HOST-GRAFT INTERACTIONS OF CNS CHROMAFFIN CELL IMPLANTS

描述（申请人的摘要）：我们已经表明，疼痛敏感性可以 通过移植肾上腺髓质组织或分离的嗜铬细胞减少 细胞进入大鼠中脑的CNS疼痛调节区 中脑导水管周围灰质（PAG）或蛛网膜下腔的实质外 背侧腰椎脊髓的损伤 我们已经取得了可喜的成果， 同种异体肾上腺髓质移植缓解肾上腺皮质功能障碍的初步临床研究 癌症疼痛。 除了同种异体移植，我们发现牛 嗜铬细胞在大鼠CNS中存活良好。 异种移植是一种潜在的 重要的未开发捐助来源，可能克服有限的可用性 人类捐赠者。 然而，在大规模临床实施之前， 在进行这些程序时，重要的是要深入了解 嗜铬细胞移植后宿主反应实验室研究进展 动物 关键是要确定引入的后果 同种异体和异种异体的外来组织进入宿主CNS。 这些 研究将集中在确定宿主中枢神经系统对肾上腺素的反应， 骨髓组织和分离的嗜铬细胞移植 最近在我们的实验室里开发的。 此外， 移植和宿主-移植物整合，以及 继续移植物维持，是至关重要的，将得到解决。 具体来说，拟议的研究将分析免疫反应， 同种异体移植物和异种移植物，在实质内和实质外植入。 这些将包括诱导主要组织相容性的染色 抗原（MHC I和II）。 我们还将确定捐赠者和接受者 混合淋巴细胞反应（MLR）。 的必要性 对于持续或短期免疫抑制以及添加 还将评估推定的抗原呈递细胞。 移植物存活率和 宿主应答将在免疫攻击后进行评价，例如 血脑屏障的短暂破坏和全身致敏。 移植引起的血脑屏障通透性和摄取的变化 将研究性质、神经胶质反应性和细胞浸润。 我们 先前的研究结果表明，移植的孤立嗜铬细胞 细胞和肾上腺髓质组织变得很好地整合， 与宿主神经元突起形成突触。 营养的影响 将比较对培养细胞和移植细胞的影响。 一 这些拟议研究的优势在于能够将移植物 存活和与抗伤害感受活性的整合。

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.