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Therapy with Nonglycosaminoglycan‐Binding Mutant CCL7: A Novel Strategy to Limit Allograft Inflammation
Author(s) -
Ali S.,
O’Boyle G.,
Hepplewhite P.,
Tyler J. R.,
Robertson H.,
Kirby J. A.
Publication year - 2010
Publication title -
american journal of transplantation
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.89
H-Index - 188
eISSN - 1600-6143
pISSN - 1600-6135
DOI - 10.1111/j.1600-6143.2009.02868.x
Subject(s) - ccl7 , chemokine , immunology , inflammation , medicine , transplantation , glycosaminoglycan , chemokine receptor , microbiology and biotechnology , biology , anatomy
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‐γ 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 α4β1 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.