Analgesic effects of adrenal chromaffin cell transplants

描述（由申请人提供）：已广泛显示，将同种（同种异体）嗜铬细胞从肾上腺移植至中枢神经系统可产生深度镇痛。这一点首先在大鼠身上得到证实，但这项技术也成功地减轻了35多名癌症患者的疼痛。脊髓移植后，这些患者显示出脊髓液内源性阿片类物质和儿茶酚胺水平的明显增加，具有强大的镇痛作用。其作用持续数月，并伴有对外源性阿片类镇痛药物耐受性的明确抑制，这是这些患者的常见问题。因此，同种异体嗜铬细胞移植物的移植清楚地显示出作为治疗慢性顽固性疼痛的一种手段的潜力。 不幸的是，同种异体嗜铬细胞的移植具有与其他移植类似的局限性，例如，合适的人体组织的可用性。为了应对这一挑战，异种（跨物种）移植在啮齿动物中表现出明显的镇痛作用。然而，将这种方法转移到人类身上存在重大障碍。早期的研究表明，牛或猪细胞的纯化可以最大限度地减少大鼠的排斥反应。初步工作还表明，将细胞包埋在胶原基质中可能会提高其活力和镇痛潜力。然而，在尝试人类跨物种移植之前，在免疫学和神经生理学上更接近人类的物种，即非人类灵长类动物中详细检查这些影响至关重要。因此，这里提出的工作需要调查，旨在优化移植到灵长类动物的异种嗜铬细胞的镇痛潜力。该实验将在体外确定在胶原基质中接种细胞对纯化的嗜铬细胞的活力、完整性和排斥潜力的影响。在体内实验将这些制剂的猴子，研究细胞剂量依赖性和胶原蛋白基质的异种移植的镇痛效果的影响。通过这种方式，我们希望能够更接近用一种新型治疗方法治疗严重慢性疼痛患者的能力，这种治疗方法不仅持久，而且不会促进耐受性，而且似乎会阻碍其发展。

DESCRIPTION (provided by applicant): Transplantation of same species (allogeneic) chromaffin cells from the adrenal gland to the central nervous system has been widely shown to produce profound analgesia. This was first demonstrated in rats, but the technique has also successfully alleviated pain in more than 35 cancer patients. After spinal transplant, these patients show a distinct increase in spinal fluid levels of endogenous opioids and catecholamines, with a robust analgesic effect. The effects last many months and are accompanied by a definite inhibition in the development of tolerance to exogenous opiate analgesic drugs, a common problem with these patients. Thus transplantation of allogeneic chromaffin cell graft clearly shows potential as a means of treating chronic, intractable pain. Unfortunately, transplantation of allogeneic chromaffin cells has limitations similar to other transplants, e.g., the availability of suitable human tissue. To meet this challenge, xenogeneic (cross-species) transplants have demonstrated clear analgesic effects in rodents. However, there are significant roadblocks in transferring this method to humans. Earlier work indicates that purification of bovine or porcine cells minimizes rejection potential in rats. Preliminary work also indicates that embedding cells in a collagen matrix may improve their viability and analgesic potential. However, prior to attempting cross-species transplants in humans, it is critical to examine these effects in detail in species that are much closer to man immunologically and neurophysiologically, namely nonhuman primates. Thus, the work proposed here entails investigations designed to optimize the analgesic potential of xenogeneic chromaffin cells when transplanted into primates. The experiments will determine, in vitro, the effects of seeding cells in collagen matrices on the viability, integrity, and rejection potential of purified chromaffin cells. In vivo experiments will take these preparations to monkeys, investigating cell-dose dependence and collagen matrix effects on the analgesic efficacy of xenogeneic transplants. In this way, we hope to move much closer to the capability of treating patients with severe chronic pain with a novel treatment that is long-lasting and not only does not precipitate tolerance, but also appears to impede its development.