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Therapy with Nonglycosaminoglycan-Binding Mutant CCL7: A Novel Strategy to Limit Allograft Inflammation

Lookup NU author(s): Professor Simi Ali, Dr Graeme O'Boyle, Philippa Hepplewhite, Dr Helen Robertson, Professor John Kirby

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Abstract

Chemokines are immobilized by binding to glycosaminoglycans (GAGs). A non-GAG-binding mutant CCL7 (mtCCL7) was developed that retained its affinity for chemokine receptors. This mtCCL7 induced leukocyte chemotaxis in diffusion gradients but did not stimulate trans-endothelial migration (p < 0.01). Unlike wild-type CCL7, mtCCL7 persisted in the circulation of BALB/c mice for more than 6 h and prevented leukocyte infiltration of skin isografts (p < 0.05). Treatment with mtCCL7 marginally increased the survival of C57BL/6 to BALB/c skin allografts and reduced graft infiltration by CD3+ cells (p < 0.05). Importantly, mtCCL7 promoted long-term (> 40 day) graft survival following minor histocompatibility (HY) antigen mismatched C57BL/6 skin transplantation; control grafts were rejected by day 24. Treatment with mtCCL7 produced a significant decrease in the frequency of IFN-gamma producing donor-reactive splenic T cells, reduced CCR2 expression by circulating leukocytes for 6 h (p < 0.01) and blocked the normal increase in affinity of alpha 4 beta 1 integrins for VCAM-1 following transient chemokine stimulation. These data suggest that mtCCL7 persists in the circulation and reduces both specific T-cell priming and the capacity of circulating immune cells to respond to GAG-bound chemokine at sites of developing inflammation.


Publication metadata

Author(s): Ali S, O'Boyle G, Hepplewhite P, Tyler JR, Robertson H, Kirby JA

Publication type: Article

Publication status: Published

Journal: American Journal of Transplantation

Year: 2010

Volume: 10

Issue: 1

Pages: 47-58

ISSN (print): 1600-6135

ISSN (electronic): 1600-6143

Publisher: Wiley-Blackwell Publishing Ltd.

URL: http://dx.doi.org/10.1111/j.1600-6143.2009.02868.x

DOI: 10.1111/j.1600-6143.2009.02868.x


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