IMMUNOPHARMACOLOGY OF THALIDOMIDE

沙利度胺的免疫药理学

• 批准号: 3187573
• 负责人: GEORGIA B VOGELSANG
• 金额: $ 23.76万
• 依托单位: JOHNS HOPKINS UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 1987
• 资助国家: 美国
• 起止时间: 1987-05-01 至 1995-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/3187573
• 关键词: autologous transplantation; azathioprine; blood disorder chemotherapy; bone marrow transplantation; chemical structure function; clinical trials; cyclodextrins; cyclosporines; disease /disorder model; disease /disorder prevention /control; drug metabolism; gene expression; graft versus host disease; high performance liquid chromatography; homologous transplantation; human subject; human therapy evaluation; hydrolysis; immunopharmacology; immunosuppression; isoantigen; laboratory rat; major histocompatibility complex; neurotoxins; nonhuman therapy evaluation; prednisone; radiopharmacology; radiotracer; skeletal disorder chemotherapy; thalidomide

Acute and chronic graft-versus-host disease (GHVD) remain a significant cause of morbidity and mortality following allogeneic bone marrow transplant (BMT). Although there have been recent advances in treatment and prevention of GVHD, significant problems remain with these approaches. We have used thalidomide, a potent non-toxic immunosuppressant, to treat acute and chronic GVHD. In a rat major mismatch BMT model, 22 of 23 animals with severe established acute GVHD responded to thalidomide therapy. Of 42 animals receiving thalidomide prophylactically, only 8 developed mild GVHD and all of these responde to continued therapy. Eleven of 11 animals with chronic GVHD responded to thalidomide with one responding animal dying of an apparent viral infection. We propose to develop these studies with goal of introducing the drug clinically. For both prophylaxis and treatment of acute and chronic GVHD, transplants will be performed to address the maximally severe acute or chronic GVHD treatable with thalidomide, the optimal length of therapy, the optimal dosing frequency, and combination therapy with CsA or methylprednisolone. To help study thalidomides mechanism of action, we have developed a fluorescent thalidomide derivative (FT) which is more soluble than native thalidomide. FT binds primarily to T lymphocytes with a small avidly binding bright population and a larger less avidly binding dim population. A similar picture of bright and dim populations is seen with a fluorescent dansylated CsA; these population as well as unsorted cells have been extensively characterized in our laboratory. We propose to carry out similar studies using the FT to characterize each of the three lymphocyte populations which bind to FT. Each cell population will be characterized as to phenotype; response to alloantigen, mitogens, IL-2 and viral antigen; ability to induce cytotoxic and suppressor cells by alloantigen IL-2 production in response to alloantigen or mitogen; NK activity; and stimulatory activity. The similarities and differences between the responses seen with CsA and thalidomide will be explored as they may offer clues or the basic immunoregulatory mechanism for the induction of tolerance.

急性和慢性移植抗宿主病（GHVD）仍然很重要 同种异体骨髓移植后发病和死亡率的原因 （BMT）。 尽管最近在治疗和预防方面取得了进步 在GVHD中，这些方法仍然存在重大问题。 我们已经使用过 沙利度胺是一种有效的无毒免疫抑制剂，可治疗急性和 慢性GVHD。 在大鼠主要不匹配的BMT模型中，23只动物中有22只 严重的急性GVHD对沙利度胺治疗有反应。 42 预防性接受沙利度胺的动物只有8种出现了温和的GVHD 所有这些都对继续治疗做出了反应。 11只动物中有11只 慢性GVHD对沙利度胺做出了反应 明显的病毒感染。 我们建议以目标 在临床上引入药物。 预防和治疗 急性和慢性GVHD将进行移植以解决 可用沙利度胺治疗的最大严重急性或慢性GVHD， 最佳治疗长度，最佳给药频率和组合 用CSA或甲基丙糖酮治疗。 帮助研究沙利度胺 作用机理，我们开发了荧光沙利度胺衍生物 （ft）比天然沙利度胺更可溶。 FT主要与T结合 淋巴细胞具有较小的鲜明结合的明亮种群，较小的淋巴细胞 卑鄙的昏暗人群。 明亮和昏暗的类似图片 种群可以使用荧光丹烷化的CSA。这些人口为 以及未分类的细胞在我们的 实验室。 我们建议使用FT进行类似的研究 表征与ft结合的三个淋巴细胞种群中的每个人。 每个细胞群体都将以表型为特征。 对 同种抗原，有丝分裂原，IL-2和病毒抗原；诱导细胞毒性的能力 以及同种抗原IL-2产生的抑制细胞响应 同种剂或有丝分裂原； NK活动； 和刺激活动。 这 CSA和CSA的反应之间的相似性和差异 将其探索沙利度胺，因为它们可能会提供线索或基本 诱导耐受性的免疫调节机制。