Kimball J A, Pescovitz M D, Book B K, Norman D J
Laboratory of Immunogenetics and Transplantation, Oregon Health Sciences University, Portland 97201, USA.
Transplantation. 1995 Dec 27;60(12):1379-83. doi: 10.1097/00007890-199560120-00001.
Exposure to the equine-derived polyclonal antithymocyte preparation, ATGAM, frequently elicits human anti-ATGAM antibody formation. The influence of concomitant immunosuppressants on this antiantibody response has not been established. We therefore evaluated IgG antibody formation to ATGAM in 47 patients receiving ATGAM as part of a prospective, randomized, double-blinded study of mycophenolate mofetil versus azathioprine for maintenance immunosuppression after primary cadaveric renal transplantation. All patients received ATGAM for induction of immunosuppression plus methylprednisolone, prednisone, and cyclosporine. In addition, patients were randomized to receive maintenance immunosuppression consisting of either azathioprine (AZA) 1-2 mg/kg/day, mycophenolate mofetil 2 gm/day (MMF2), or mycophenolate mofetil 3 gm/day (MMF3). Patient sequential sera were independently tested for IgG anti-ATGAM antibody by 2 laboratories, which were blinded to treatment arm assignments, using enzyme-linked immunosorbent assays. Both laboratories found significantly greater anti-ATGAM antibody formation in group AZA compared with groups MMF2 and MMF3: laboratory 1 reported sensitization rates in the 3 groups of 94% (AZA), 50% (MMF2) (P < 0.02 vs. AZA), and 60% (MMF3) (P < 0.05 vs. AZA); and laboratory 2 reported rates of 67% (AZA), 17% (MMF2) (P < 0.02 vs. AZA), and 10% (MMF3) (P < 0.02 vs. AZA). In addition, fewer patients formed high titer antibody in the MMF arms compared to the AZA arm: 56% (AZA), 0% (MMF2) (P < 0.02 vs. AZA), and 20% (MMF3) (P < 0.02 vs. AZA) of patients for laboratory 1; and 20% (AZA), 0% (MMF2) (P < 0.05 vs. AZA), and 0% (MMF3) (P < 0.05 vs. AZA) of patients for laboratory 2. Differences in test results between the 2 laboratories were explained by differences in the sensitivity of their respective immunoassays and in the criteria used for assigning a positive result to test specimens. In this protocol, MMF at 2-3 gm/day was associated with a reduced incidence and titer of IgG anti-ATGAM antibody formation compared with standard azathioprine dosing. Although MMF previously has been reported to inhibit T cell responses that mediate acute cellular rejection, this is the first demonstration that MMF significantly inhibits human B cell responses to antigen in vivo.
接触马源多克隆抗胸腺细胞制剂即抗胸腺细胞球蛋白（ATGAM），常引发人体抗ATGAM抗体的形成。联合使用的免疫抑制剂对这种抗抗体反应的影响尚未明确。因此，我们在一项前瞻性、随机、双盲研究中，评估了47例接受ATGAM治疗的患者体内IgG抗体对ATGAM的形成情况，该研究旨在比较霉酚酸酯与硫唑嘌呤在尸体肾移植术后维持免疫抑制中的作用。所有患者均接受ATGAM诱导免疫抑制，同时使用甲泼尼龙、泼尼松和环孢素。此外，患者被随机分为接受以下维持免疫抑制治疗：硫唑嘌呤（AZA）1 - 2mg/kg/天、霉酚酸酯2g/天（MMF2）或霉酚酸酯3g/天（MMF3）。由两个对治疗分组不知情的实验室，采用酶联免疫吸附测定法，对患者的系列血清独立检测IgG抗ATGAM抗体。两个实验室均发现，与MMF2组和MMF3组相比，AZA组中抗ATGAM抗体的形成显著更多：实验室1报告3组的致敏率分别为94%（AZA）、50%（MMF2）（与AZA组相比P < 0.02）和60%（MMF3）（与AZA组相比P < 0.05）；实验室2报告的比率分别为67%（AZA）、17%（MMF2）（与AZA组相比P < 0.02）和10%（MMF3）（与AZA组相比P < 0.02）。此外，与AZA组相比，MMF组中形成高滴度抗体的患者更少：实验室1中分别为56%（AZA）、0%（MMF2）（与AZA组相比P < 0.02）和20%（MMF3）（与AZA组相比P < 0.02）的患者；实验室2中分别为20%（AZA）、0%（MMF2）（与AZA组相比P < 0.05）和0%（MMF3）（与AZA组相比P < 0.05）的患者。两个实验室检测结果的差异，是由各自免疫测定的灵敏度以及用于判定检测标本阳性结果的标准不同所致。在此方案中，与标准剂量的硫唑嘌呤相比，每天2 - 3g的霉酚酸酯与IgG抗ATGAM抗体形成的发生率和滴度降低相关。尽管此前已有报道称霉酚酸酯可抑制介导急性细胞排斥反应的T细胞反应，但这是首次证明霉酚酸酯在体内能显著抑制人体B细胞对抗原的反应。
