title: Arsenic trioxide is a novel agent for combination therapy to prolong heart allograft survival in allo-primed T cells transferred mice.
abstract: Alloreactive memory T cells are major barriers to transplantation acceptance due to their capacity to accelerate rejection. Here, we investigated the effects of combined treatment with arsenic trioxide (As(2)O(3)) and blocking monoclonal antibodies (mAb) against CD154 and LFA-1 (anti-CD154/LFA-1) on graft survival as well as changes in pathology and immunological responses in mice with adoptively transferred allo-primed T cells. The mean survival time (MST) for the cardiac allografts in recipient mice receiving the combination of As(2)O(3) and anti-CD154/LFA-1 was significantly longer (>113.7days) compared to those receiving anti-CD154/LFA-1 (23.2days), As(2)O(3) (12.5days) alone or no treatment (5.5days). This combined strategy distinctly inhibited lymphocyte infiltration in grafts, proliferation of splenic T cells and the generation of memory T cells in spleens. Moreover, the combined treatment caused the significant down-regulation of IL-2 and IFN-γ accompanied by increased expression of TGF-β and regulatory T cells (Tregs) in spleens, which led to long-term cardiac allograft survival in recipient mice. These results highlight the potential application of As(2)O(3) and its contribution in combination therapy with antibody blockade to delay rejection by memory T cells.
authors.affiliation: Organ Transplantation Institute, Xiamen University, Fujian Province, PR China.
authors.forename: Yingying
authors.initials: Y
authors.lastname: Lin
authors.forename: Helong
authors.initials: H
authors.lastname: Dai
authors.forename: Jingjun
authors.initials: J
authors.lastname: Su
authors.forename: Guoliang
authors.initials: G
authors.lastname: Yan
authors.forename: Yanfeng
authors.initials: Y
authors.lastname: Xi
authors.forename: Henrik
authors.initials: H
authors.lastname: Ekberg
authors.forename: Jibing
authors.initials: J
authors.lastname: Chen
authors.forename: Zhongquan
authors.initials: Z
authors.lastname: Qi
mesh_terms: D019264:Adoptive Transfer; D000818:Animals; D058846:Antibodies, Monoclonal, Murine-Derived / Q000494:pharmacology; D057134:Antibodies, Neutralizing / Q000494:pharmacology; D000970:Antineoplastic Agents / Q000494:pharmacology*; D000077237:Arsenic Trioxide; D001152:Arsenicals / Q000494:pharmacology*; D049109:Cell Proliferation / Q000187:drug effects; D005260:Female; D006085:Graft Survival / Q000187:drug effects* / Q000276:immunology; D006321:Heart; D016027:Heart Transplantation / Q000276:immunology*; D007371:Interferon-gamma / Q000276:immunology; D007376:Interleukin-2 / Q000276:immunology; D017710:Lymphocyte Transfusion / Q000379:methods; D051379:Mice; D008807:Mice, Inbred BALB C; D010087:Oxides / Q000494:pharmacology*; D013154:Spleen / Q000276:immunology; D013601:T-Lymphocytes / Q000276:immunology / Q000637:transplantation*; D014184:Transplantation, Homologous
chemical_list: D058846:Antibodies, Monoclonal, Murine-Derived; D057134:Antibodies, Neutralizing; D000970:Antineoplastic Agents; D001152:Arsenicals; D007376:Interleukin-2; D010087:Oxides; D007371:Interferon-gamma; D000077237:Arsenic Trioxide