Analgesic effects of adrenal chromaffin cell transplants

描述(由申请人提供)：将同种(同种异体)嗜铬细胞从肾上腺移植到中枢神经系统已被广泛证明能产生深刻的止痛作用。这最初是在老鼠身上证明的，但这项技术也成功地减轻了超过35名癌症患者的疼痛。脊柱移植后，这些患者的脊髓液内源性阿片类药物和儿茶酚胺水平明显增加，具有强大的止痛效果。这些效应持续数月，并伴有对外源性阿片类止痛药耐受性的明确抑制，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，同种异体嗜铬细胞移植有类似于其他移植的限制，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)移植在啮齿动物身上显示了明显的止痛效果。然而，将这种方法转移到人类身上有很大的障碍。早期的工作表明，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，将细胞植入胶原基质中可能会提高它们的活性和止痛潜力。然而，在尝试对人类进行跨物种移植之前，在免疫和神经生理学上与人类更接近的物种，即非人类灵长类动物中，详细检查这些影响是至关重要的。因此，这里提出的工作需要进行研究，旨在优化异种嗜铬细胞移植到灵长类动物体内时的止痛潜力。这些实验将在体外确定在胶原基质中种植细胞对纯化的嗜铬细胞的活力、完整性和排斥潜力的影响。体内实验将把这些制剂带到猴子身上，研究细胞剂量依赖和胶原基质对异种移植止痛效果的影响。通过这种方式，我们希望更接近于用一种新的治疗方法来治疗严重的慢性疼痛患者，这种治疗方法是长期的，不仅不会导致耐受性，而且似乎还会阻碍其发展。

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.