HOST-GRAFT INTERACTIONS OF CNS CHROMAFFIN CELL IMPLANTS

描述(申请者摘要)：我们已经证明，疼痛敏感可以 通过移植肾上腺髓质组织或分离的嗜铬细胞减少 大鼠中脑内这种中枢神经系统痛觉调节区的细胞 蛛网膜下腔中脑导水管周围灰质(PAG)或实质外 腰椎背侧脊髓。我们在以下方面取得了可喜的成果 同种异体肾上腺髓质移植缓解肾功能不全的初步临床研究 癌痛。除了同种异体移植，我们还发现了牛 嗜铬细胞在大鼠中枢神经系统内存活良好。异种移植是一种潜在的 重要的未开发的捐赠者来源，可能会克服有限的可获得性 人类捐赠者。然而，在大规模临床实施之前， 这些程序是要进行的，重要的是要获得深入的 实验室中宿主对嗜铬细胞移植反应的信息 动物。关键是要确定引入 异体和异种组织进入宿主中枢神经系统。这些 研究将集中于确定宿主中枢神经系统对肾上腺的反应 应用技术的骨髓组织和分离的嗜铬细胞移植 是我们实验室最近开发出来的。此外，中国股市的稳定性 移植和宿主-移植物融合，以及 继续移植物维护是至关重要的，并将得到解决。 具体地说，拟议的研究将分析免疫反应 异体移植物和异种移植物，分别植入实质内和实质外。 这些将包括主要组织相容性的诱导染色 抗原(MHC I和II)。我们还将确定捐赠者-接受者 组织相容性与混合淋巴细胞反应(MLR)。必然性 对于持续或短期的免疫抑制以及添加 还将对假定的抗原提呈细胞进行评估。移植物存活率和 宿主反应将在免疫学挑战之后进行评估，例如 血脑屏障的一过性破坏和全身敏感化。 移植引起的血脑屏障通透性和摄取的变化 将研究其性质、胶质细胞反应性和细胞渗透情况。我们的 先前的研究结果表明，两者都移植了分离的嗜铬细胞 细胞和肾上腺髓质组织整合良好并参与 与宿主神经元突起形成突触。营养的影响 对培养细胞和移植细胞的影响因素进行比较。一个 这些被提议的研究的优势在于将移植物与 具有抗伤害活性的生存和整合。

DESCRIPTION (Applicant's Abstract): We have shown that pain sensitivity can be reduced by transplanting adrenal medullary tissue or isolated chromaffin cells into such CNS pain modulatory regions in the rat at the midbrain periaqueductal gray (PAG) or extra- parenchymally in the subarachnoid space of the dorsal lumbar spinal cord. We have obtained promising results in preliminary clinical studies using allografts of adrenal medulla to relieve cancer pain. In addition to allografts, we have found that bovine chromaffin cells survive well in the rat CNS. Xenografts are a potentially important untapped donor source that may overcome the limited availability of human donors. However, before large scale clinical implementation of these procedures is undertaken, it is important to obtain in-depth information on host response to chromaffin cell grafts in laboratory animals. It is critical to establish the consequences of introducing foreign tissues, both allo- and xenogeneic, into the host CNS. These studies will focus on a determination of host CNS responses to adrenal medullary tissue and isolated chromaffin cell transplants using techniques recently developed in our laboratory. In addition, the stability of the transplants and host-graft integration, and conditions necessary for continue graft maintenance, are critical and will be addressed. Specifically, the proposed studies will analyze immunological responses to allografts and xenografts, implanted both intra- and extraparenchymally. These will include staining for induction of major histocompatibility antigens (MHC I and II). We will also determine donor-recipient histocompatibility with the mixed lymphocyte reaction (MLR). The necessity for continual or short-term immunosuppression and the effects of addition of putative antigen-presenting cells will also be assessed. Graft survival and host responses will be evaluated following immunologic challenges, such as transient disruption of the blood-brain barrier and systemic sensitization. Transplant-induced changes in blood-brain barrier permeability and uptake properties, glial reactivity and cellular infiltration will be studied. Our previous findings have revealed that both transplanted isolated chromaffin cells and adrenal medullary tissue become well integrated and participate in forming synapses with host neuronal processes. The effect of trophic factors on cultured cells and transplanted cells will be compared. A strength of these proposed studies is the ability to correlate graft survival and integration with antinociceptive activity.