Cuturi M C, Josien R, Cantarovich D, Bugeon L, Anegon I, Menoret S, Smit H, Douillard P, Soulillou J P
Institut National de la Santé et de la Recherche Médicale (INSERM U211), Nantes, France.
Eur J Immunol. 1994 Jul;24(7):1627-31. doi: 10.1002/eji.1830240726.
Permanent tolerance to allografts can be induced in adult rats by donor-specific transfusions (DST) prior to transplantation. We have previously reported, in a model of heart allograft, the presence of a heavy leukocyte infiltrate, in the allograft which displayed a strong allospecific cytotoxicity when tested in vitro against donor cells, and a strong accumulation of mRNA for granzyme A and perforin in vivo. In contrast, there was a major decrease in the accumulation of mRNA for interleukin-2 and interferon-gamma. These results suggested that the DST-induced tolerance was associated with a decrease in type-1 T helper (Th1) cell function. The major role of preformed antibodies in xeno and allorejection is clearly established. Nevertheless, the consequences of alloantibody production in acute rejection and tolerance induction remains to be elucidated. We here analyze the alloantibody response in rejecting and DST-treated recipients. We show that, after transplantation, tolerant recipients, in contrast to rejecting ones, mount a low IgM alloresponse that switches to low IgG production. Detailed analysis of IgG alloantibodies in DST-treated recipients revealed that their production decrease was not equally distributed. Whereas rejecting animals mounted a strong anti-class I and II IgG alloantibody response, DST-treated recipients produced anti-class II and low titers of anti-class I IgG alloantibodies. Furthermore, among IgG subclasses, tolerant recipients predominantly produced IgG2a, a profile which, in the rat, is compatible with a Th2-controlled response. Finally, the passive transfer of immune serum from rejecting animals to DST-treated recipients could abrogate the tolerance. We suggest that the absence of anti-class I alloantibodies combined with preserved and/or increased anti-class II production plays a major role in graft tolerance in this model. These results reinforced the role of alloantibodies in rejection and in induction of tolerance.
成年大鼠在移植前通过供体特异性输血（DST）可诱导对同种异体移植物产生永久性耐受。我们之前在心脏同种异体移植模型中报道，同种异体移植物中存在大量白细胞浸润，该移植物在体外针对供体细胞进行检测时表现出强烈的同种特异性细胞毒性，并且在体内颗粒酶A和穿孔素的mRNA大量积累。相比之下，白细胞介素-2和干扰素-γ的mRNA积累大幅减少。这些结果表明，DST诱导的耐受与1型辅助性T（Th1）细胞功能的降低有关。预先形成的抗体在异种和同种异体排斥反应中的主要作用已明确确立。然而，同种异体抗体产生在急性排斥反应和耐受诱导中的后果仍有待阐明。我们在此分析排斥反应和DST处理的受体中的同种异体抗体反应。我们发现，移植后，与发生排斥反应的受体相比，耐受的受体产生低水平的IgM同种异体反应，且转变为低水平的IgG产生。对DST处理的受体中IgG同种异体抗体的详细分析表明，其产生的减少并非均匀分布。发生排斥反应的动物产生强烈的抗I类和II类IgG同种异体抗体反应，而DST处理的受体产生抗II类和低滴度的抗I类IgG同种异体抗体。此外，在IgG亚类中，耐受的受体主要产生IgG2a，在大鼠中，这种情况与Th2控制的反应相符。最后，将排斥反应动物的免疫血清被动转移至DST处理的受体可消除耐受。我们认为，抗I类同种异体抗体的缺失与抗II类产生的保留和/或增加相结合，在该模型的移植物耐受中起主要作用。这些结果强化了同种异体抗体在排斥反应和耐受诱导中的作用。
