Role of Memory T Cells In Allograft Tolerance

我们最近的研究表明，与实验室小鼠相反，在移植前，食蟹猴中可以检测到大量的抗供体同种异体反应性记忆T细胞。这些记忆T细胞对许多常规免疫抑制药物和抗体治疗的共刺激阻断具有抗性。这些细胞可能在骨髓移植后迅速破坏供体细胞，从而防止嵌合体的诱导/维持。这得到了以下证据的有力支持：已经过继转移了同种特异性记忆而不是幼稚T细胞的小鼠不能再通过混合嵌合或共刺激阻断而耐受同种异体移植。基于这些 根据这些观察，我们假设移植前灵长类动物中同种特异性记忆T细胞的存在阻碍了它们对同种异体移植物的成功耐受。为了验证这一假设，我们提出了两个具体目标： 具体目标1.表征移植前食蟹猴中存在的同种异体反应性记忆T细胞 具体目标2。评估同种异体反应性记忆T细胞对同种异体心脏和肺移植耐受和排斥反应的影响。 我们的初步结果表明，在移植前，同种异体反应性T细胞记忆的水平显着变化的性质的供体/受体组合。在这里，我们将在具有高或低记忆同种异体反应性的供体/受体组合中进行心脏和肺移植，并比较：同种异体反应，同种异体移植物的排斥反应（急性和慢性），骨髓移植诱导稳定混合嵌合体的能力，混合嵌合体的耐受性和共刺激阻断方案。 心脏和肺移植

Our recent studies show that, in contrast to laboratory mice, significant numbers of anti-donor alloreactive memory T cells can be detected in cynomolgus monkeys prior to transplantation. These memory T cells are resistant to many conventional immunosuppressive drugs and to costimulation blockade by antibody treatments. It is likely that these cells can rapidly destroy donor cells after bone marrow transplantation thereby preventing the induction/maintenance of chimerism. This is strongly supported by the demonstration that mice that have been adoptively transferred with allospecific memory but not naive T cells can no longer be rendered tolerant to allotransplants via mixed chimerism or costimulation blockade. Based upon these observations, we hypothesize that the presence of allospecific memory T cells in primates prior to transplantation hinders their successful tolerization to allogeneic transplants. To test this hypothesis, we propose two specific aims: Specific aim 1. Characterize the alloreactive memory T cells present in cynomolgus pre-transplantation Specific aim 2. Evaluate the influence of alloreactive memory T cells on tolerance to and rejection of allogeneic heart and lung transplants. Our preliminary results indicate that, prior to transplantation, the level of alloreactive T cell memory varies dramatically upon the nature of the donor/recipient combination. Here, we will perform heart and lung transplants in donor/recipient combinations with either high or low memory alloreactivity and compare: the alloresponse, the rejection of allografts (acute and chronic), the ability of bone marrow transplant to induce stable mixed chimerism, the tolerogenicty of mixed chimerism and costimulation blockade protocols If successful, this research should significantly expand the successful application of tolerance protocols in heart and lung transplantation.