title: ICOS-Dependent and -independent functions of memory CD4 T cells in allograft rejection.
abstract: Donor-reactive memory T cells undermine the survival of transplanted organs through multiple pathways. We have previously reported that memory CD4 T cells resist treatment with anti-CD154 antibody and donor-specific transfusion (DST/MR1) and promote cardiac allograft rejection via generation of effector CD4 T cells and alloantibody. We hypothesized that the helper functions of memory CD4 T cells are independent of T-cell costimulation through CD154 but instead are regulated by alternative costimulatory pathways. This study investigated how blocking ICOS/B7RP-1 interactions affects functions of donor-reactive memory CD4 T cells. Treatment with blocking anti-ICOS mAb synergized with DST/MR1 and prolonged mouse cardiac allograft survival despite the presence of donor-reactive memory CD4 T cells. While blocking ICOS did not diminish the expansion of preexisting memory CD4 T cells or the induction of allospecific effector T cells, it did inhibit recruitment of the activated memory and effector T cells into the graft. In addition, anti-ICOS mAb treatment in combination with DST/MR1 prevented help provided by memory CD4 T cells for production of donor-specific IgG antibody. These results demonstrate the potential efficacy of ICOS blockade in sensitized transplant patients and provide the foundation for rational use of ICOS blockade in combination with other graft-prolonging strategies.
authors.affiliation: Department of Immunology, the Cleveland Clinic Foundation, Cleveland, OH, USA.
authors.forename: Q-W
authors.initials: QW
authors.lastname: Zhang
authors.forename: M
authors.initials: M
authors.lastname: Rabant
authors.forename: A
authors.initials: A
authors.lastname: Schenk
authors.forename: A
authors.initials: A
authors.lastname: Valujskikh
mesh_terms: D000818:Animals; D000911:Antibodies, Monoclonal / Q000494:pharmacology; D000945:Antigens, Differentiation, T-Lymphocyte / Q000187:drug effects* / Q000378:metabolism*; D018122:B7-1 Antigen / Q000378:metabolism; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology*; D018414:CD8-Positive T-Lymphocytes / Q000187:drug effects / Q000276:immunology; D002352:Carrier Proteins / Q000187:drug effects; D003598:Cytoskeletal Proteins / Q000187:drug effects; D000071821:Dystonin; D005260:Female; D006084:Graft Rejection / Q000276:immunology* / Q000473:pathology / Q000517:prevention & control*; D006085:Graft Survival / Q000187:drug effects; D016027:Heart Transplantation; D015395:Histocompatibility Antigens Class I / Q000187:drug effects; D007134:Immunoglobulin Switch Region / Q000187:drug effects; D007156:Immunologic Memory / Q000187:drug effects; D060945:Inducible T-Cell Co-Stimulator Ligand; D060889:Inducible T-Cell Co-Stimulator Protein; D008297:Male; D051379:Mice; D008815:Mice, Inbred Strains; D015778:Minor Histocompatibility Antigens; D009419:Nerve Tissue Proteins / Q000187:drug effects
chemical_list: D000911:Antibodies, Monoclonal; D000945:Antigens, Differentiation, T-Lymphocyte; D018122:B7-1 Antigen; D002352:Carrier Proteins; D003598:Cytoskeletal Proteins; C095667:Dst protein, mouse; D000071821:Dystonin; D015395:Histocompatibility Antigens Class I; C556694:Icos protein, mouse; D060945:Inducible T-Cell Co-Stimulator Ligand; D060889:Inducible T-Cell Co-Stimulator Protein; D015778:Minor Histocompatibility Antigens; C490628:Mr1 protein, mouse; D009419:Nerve Tissue Proteins