PDF(Pubmed)
Abstract：
UNASSIGNED: Thymus implantation is a recently FDA-approved therapy for congenital athymia. Patients receiving thymus implantation develop a functional but incomplete T cell compartment. Our objective was to develop a mouse model to study clinical thymus implantation in congenital athymia and to optimise implantation procedures to maximise T cell education and expansion of naïve T cells.
UNASSIGNED: Using Foxn1 nu athymic mice as recipients, we tested MHC-matched and -mismatched donor thymi that were implanted as fresh tissue or cultured to remove donor T cells. We first implanted thymus under the kidney capsule and then optimised intramuscular implantation. Using competitive adoptive transfer assays, we investigated whether the failure of newly developed T cells to expand into a complete T cell compartment was because of intrinsic deficits or whether there were deficits in engaging MHC molecules in the periphery. Finally, we tested whether recombinant IL-7 would promote the expansion of host naïve T cells educated by the implanted thymus.
UNASSIGNED: We determined that thymus implants in Foxn1 nu athymic mice mimic many aspects of clinical thymus implants in patients with congenital athymia. When we implanted cultured, MHC-mismatched donor thymus into Foxn1 nu athymic mice, mice developed a limited T cell compartment with notably underdeveloped naïve populations and overrepresented memory-like T cells. Newly generated T cells were predominantly educated by MHC molecules expressed by the donor thymus, thus potentially undergoing another round of selection once in the peripheral circulation. Using competitive adoptive transfer assays, we compared expansion rates of T cells educated on donor thymus versus T cells educated during typical thymopoiesis in MHC-matched and -mismatched environments. Once in the circulation, regardless of the MHC haplotypes, T cells educated on a donor thymus underwent abnormal expansion with initially more robust proliferation coupled with greater cell death, resembling IL-7 independent spontaneous expansion. Treating implanted mice with recombinant interleukin (IL-7) promoted homeostatic expansion that improved T cell development, expanded the T cell receptor repertoire, and normalised the naïve T cell compartment.
UNASSIGNED: We conclude that implanting cultured thymus into the muscle of Foxn1 nu athymic mice is an appropriate system to study thymus implantation for congenital athymia and immunodeficiencies. T cells are educated by the donor thymus, yet naïve T cells have deficits in expansion. IL-7 greatly improves T cell development after thymus implantation and may offer a novel strategy to improve outcomes of clinical thymus implantation.
UNASSIGNED: Using Foxn1 nu athymic mice as recipients, we tested MHC-matched and -mismatched donor thymi that were implanted as fresh tissue or cultured to remove donor T cells. We first implanted thymus under the kidney capsule and then optimised intramuscular implantation. Using competitive adoptive transfer assays, we investigated whether the failure of newly developed T cells to expand into a complete T cell compartment was because of intrinsic deficits or whether there were deficits in engaging MHC molecules in the periphery. Finally, we tested whether recombinant IL-7 would promote the expansion of host naïve T cells educated by the implanted thymus.
UNASSIGNED: We determined that thymus implants in Foxn1 nu athymic mice mimic many aspects of clinical thymus implants in patients with congenital athymia. When we implanted cultured, MHC-mismatched donor thymus into Foxn1 nu athymic mice, mice developed a limited T cell compartment with notably underdeveloped naïve populations and overrepresented memory-like T cells. Newly generated T cells were predominantly educated by MHC molecules expressed by the donor thymus, thus potentially undergoing another round of selection once in the peripheral circulation. Using competitive adoptive transfer assays, we compared expansion rates of T cells educated on donor thymus versus T cells educated during typical thymopoiesis in MHC-matched and -mismatched environments. Once in the circulation, regardless of the MHC haplotypes, T cells educated on a donor thymus underwent abnormal expansion with initially more robust proliferation coupled with greater cell death, resembling IL-7 independent spontaneous expansion. Treating implanted mice with recombinant interleukin (IL-7) promoted homeostatic expansion that improved T cell development, expanded the T cell receptor repertoire, and normalised the naïve T cell compartment.
UNASSIGNED: We conclude that implanting cultured thymus into the muscle of Foxn1 nu athymic mice is an appropriate system to study thymus implantation for congenital athymia and immunodeficiencies. T cells are educated by the donor thymus, yet naïve T cells have deficits in expansion. IL-7 greatly improves T cell development after thymus implantation and may offer a novel strategy to improve outcomes of clinical thymus implantation.
