MST: wild-type A/J, day 21.5 vs. A/J.CCL2-/-, day 58, P < 0.01) with lower titers of donor-reactive antibody and decreased leukocyte infiltration. CCL2 deficiency also reduced pro-fibrotic gene expression and delayed the development of interstitial fibrosis when compared to wild-type A/J allografts. The results indicate that allograft-derived CCL2/MCP-1 plays an important role in directing M1 macrophages and other inflammatory cell infiltration into allografts and in the development of donor-reactive antibody and vascular rejection and suggest CCL2/MCP-1 as a therapeutic target for antibody-mediated vascular rejection and chronic graft injury.
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