SummaryMixed chimerism has been shown to lead to prolonged major histocompatibility complex (MHC) disparate allograft survival and immune‐specific tolerance; however, traditional conditioning regimes often involve myeloablation, which may pose a significant safety risk. In this study we examined the use of donor C57BL/6 (H‐2b) immature dendritic cells (imDCs) to tolerize the BALB/c (H‐2d) recipient to bone marrow transplantation (BMT), allowing the induction of mixed chimerism without immunosuppression or myeloablation. We showed that successful mismatched bone marrow engraftment can be achieved using imDCs given up to 3 days prior to BMT and that mixed chimerism can be established and detected in excess of 100 days post‐BMT without evidence of graft‐versus‐host disease. Furthermore, we showed that imDCs can suppress lymphocyte proliferation in response to mismatched MHC stimulation, leading to increased expression of interleukin (IL)‐4 and IL‐10 and decreased expression of IL‐2 and interferon‐γ (IFN‐γ). The induction of stable chimeras through pre‐conditioning of mice with donor imDCs followed by BMT led to tolerance, allowing the long‐term survival (> 110 days) of mismatched cardiac allografts and the prolonged survival of mismatched skin allografts without the need for immunosuppression or myeloablation. Transplantation with third‐party C3H allografts were rapidly rejected in this model, suggesting that immune‐specific tolerance was achieved. The induction of immune‐specific tolerance without the need for immunosuppression or myeloablation represents a significant advance in transplant immunology and may provide clinicians with a plausible alternative in combating organ rejection following transplantation.

建立异基因嵌合体可诱导形成针对供体的特异性免疫耐受,可能是克服器官移植排斥的有效途径.我们曾报道利用未成熟树突状细胞(DC)可成功诱导受体动物建立异基因嵌合体,维持时间超过100 d.但嵌合体与移植物存活的关系,目前尚无一致结论.我们通过2个移植模型观察了异基因嵌合体与移植物存活的关系.

Objective:To explore the possibly mechanisms of inducing allogeneic chimerism and prolonging allografts survival in recipients by immature dendritic cells (imDCs) Methods:Bone marrow cells (BMCs) derived from donor (C57BL/6) were used to generate imDCs The splenocytes of recipients were pretreated by inactivated imDCs in vitro, or the recipients (Balb/C) were injected of inactivated imDCs via vein in vivo Then collected the splenocytes mixed with the inactivated splenocytes from donor to detect the responsiveness Mixed lymphocyte reaction was also used to evaluate the reactivity of the chimerism mice to the donor splenocytes At the same time the diversion of Th1/Th2 paradigm was studied by semi quantitative RT PCR Results:The splenocytes conditioned with imDCs pretreatment expressed hypo responsiveness to the donor stimulation, and the immunized mice also proliferated less degree compared with the naive mice The hyporeactivity was evidently seen within 72 hours after stimulation by donor splenocytes There was significant difference between them The chimerism mice showed unresponsiveness to donor antigens, while reactivity to the third party antigens was retained The result of RT PCR suggested, to some extent, there was a diversion of Th1/Th2 paradigm in the establishment of chimerism in the model Conclusion:The putative mechanism of immature dendritic cells inducing the generation of allogeneic chimerism may based on the hypo responsiveness produced by imDCs, and there may also exist some kinds of diversion of Th1/Th2 paradigm

Objective:To explore the possibility of immature dendritic cells (imDCs) in the induction of mixed allogeneic chimerism in recipients without irradiation or cytoreduction treatment. Methods: Bone marrow cells (BMCs) derived from donor (C57BU6) were used to generate imDCs. imDCs were injected to the recipients (BALB/c)i v. Fresh-made bone marrow cells from donor were then transfused i.v to the recipients treated with imDCs at different time points. The different levels of chimerism induced by single or multiple injections of imDCs were studied. Results: imnDCs can induce mixed allogeneic chimerism, which was observed at different time points after donor-derived BMCS injection. However, only those injected the BMCs at the third day after the immunization with imDCs could lead to significantly longer mixed alogeneic chimerism( 100 d) than those injected BMCs at the fifth day (21 d), and the recipients who received BMCs at the seventh day could not induce chimerism at all. Although all injections induced a long- tenn chimerism, the levels of chimedsm were significantly different in the recipients after the single,twice and three times injection of imDCs. COnclusion: hnniature dendritic cells alone can induce the generation of mixed allogeneic chimerism in allogeneic recipients without irradiation and other cytoreduction host treatment.