摘要：
■胸腺植入是最近FDA批准的一种治疗先天性甲状腺功能异常的疗法。接受胸腺植入的患者会发展出功能性但不完整的T细胞区室。我们的目标是开发一种小鼠模型，以研究先天性异常中的临床胸腺植入，并优化植入程序，以最大程度地提高T细胞教育和原始T细胞的扩增。
■使用Foxn1nu无胸腺小鼠作为受体，我们测试了MHC匹配和不匹配的供体胸腺,它们作为新鲜组织植入或培养以去除供体T细胞.我们首先将胸腺植入肾囊下，然后优化肌内植入。使用竞争性过继转移试验，我们调查了新开发的T细胞未能扩增到完整的T细胞区室的原因是由于内在缺陷还是由于外周参与MHC分子的缺陷.最后,我们测试了重组IL-7是否会促进由植入的胸腺培养的宿主初始T细胞的扩增。
■我们确定Foxn1nu无胸腺小鼠的胸腺植入物模拟了先天性无胸腺综合征患者临床胸腺植入物的许多方面。当我们植入培养器时，MHC错配供体胸腺进入Foxn1nu无胸腺小鼠，小鼠发育出有限的T细胞区室，其原始种群明显不发达，记忆样T细胞过多。新产生的T细胞主要受供体胸腺表达的MHC分子的教育，因此，有可能在外周循环中进行另一轮选择。使用竞争性过继转移试验，我们比较了在MHC匹配和不匹配环境中接受供体胸腺教育的T细胞与在典型胸腺生成期间接受教育的T细胞的扩增率。一旦进入循环，无论MHC单倍型，在供体胸腺上接受教育的T细胞经历了异常扩增，最初更强劲的增殖以及更多的细胞死亡，类似于IL-7独立的自发扩增。用重组白细胞介素（IL-7）治疗植入的小鼠促进稳态扩增，改善T细胞发育，扩大了T细胞受体库，并使初始T细胞隔室正常化。
■我们得出的结论是，将培养的胸腺植入到Foxn1nu无胸腺小鼠的肌肉中是研究胸腺植入先天性无性系和免疫缺陷的合适系统。T细胞受供体胸腺的教育，然而，幼稚的T细胞在扩增方面存在缺陷。IL-7极大地改善了胸腺植入后的T细胞发育，并可能为改善临床胸腺植入的结果提供新的策略。
■使用Foxn1nu无胸腺小鼠作为受体，我们测试了MHC匹配和不匹配的供体胸腺,它们作为新鲜组织植入或培养以去除供体T细胞.我们首先将胸腺植入肾囊下，然后优化肌内植入。使用竞争性过继转移试验，我们调查了新开发的T细胞未能扩增到完整的T细胞区室的原因是由于内在缺陷还是由于外周参与MHC分子的缺陷.最后,我们测试了重组IL-7是否会促进由植入的胸腺培养的宿主初始T细胞的扩增。
■我们确定Foxn1nu无胸腺小鼠的胸腺植入物模拟了先天性无胸腺综合征患者临床胸腺植入物的许多方面。当我们植入培养器时，MHC错配供体胸腺进入Foxn1nu无胸腺小鼠，小鼠发育出有限的T细胞区室，其原始种群明显不发达，记忆样T细胞过多。新产生的T细胞主要受供体胸腺表达的MHC分子的教育，因此，有可能在外周循环中进行另一轮选择。使用竞争性过继转移试验，我们比较了在MHC匹配和不匹配环境中接受供体胸腺教育的T细胞与在典型胸腺生成期间接受教育的T细胞的扩增率。一旦进入循环，无论MHC单倍型，在供体胸腺上接受教育的T细胞经历了异常扩增，最初更强劲的增殖以及更多的细胞死亡，类似于IL-7独立的自发扩增。用重组白细胞介素（IL-7）治疗植入的小鼠促进稳态扩增，改善T细胞发育，扩大了T细胞受体库，并使初始T细胞隔室正常化。
■我们得出的结论是，将培养的胸腺植入到Foxn1nu无胸腺小鼠的肌肉中是研究胸腺植入先天性无性系和免疫缺陷的合适系统。T细胞受供体胸腺的教育，然而，幼稚的T细胞在扩增方面存在缺陷。IL-7极大地改善了胸腺植入后的T细胞发育，并可能为改善临床胸腺植入的结果提供新的策略。
