Role of CD44 in EC injury and melanoma therapy

CD44 在 EC 损伤和黑色素瘤治疗中的作用

基本信息

批准号：
7151173
负责人：
Mitzi Nagarkatti
金额：
$ 27.58万
依托单位：
UNIVERSITY OF SOUTH CAROLINA AT COLUMBIA
依托单位国家：
美国
项目类别：
财政年份：
2002
资助国家：
美国
起止时间：
2002-12-01 至 2008-11-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7151173
关键词：
Abbreviations Acquired Immunodeficiency Syndrome Address Antibodies Autologous Bone Marrow Transplantation Binding Binding Sites Blood Vessels CD4 Positive T Lymphocytes CD44 gene Cancer Patient Cells Chimeric Proteins Clinical Clinical Trials Combined Modality Therapy Condition Cutaneous Cytotoxic T-Lymphocytes Denileukin Diftitox Development Disease Dose Dose-Limiting Effector Cell Endothelial Cells Exhibits Exons Experimental Autoimmune Encephalomyelitis Giant Cells Green Fluorescent Proteins Growth Hematologic Neoplasms Hodgkin Disease Human Hyaluronic Acid IL2RA gene Immunosuppression Immunotherapy Immunotoxin Therapy Immunotoxins Infection Injury Interleukin 2 Receptor Interleukin-2 Knockout Mice Lead Life Ligands Ligation Lung Lymphocyte Lymphocytic Choriomeningitis Lymphoma Mediating Melanoma Cell Mus Natural Killer Cells Nature Neoplasm Metastasis Non-Hodgkin&apos s Lymphoma Organ Patients Peptides Phase Protein Binding Protein Fragment Protein Isoforms Proteins Range Recombinants Recovery Renal Cell Carcinoma Resistance Reverse Transcriptase Polymerase Chain Reaction Rheumatoid Arthritis Role Standards of Weights and Measures Syndrome T-Lymphocyte Testing Therapeutic immunosuppression Toxic effect Toxin Transgenic Organisms Transplantation Up-Regulation Variant Vasculitis Virus Diseases Wild Type Mouse antigen binding base cancer immunotherapy cell injury chemotherapy cytokine cytotoxic cytotoxicity graft vs host disease hyaluronate inhibitor/antagonist insight killings macrophage melanoma mimetics neoplastic cell novel prevent tumor tumor eradication

项目摘要

High dose interleukin-2 (IL-2) therapy has been shown to be effective against human melanomas. IL-2 has also been used to overcome immunosuppression in patients treated with chemotherapy and to treat viral infections including AIDS so as to facilitate recovery of CD4+ T cells. However, such a therapy is also accompanied by severe life threatening toxicity characterized by vascular leak syndrome (VLS) which results from endothelial cell (EC) injury. EC damage has also been noted in certain infections, experimental allergic encephalomyelitis, vasculitides, rheumatoid arthritis, giant cell arthridis as well as following transplantation and graft-versus-host disease. We have demonstrated that IL-2 administration leads to upregulation of several CD44 isoforms on cytotoxic lymphocytes which migrate to various organs and cause EC damage by using CD44 as an effector molecule. We have shown that CD44KO mice are more resistant to IL-2 induced VLS and furthermore,VLS can be effectively blocked by CD44 antagonists. In the current study we will test the hypothesis that preventing EC injury would permit the use of high doses of IL-2 to effectively treat melanomas. To address this, we will 1) Identify the CD44 isoforms used by cytolytic cells, EC and tumor cells to delineate their role in EC injury and tumor metastasis 2) Use mice deficient in all isoforms of CD44 or those deficient in V7 or V6 and V7 exons to test whether decreased EC injury would facilitate immunotherapy of melanomas. 3) Use CD44 antagonists such as hyaluronic acid (HA), Abs to CD44 isoforms, CD44:Fc fusion proteins, etc. to prevent VLS, block metastasis of melanoma and facilitate tumor therapy. 4) Develop a fusion protein consisting of a part of IL-2 and antigen binding sites of anti-CD44. We will use this protein to prevent tumor metastasis and increase the efficacy of IL-2 in the treatment of melanomas, and 5) Study the differential effects of IL-2 on cytotoxic T cells and natural killer cells by using IL-2 mutein and NK cell deficient NKCD Tg mice. Together, the current study should provide novel insights into the varied function of CD44 isoforms and how these molecules can be manipulated to enhance IL-2 based melanoma therapy. The proposed studies also form the basis for prventing EC injury in wide range of clinical manifestations.

高剂量白介素 2 (IL-2) 疗法已被证明对人类黑色素瘤有效。白细胞介素2 也被用于克服接受化疗的患者的免疫抑制并治疗包括艾滋病在内的病毒感染，以促进 CD4+ T 细胞的恢复。然而，这样的疗法是还伴有严重危及生命的毒性，其特征是血管渗漏综合征（VLS）这是由内皮细胞（EC）损伤引起的。在某些感染中也发现了 EC 损伤，实验性过敏性脑脊髓炎、血管炎、类风湿性关节炎、巨细胞关节炎以及移植后和移植物抗宿主病。我们已经证明 IL-2 给药导致细胞毒性淋巴细胞上几种 CD44 同工型的上调，这些淋巴细胞迁移到各种器官并通过使用CD44作为效应分子引起EC损伤。我们已经证明 CD44KO 小鼠对IL-2诱导的VLS具有更强的抵抗力，而且CD44可以有效阻断VLS 对手。在当前的研究中，我们将检验以下假设：预防 EC 损伤将允许使用高剂量的IL-2可以有效治疗黑色素瘤。为了解决这个问题，我们将 1) 识别 CD44 溶细胞细胞、EC 和肿瘤细胞使用的亚型来描述它们在 EC 损伤和肿瘤中的作用 2) 使用缺乏 CD44 所有亚型的小鼠或缺乏 V7 或 V6 和 V7 外显子的小鼠来检测转移测试减少 EC 损伤是否会促进黑色素瘤的免疫治疗。 3）使用CD44 拮抗剂，如透明质酸 (HA)、CD44 亚型抗体、CD44:Fc 融合蛋白等预防VLS，阻断黑色素瘤转移，促进肿瘤治疗。 4) 开发融合蛋白由部分IL-2和抗CD44的抗原结合位点组成。我们将使用这种蛋白质来预防肿瘤转移并增加 IL-2 在黑色素瘤治疗中的功效，以及 5) 研究利用 IL-2 突变蛋白和 NK 细胞研究 IL-2 对细胞毒性 T 细胞和自然杀伤细胞的不同影响 NKCD 缺陷型 Tg 小鼠。总之，当前的研究应该为不同的领域提供新颖的见解。 CD44同种型的功能以及如何操纵这些分子来增强基于IL-2的黑色素瘤治疗。拟议的研究也为预防广泛的 EC 损伤奠定了基础。临床表现。