title: Deletion of the chemokine receptor CCR1 prolongs corneal allograft survival.
abstract: OBJECTIVE
  Many corneal grafts undergo immune rejection, and current therapies are associated with many side effects. The purpose of this study was to identify critical chemokine pathways involved in generating the alloimmune response to corneal transplants.
  
  
  METHODS
  Orthotopic corneal transplantation was performed in fully mismatched strains. Cytokine and chemokine receptor gene expression was determined by the RNase protection assay. Knockout (KO) strains for chemokine-chemokine receptors that are upregulated after transplantation underwent corneal transplantation. Results derived from KO murine hosts were compared with cyclosporine (Cy) therapy. In addition to graft survival, graft infiltration, allospecific delayed-type hypersensitivity (DTH), and cytokine expression were compared among the recipient groups.
  
  
  RESULTS
  Initial experiments revealed gene upregulation of the chemokine receptors CCR1, -2, and -5 after corneal allorejection. Although CCR1 KO hosts showed a significant increase in graft survival compared with wild-type (WT) hosts, allografts in CCR5, CCR2/CCL3(MIP-1alpha), CXCR3, CXCL10/IP-10, and CCL3/MIP-1alpha KO mice did not show a significant improvement in graft survival. Further, CCR1 KO hosts showed a significantly higher survival rate than with systemic Cy therapy in WT hosts. Moreover, graft infiltration by leukocytes and gene expression of proinflammatory cytokines were reduced in CCR1 KO mice compared with both Cy treated and untreated WT mice, as was the induction of allospecific DTH.
  
  
  CONCLUSIONS
  These studies provide, for the first time, evidence that targeting of specific chemokine pathways can significantly promote survival of corneal transplants, and suggest that select deletion or suppression of CCR1 can be a useful therapeutic target in corneal transplant immunity.
authors.affiliation: Laboratory of Immunology, Schepens Eye Research Institute, and the Massachusetts Eye and Ear Infirmary, Department of Ophthalmology, Boston, USA.
authors.forename: Pedram
authors.initials: P
authors.lastname: Hamrah
authors.forename: Satoru
authors.initials: S
authors.lastname: Yamagami
authors.forename: Ying
authors.initials: Y
authors.lastname: Liu
authors.forename: Qiang
authors.initials: Q
authors.lastname: Zhang
authors.forename: Sudhir S
authors.initials: SS
authors.lastname: Vora
authors.forename: Bao
authors.initials: B
authors.lastname: Lu
authors.forename: Craig J
authors.initials: CJ
authors.lastname: Gerard
authors.forename: M Reza
authors.initials: MR
authors.lastname: Dana
mesh_terms: D000818:Animals; D018946:Chemokine CCL5 / Q000276:immunology; D003315:Cornea / Q000276:immunology*; D016039:Corneal Transplantation / Q000502:physiology*; D016572:Cyclosporine / Q000627:therapeutic use; D019084:Fluorescent Antibody Technique, Indirect; D017353:Gene Deletion; D015870:Gene Expression / Q000502:physiology; D020868:Gene Silencing / Q000502:physiology; D006084:Graft Rejection / Q000378:metabolism / Q000517:prevention & control; D006085:Graft Survival / Q000187:drug effects / Q000502:physiology*; D006968:Hypersensitivity, Delayed / Q000276:immunology; D007166:Immunosuppressive Agents / Q000627:therapeutic use; D007962:Leukocytes / Q000502:physiology; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D054389:Receptors, CCR1; D019707:Receptors, Chemokine / Q000502:physiology*; D014184:Transplantation, Homologous
chemical_list: C515301:Ccr1 protein, mouse; D018946:Chemokine CCL5; D007166:Immunosuppressive Agents; D054389:Receptors, CCR1; D019707:Receptors, Chemokine; D016572:Cyclosporine