Keever C A, Flomenberg N, Small T, Brochstein J, Collins N, Young-Yang S, Insel R, Dupont B, O'Reilly R J
Bone Marrow Transplantation Service, Memorial Sloan-Kettering Cancer Center, New York, New York 10021.
Hum Immunol. 1989 Sep;26(1):27-38. doi: 10.1016/0198-8859(89)90030-x.
We have studied the tolerance of engrafted T cells from a severe combined immunodeficiency disease patient sequentially transplanted with T-cell-depleted bone marrow from both HLA haploidentical parents. The T cells from this patient were shown by HLA typing and cytogenetic analysis to be of material origin (donor of the second graft) while HLA typing of peripheral E--populations and of an Epstein-Barr virus-transformed B-cell line established 2 1/2 years after transplantation revealed the presence of host, maternal, and paternal (donor of the first graft) HLA antigens. When tested at 30 and 60 months after the last transplant, engrafted T cells from this patient had only weak mixed lymphocyte culture reactivity to paternal cells which could be inhibited by monoclonal antibodies to HLA-DQ and DR but not by anti-DP. T cells obtained 60 months after transplant were stimulated with paternal cells in both bulk and limiting dilution cultures and failed to generate typical allocytotoxic cells to paternal T- or B-cell targets. Mixed lymphocyte cultures performed at 71 months revealed an increased proliferative response by patient cells to paternal antigens; however, the engrafted T cells remained tolerant to maternal and host antigens. Limiting dilution analysis performed at this time revealed the presence of cytolytic cells directed to paternal antigens. There were no detectable B cells (only identified source of paternal antigen) as measured by immunofluorescent analysis of peripheral blood, nor any evidence of B-cell function as assessed by in vitro assays (proliferation to staphylococcus aureus Cowen strain A and mitogen-stimulated immunoglobulin production) or in vivo production of serum immunoglobulin at 60 and 71 months. The appearance of alloreactivity associated with the loss of B cells in this patient further supports the conclusion that the maintenance of tolerance to major histocompatibility complex disparate cells requires the continued in vivo presence of cells bearing the tolerizing antigens.
我们研究了一名重症联合免疫缺陷病患者移植的T细胞的耐受性，该患者先后接受了来自两位HLA单倍型相同父母的T细胞去除的骨髓移植。通过HLA分型和细胞遗传学分析表明，该患者的T细胞来自物质来源（第二次移植的供体），而移植后2年半建立的外周E - 群体和爱泼斯坦 - 巴尔病毒转化的B细胞系的HLA分型显示存在宿主、母体和父体（第一次移植的供体）HLA抗原。在最后一次移植后30个月和60个月进行检测时，该患者移植的T细胞对父体细胞只有微弱的混合淋巴细胞培养反应，这种反应可被针对HLA - DQ和DR的单克隆抗体抑制，但不能被抗DP抗体抑制。移植后60个月获得的T细胞在大量培养和有限稀释培养中用父体细胞刺激，未能产生针对父体T细胞或B细胞靶标的典型同种细胞毒性细胞。在71个月进行的混合淋巴细胞培养显示患者细胞对父体抗原的增殖反应增加；然而，移植后的T细胞对母体和宿主抗原仍保持耐受。此时进行的有限稀释分析显示存在针对父体抗原的溶细胞性细胞。通过外周血免疫荧光分析未检测到B细胞（唯一确定的父体抗原来源），在60个月和71个月时通过体外试验（对金黄色葡萄球菌考恩菌株A的增殖和丝裂原刺激的免疫球蛋白产生）或体内血清免疫球蛋白产生评估也没有任何B细胞功能的证据。该患者中与B细胞缺失相关的同种异体反应性的出现进一步支持了这样的结论，即对主要组织相容性复合体不同细胞的耐受性维持需要体内持续存在携带耐受抗原的细胞。
