title: Rapamycin or tacrolimus alone fails to resist cardiac allograft accelerated rejection mediated by alloreactive CD4(+) memory T cells in mice.
abstract: Donor-reactive memory T (Tm) cells undermine transplanted organs more readily than naive T cells. Rapamycin (RAPA) and tacrolimus (FK-506) are current mainstay immunosuppressants used for preventing acute allograft rejection. Although their efficacy in suppressing naive T cell is established, their suppressing effect on memory T cells is undefined. This study was conducted to investigate the inhibiting capability of RAPA or FK-506 against transferred alloreactive CD4(+) Tm cells in a mouse cardiac transplant model. We found that these drugs alone prolonged the median survival time (MST) of allograft from 5days to 9days in recipient mice with CD4(+) Tm infusion (P<0.01), which however was not significantly longer than that (8days) in untreated recipient mice without CD4(+) Tm infusion (naive control). Mean histologic rank of rejection activity in section of cardiac allograft on day 5 postgrafting was Grade 4 in the Tm control recipients versus Grade 3A in both of the immunosuppressant treatment recipients with CD4(+) Tm infusion. RAPA or FK-506 alone failed to completely suppress proliferation and differentiation of the alloreactive CD4(+) Tm, which was confirmed by in vitro mixed lymphocyte reaction (MLR) and by flow cytometry (FCM) of the splenocytes for detecting CD44(high)CD62L(-) effector/memory as well as CD69(+)/CD25(+) activation phenotype cells from the respective recipients. Furthermore, the agent alone didn't completely inhibit the activation of CD4(+) Tm, for serum level of IFN-gamma and its gene expression at the cardiac allograft from the immunosuppressant-treated recipients were as still high as the untreated naive control. Thus, RAPA or FK-506 alone couldn't completely suppress the proliferation and activation of the alloantigen-primed CD4(+) Tm cells responding to the alloantigen, indicating that alloreactive CD4(+) Tm was insensitive to these immunosuppressants. The characteristics of alloreactive CD4(+) Tm to resist immunosuppressants and its potency to initiate quick and vigorous rejection despite treatment with the immunosuppressant make it to be a critical barrier to prolongation of allograft survival and induction of transplant tolerance.
authors.affiliation: Department of Cardiac Surgery, Zhongshan Hospital, Xiamen University, Fujian Province, PR China.
authors.forename: Hua
authors.initials: H
authors.lastname: Liang
authors.forename: Chongxian
authors.initials: C
authors.lastname: Liao
authors.forename: Zhongquan
authors.initials: Z
authors.lastname: Qi
authors.forename: Chuang
authors.initials: C
authors.lastname: Sha
authors.forename: Baiyi
authors.initials: B
authors.lastname: Xie
authors.forename: Jibing
authors.initials: J
authors.lastname: Chen
authors.forename: Junjie
authors.initials: J
authors.lastname: Xia
authors.forename: Yongzhi
authors.initials: Y
authors.lastname: Wang
authors.forename: Qing
authors.initials: Q
authors.lastname: Yao
authors.forename: Yongxiang
authors.initials: Y
authors.lastname: Zhao
mesh_terms: D019264:Adoptive Transfer; D000818:Animals; D015703:Antigens, CD / Q000096:biosynthesis; D015496:CD4-Positive T-Lymphocytes / Q000187:drug effects / Q000276:immunology / Q000378:metabolism* / Q000473:pathology; D002454:Cell Differentiation / Q000187:drug effects / Q000276:immunology; D049109:Cell Proliferation / Q000187:drug effects; D002478:Cells, Cultured; D018450:Disease Progression; D006084:Graft Rejection / Q000188:drug therapy* / Q000276:immunology / Q000503:physiopathology; D006085:Graft Survival / Q000187:drug effects; D016027:Heart Transplantation; D007156:Immunologic Memory; D007166:Immunosuppressive Agents / Q000008:administration & dosage*; D007959:Lymphocyte Culture Test, Mixed; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D020123:Sirolimus / Q000008:administration & dosage*; D016176:T-Lymphocyte Subsets / Q000187:drug effects / Q000276:immunology / Q000378:metabolism* / Q000473:pathology; D016559:Tacrolimus / Q000008:administration & dosage*
chemical_list: D015703:Antigens, CD; D007166:Immunosuppressive Agents; D020123:Sirolimus; D016559:Tacrolimus