Plain Karren M, Boyd Rochelle, Verma Nirupama D, Robinson Catherine M, Tran Giang T, Hodgkinson Suzanne J, Hall Bruce M
Immune Tolerance Laboratory, Faculty of Medicine, University of New South Wales, Sydney, Australia.
Transplantation. 2007 Mar 27;83(6):764-73. doi: 10.1097/01.tp.0000256326.11647.2e.
Specific transplant tolerance is mediated by CD4 T cells that die unless supported by T-cell derived cytokines and donor antigen. This study examined the role of Th1 and Th2 cytokines in the maintenance of tolerance.
Tolerance to fully allogeneic PVG cardiac allografts in DA rats was induced by short-term anti-CD3 monoclonal antibody therapy. Responses of tolerant cells to donor and third party antigen were assessed in vivo by examination of the infiltrate in the heart and application of skin grafts, and in vitro in mixed lymphocyte culture. Cell subsets were stained, induction of cytokine mRNA assayed by reverse-transcriptase polymerase chain reaction and the role of cytokines determined by treating with blocking monoclonal antibody to cytokines or cytokine administration.
Tolerated grafts had a T cell and macrophage infiltrate with increased mRNA for Th1 cytokines, interleukin (IL)-2, and interferon (IFN)-gamma but not Th2 cytokines. Peripheral lymphocytes proliferated in mixed lymphocyte culture and expressed Th1 cytokine mRNA. Tolerant hosts accepted PVG and rejected Lewis skin allografts and the lymph nodes draining both these grafts had similar induction of Th1 and Th2 cytokine mRNA. Treatment of tolerant rats with Th1 cytokines IL-2, IFN-gamma, and IL-12p70 or monoclonal antibody that blocked IL-4, IL-5, and transforming growth factor-beta did not prevent acceptance of PVG skin grafts.
These studies in a model of tolerance regulated by CD4CD25 T cells demonstrated there was no defect in Th1 responses. Tolerance was due to regulation that was not solely dependent on IL-4, IL-5, or transforming growth factor-beta and was not inactivated or overwhelmed by administration of Th1 cytokines, IL-2, IFN-gamma or IL-12p70.
特异性移植耐受由CD4 T细胞介导，这些细胞若没有T细胞衍生的细胞因子和供体抗原的支持就会死亡。本研究检测了Th1和Th2细胞因子在维持耐受中的作用。
通过短期抗CD3单克隆抗体治疗诱导DA大鼠对完全同种异体PVG心脏移植的耐受。通过检查心脏浸润情况和应用皮肤移植在体内评估耐受细胞对供体和第三方抗原的反应，并在体外进行混合淋巴细胞培养。对细胞亚群进行染色，通过逆转录聚合酶链反应检测细胞因子mRNA的诱导情况，并通过用细胞因子阻断单克隆抗体处理或给予细胞因子来确定细胞因子的作用。
耐受的移植物有T细胞和巨噬细胞浸润，Th1细胞因子、白细胞介素（IL）-2和干扰素（IFN）-γ的mRNA增加，但Th2细胞因子没有增加。外周淋巴细胞在混合淋巴细胞培养中增殖并表达Th1细胞因子mRNA。耐受宿主接受PVG并排斥Lewis皮肤同种异体移植物，引流这两种移植物的淋巴结中Th1和Th2细胞因子mRNA的诱导情况相似。用Th1细胞因子IL-2、IFN-γ和IL-12p70或阻断IL-4、IL-5和转化生长因子-β的单克隆抗体处理耐受大鼠，并未阻止对PVG皮肤移植物的接受。
这些在由CD4CD25 T细胞调节的耐受模型中的研究表明，Th1反应没有缺陷。耐受是由于一种调节作用，该调节作用不仅不依赖于IL-4、IL-5或转化生长因子-β，而且不会因给予Th1细胞因子、IL-2、IFN-γ或IL-12p70而失活或被克服。
