title: Neutralizing IL-7 promotes long-term allograft survival induced by CD40/CD40L costimulatory blockade.
abstract: Memory T cells are somewhat resistant to immunosuppresion. They therefore pose a threat to inducing long-term allograft survival. IL-7 is essential for memory T-cell generation. Here, we investigated whether neutralizing IL-7 promotes allograft survival. We found that neutralizing IL-7 alone did not significantly prolong allograft survival. However, blocking both IL-7 and CD154 signaling synergistically prolonged allograft survival. In contrast, neutralizing IL-2 failed to further prolong allograft survival induced by CD40/CD154 costimulatory blockade. Allospecific memory CD8+ T-cell generation was severely impaired under the treatment of anti-IL-7 plus anti-CD154 Ab while administering recombinant IL-7 enhanced CD8+ memory generation even under donor-specific transfusion plus anti-CD154 Ab treatment. Neutralizing IL-7, but not IL-2, together with blocking CD154 synergistically suppressed the proliferation of naïve/effector CD8+ T cells infiltrating grafts. Nevertheless, neutralizing IL-7 did not alter regulatory T-cell generation while neutralizing IL-2 suppressed their generation. Hence, targeting IL-7 represents a new strategy to prolong allograft survival by acting on both naïve and memory T cells. Long-term allograft survival may be achieved by neutralizing IL-7 plus CD40/CD154 blockade, since CD40/CD154 costimulatory blockade prevents acute rejection while neutralizing IL-7 suppresses the generation of memory T cells that persist and mediate late or chronic rejection.
authors.affiliation: Center for Biomedical Research, University of Texas Health Center at Tyler, Tyler, Texas, USA.
authors.forename: Y
authors.initials: Y
authors.lastname: Wang
authors.forename: H
authors.initials: H
authors.lastname: Dai
authors.forename: Z
authors.initials: Z
authors.lastname: Liu
authors.forename: X
authors.initials: X
authors.lastname: Cheng
authors.forename: G
authors.initials: G
authors.lastname: Tellides
authors.forename: Z
authors.initials: Z
authors.lastname: Dai
mesh_terms: D000818:Animals; D019013:CD40 Antigens / Q000037:antagonists & inhibitors*; D023201:CD40 Ligand / Q000037:antagonists & inhibitors*; D002455:Cell Division; D003713:Dendritic Cells / Q000166:cytology / Q000276:immunology; D006085:Graft Survival / Q000276:immunology*; D016027:Heart Transplantation / Q000276:immunology*; D007156:Immunologic Memory; D016130:Immunophenotyping; D015851:Interleukin-7 / Q000276:immunology*; D008213:Lymphocyte Activation; D051379:Mice; D008810:Mice, Inbred C57BL; D009500:Neutralization Tests; D007703:Peptidyl-Dipeptidase A / Q000378:metabolism; D016038:Skin Transplantation / Q000276:immunology*; D013601:T-Lymphocytes / Q000276:immunology; D014184:Transplantation, Homologous / Q000276:immunology*
chemical_list: D019013:CD40 Antigens; D015851:Interleukin-7; D023201:CD40 Ligand; D007703:Peptidyl-Dipeptidase A