title: An immunotherapeutic strategy for prolonging graft survival in mice.
abstract: BACKGROUND
  Immunological memory is one barrier to inducing immune tolerance in alloantigen primed transplant models. Alloreactive memory cells induced by primary organ transplant are difficult to suppress and contribute to rejection following a retransplant. Here, we assess the effects of a novel immunosuppressive strategy on graft survival and host immune response.
  
  
  METHODS
  Alloantigen primed splenocytes were adoptively transferred into naïve B6 mice before heart transplant. Recipient mice were then treated with mitomycin C -pretreated donor-specific transfusion, low dose rapamycin, and anti-OX40L mAb (alone and in combination).
  
  
  RESULTS
  Treatment with donor-specific transfusion+rapamycin+anti-OX40L increased the mean graft survival time from 5.2 days (control group) to 42.5 days (p < 0.05). None of the grafts in the control group survived past 10 days, and only 1 in 3 grafts survived at least 50 days in the combined treatment group. Compared with the control and single treatment groups, the combination of donor-specific transfusion+rapamycin + anti-OX40L inhibited infiltration of inflammatory cells; reduced the percentages of CD4(+) and CD8(+) memory T cells in the blood, spleen, and lymph nodes; suppressed inflammatory cytokines; reduced serum IgG levels; and enhanced the percentage of CD4(+)Foxp3(+) T cells. The percentage of regulatory T cells was the highest in the recipients with long-term graft survival.
  
  
  CONCLUSIONS
  The combination of donor-specific transfusion+rapamycin+anti-OX40L inhibits graft rejection mediated by memory cells and is likely to contribute to prolonged allograft survival.
authors: Organ Transplant Center of The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, China.
authors: Feng
authors: F
authors: Wang
authors: Organ Transplant Center of The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, China.
authors: Jun
authors: J
authors: Li
authors: Department of Clinical Laboratory of The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, China.
authors: Dong
authors: D
authors: Wang
authors: Organ Transplant Center of The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, China.
authors: Qian
authors: Q
authors: Fu
authors: Organ Transplant Center of The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, China.
authors: Yun-Yi
authors: YY
authors: Xiong
authors: Organ Transplant Center of The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, China.
authors: Hui-Ting
authors: HT
authors: Huang
authors: Organ Transplant Center of The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, China. Electronic address: liulshan@mail.sysu.edu.cn.
authors: Long-Shan
authors: LS
authors: Liu
authors: Organ Transplant Center of The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, China. Electronic address: wangchx@mail.sysu.edu.cn.
authors: Chang-Xi
authors: CX
authors: Wang
mesh_terms: D019264:Adoptive Transfer; D000818:Animals; D000911:Antibodies, Monoclonal / Q000008:administration & dosage; D001803:Blood Transfusion; D002478:Cells, Cultured; D003131:Combined Modality Therapy; D006085:Graft Survival / Q000187:drug effects; D016027:Heart Transplantation; D006801:Humans; D007114:Immunization; D007156:Immunologic Memory; D007167:Immunotherapy / Q000379:methods*; D007519:Isoantigens / Q000276:immunology; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D016685:Mitomycin / Q000378:metabolism; D053278:OX40 Ligand / Q000276:immunology; D020123:Sirolimus / Q000008:administration & dosage; D050378:T-Lymphocytes, Regulatory / Q000187:drug effects* / Q000276:immunology
chemical_list: D000911:Antibodies, Monoclonal; D007519:Isoantigens; D053278:OX40 Ligand; D016685:Mitomycin; D020123:Sirolimus
keywords: Anti-OX40L; Donor-specific transfusion; Memory cells; Rapamycin