Transplantation Biology Research Center Department of Surgery, Transplantation Center, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA.
Am J Transplant. 2011 Nov;11(11):2322-31. doi: 10.1111/j.1600-6143.2011.03683.x. Epub 2011 Aug 10.
Presensitization to HLA antigens limits the success of organ transplantation. The achievement of donor-specific tolerance via mixed chimerism could improve outcomes of transplantation in presensitized patients. In presensitized B-cell-deficient μMT B6 mice, we developed nonmyeloablative bone marrow transplantation (BMT) regimens that successfully tolerized presensitized T cells, achieving long-term (LT) multilineage chimerism and tolerance to donor-type skin. To apply these regimens in wild-type (WT) animals while avoiding antibody-mediated destruction of donor bone marrow cells, presensitized WT B6 mice were rested >2 years to allow alloantibody clearance. However, chimerism and tolerance were not reliably achieved in LT presensitized WT B6 mice in which alloantibody had declined to minimal or undetectable levels before BMT. Strong antidonor memory T-cell responses were detected in LT presensitized WT B6 mice after rejection of donor bone marrow (BM) occurred, whereas levels of alloantibody remained consistently low. In contrast, presensitized μMT B6 mice had diminished memory T-cell responses compared to WT B6 mice. These data implicate T-cell memory, but not alloantibody, in rejection of donor BM in LT presensitized WT mice.
HLA 抗原的预致敏限制了器官移植的成功。通过混合嵌合实现供者特异性耐受可以改善预致敏患者移植的结果。在预致敏的 B 细胞缺陷 μMT B6 小鼠中，我们开发了非清髓性骨髓移植（BMT）方案，该方案成功地耐受了预致敏的 T 细胞，实现了长期（LT）多谱系嵌合和对供体型皮肤的耐受。为了在野生型（WT）动物中应用这些方案，同时避免供体骨髓细胞的抗体介导破坏，预致敏的 WT B6 小鼠休息>2 年以允许同种抗体清除。然而，在 LT 预致敏的 WT B6 小鼠中，同种抗体在 BMT 前已降至最低或无法检测到水平，并未可靠地实现嵌合和耐受。在供体骨髓（BM）排斥后，LT 预致敏的 WT B6 小鼠中检测到强烈的抗供体记忆 T 细胞反应，而同种抗体水平始终保持较低。相比之下，预致敏的 μMT B6 小鼠与 WT B6 小鼠相比，记忆 T 细胞反应减弱。这些数据表明，在 LT 预致敏的 WT 小鼠中，T 细胞记忆而不是同种抗体参与了对供体 BM 的排斥。
