Dengler T J, Szabo G, Sido B, Nottmeyer W, Zimmerman R, Vahl C F, Hünig T, Meuer S C
Department of Cardiology, Medical University Hospital, University of Heidelberg, Germany.
Transplantation. 1999 Feb 15;67(3):392-8. doi: 10.1097/00007890-199902150-00009.
Allograft rejection depends on T cell immune responses requiring antigen recognition and costimulatory signals through accessory T cell receptors, including CD28. Inhibition of CD28 signaling with a CTLA-4-immunoglobulin (Ig) fusion protein has resulted in immunosuppression and occasional T cell anergy in mouse transplant models, but not in rats. Because this approach also inhibits a potentially tolerizing signal through CTLA-4, selective blockade of CD28 ligation might induce more profound immunosuppression and transplant tolerance.
The effects of escalating doses of the rat CD28 monoclonal antibody JJ319 on allograft survival were studied after vascularized heterotopic heart transplantation in a high responder strain combination (DA to Lewis). CD28 antigen modulation and circulating antibody levels were monitored by flow cytometry.
CD28 antibody JJ319 markedly prolonged cardiac graft survival compared with untreated controls (7 days, range: 6-8). A strictly dose-dependent increase in median graft survival time was demonstrated with a maximum of 36 days (range: 30-40; p <0.001) after the administration of 8 x 1 mg JJ319 i.p. (days -1 to +6 before/after transplantation). However, indefinite graft survival and tolerance could not be induced by JJ319 treatment. At the maximal dose, flow cytometry showed complete down modulation of the CD28 receptor for 10-14 days without T cell depletion in close temporal relation to antibody presence in serum. In vitro, CD28-modulated T cells showed significantly reduced responses to activation.
CD28 antibody JJ319 induces profound immunosuppression after rat heart transplantation, however without development of transplant tolerance. The underlying mechanism seems to be receptor modulation during primary alloantigen recognition. While still potentially applicable clinically, there are no qualitative or quantitative differences to the treatment with CTLA-4/lg or the blockade of CD2 or LFA-1, as reported elsewhere. Thus, a CD28-modulating approach seems not to allow therapeutic exploitation of a tolerizing signal delivered by CTLA-4 but may still be clinically applicable, especially in combined immune interventions.
同种异体移植排斥反应取决于T细胞免疫反应，该反应需要通过包括CD28在内的辅助性T细胞受体进行抗原识别和共刺激信号传导。在小鼠移植模型中，用CTLA-4免疫球蛋白（Ig）融合蛋白抑制CD28信号传导已导致免疫抑制和偶尔的T细胞无反应性，但在大鼠中未出现这种情况。由于这种方法也会抑制通过CTLA-4的潜在耐受信号，因此选择性阻断CD28连接可能会诱导更深刻的免疫抑制和移植耐受。
在高反应性品系组合（从DA到Lewis）的血管化异位心脏移植后，研究递增剂量的大鼠CD28单克隆抗体JJ319对同种异体移植存活的影响。通过流式细胞术监测CD28抗原调节和循环抗体水平。
与未治疗的对照组相比，CD28抗体JJ319显著延长了心脏移植物的存活时间（7天，范围：6 - 8天）。在腹腔注射8×1mg JJ319（移植前/后第 - 1至 + 6天）后，中位移植物存活时间呈现严格的剂量依赖性增加，最长可达36天（范围：30 - 40天；p <0.001）。然而，JJ319治疗不能诱导无限期的移植物存活和耐受。在最大剂量时，流式细胞术显示CD28受体在10 - 14天内完全下调，且与血清中抗体存在的时间密切相关，同时未出现T细胞耗竭。在体外，经CD28调节的T细胞对激活的反应显著降低。
CD28抗体JJ319在大鼠心脏移植后诱导了深刻的免疫抑制，但未产生移植耐受。潜在机制似乎是在初次同种异体抗原识别过程中的受体调节。虽然在临床上仍可能适用，但与CTLA-4/I g治疗或CD2或LFA-1阻断治疗相比，在质量或数量上没有差异，如其他地方所报道的那样。因此，一种调节CD28的方法似乎无法利用CTLA-4传递的耐受信号进行治疗，但仍可能在临床上适用，特别是在联合免疫干预中。
