title: CD44/CD70 blockade and anti-CD154/LFA-1 treatment synergistically suppress accelerated rejection and prolong cardiac allograft survival in mice.
abstract: Current treatments that are efficient in controlling effector T cell responses to allografts have limited efficacy on the accelerated rejection mediated by memory T cells. Effective targeting of alloreactive memory T cells may therefore be explored to improve therapeutic approaches towards solving this problem. In this study, we investigated the synergistic effect of CD44/CD70 blockade and anti-CD154/LFA-1 treatment on the accelerated rejection mediated by memory T cells. While CD44/CD70 blockade had limited effects on the alloresponses of effector T cells in vivo, it diminished the expansion of both CD4(+)  and CD8(+)  memory T cells in recipients adoptively transferred with donor-sensitized T cells. In combination with anti-CD154/LFA-1 treatment, CD44/CD70 blockade significantly prolonged cardiac allograft survival in adoptive transfer recipients. We demonstrated that treatment with the combination of all four antibodies (anti-CD154/LFA-1/CD44/CD70) inhibited accelerated rejection by markedly suppressing the alloresponses of effector and memory T cells and reducing the number of graft-infiltration lymphocytes in adoptive transfer recipients. Meanwhile, CD44/CD70 blockade and anti-CD154/LFA-1 treatment synergically enhanced regulatory T cells (Tregs) by increasing the proportion of splenic Tregs and the expression of IL-10 in these recipients. Our findings contribute to the potential design of therapies for accelerated allograft rejection.
authors.affiliation: Department of Pathology, The 174th Hospital of People's Liberation Army, Xiamen University, Fujian Province, China.
authors.forename: W
authors.initials: W
authors.lastname: Shao
authors.forename: G
authors.initials: G
authors.lastname: Yan
authors.forename: Y
authors.initials: Y
authors.lastname: Lin
authors.forename: J
authors.initials: J
authors.lastname: Chen
authors.forename: H
authors.initials: H
authors.lastname: Dai
authors.forename: F
authors.initials: F
authors.lastname: Wang
authors.forename: Y
authors.initials: Y
authors.lastname: Xi
authors.forename: H
authors.initials: H
authors.lastname: Thorlacius
authors.forename: Z
authors.initials: Z
authors.lastname: Qi
mesh_terms: D019264:Adoptive Transfer; D000818:Animals; D019138:Antibodies, Blocking / Q000494:pharmacology; D000911:Antibodies, Monoclonal / Q000494:pharmacology; D053282:CD27 Ligand / Q000276:immunology*; D049109:Cell Proliferation / Q000187:drug effects; D004357:Drug Synergism; D004359:Drug Therapy, Combination; D006084:Graft Rejection / Q000188:drug therapy* / Q000276:immunology; D006085:Graft Survival / Q000187:drug effects; D016027:Heart Transplantation; D018960:Hyaluronan Receptors / Q000276:immunology*; D007114:Immunization; D007156:Immunologic Memory; D016169:Lymphocyte Function-Associated Antigen-1 / Q000276:immunology*; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL
chemical_list: D019138:Antibodies, Blocking; D000911:Antibodies, Monoclonal; D053282:CD27 Ligand; D018960:Hyaluronan Receptors; D016169:Lymphocyte Function-Associated Antigen-1