Rapamycin or tacrolimus alone fails to resist cardiac allograft accelerated rejection mediated by alloreactive CD4(+) memory T cells in mice
| Autor: | Baiyi Xie, Zhongquan Qi, Chongxian Liao, Yongxiang Zhao, Jibing Chen, Qing Yao, Junjie Xia, Hua Liang, Chuang Sha, Yongzhi Wang |
|---|---|
| Rok vydání: | 2009 |
| Předmět: |
CD4-Positive T-Lymphocytes
Graft Rejection Naive T cell Immunology Pharmacology Tacrolimus Mice Antigens CD T-Lymphocyte Subsets Immunology and Allergy Medicine Animals PI3K/AKT/mTOR pathway Cells Cultured Cell Proliferation Sirolimus Transplantation Mice Inbred BALB C Cardiac allograft business.industry Graft Survival Cell Differentiation Adoptive Transfer Mice Inbred C57BL surgical procedures operative Allograft rejection Transplanted Organs Disease Progression Heart Transplantation Lymphocyte Culture Test Mixed business Immunologic Memory Median survival Immunosuppressive Agents |
| Zdroj: | Transplant immunology. 22(3-4) |
| ISSN: | 1878-5492 |
| Popis: | 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 (P0.01), 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. |
| Databáze: | OpenAIRE |
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