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

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

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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）疗法已被证明对人黑色素瘤有效。 IL-2 还被用于克服接受化学疗法治疗的患者的免疫抑制和治疗病毒感染在内，包括艾滋病，以促进CD4+ T细胞的恢复。但是，这种疗法是还伴有严重的生命威胁性毒性，其特征是血管泄漏综合征（VLS）这是由内皮细胞（EC）损伤引起的。在某些感染中也注意到EC损害，实验性过敏性脑脊髓炎，血管尿素，类风湿关节炎，巨细胞关节炎以及移植和移植物抗宿主病后。我们已经证明了IL-2给药导致几种CD44同工型在细胞毒性淋巴细胞上的上调，这些淋巴细胞迁移到各种器官并通过使用CD44作为效应子分子造成EC损害。我们已经证明了CD44KO 小鼠对IL-2诱导的VLS具有更耐药性，此外，VLS可以被CD44有效阻断对手。在当前的研究中，我们将检验以下假设，即防止EC损伤将允许使用高剂量的IL-2有效治疗黑色素瘤。为了解决这个问题，我们将1）确定CD44 细胞溶细胞，EC和肿瘤细胞使用的同工型描述其在EC损伤和肿瘤中的作用转移2）使用缺乏CD44的所有同工型或缺乏V7或V6和V7外显子的小鼠到测试降低EC损伤是否会促进黑色素瘤的免疫疗法。 3）使用CD44 拮抗剂，例如透明质酸（HA），ABS至CD44同工型，CD44：FC融合蛋白等预防VLS，阻断黑色素瘤的转移并促进肿瘤疗法。 4）开发融合蛋白由抗CD44的IL-2和抗原结合位点组成。我们将使用这种蛋白质预防肿瘤转移并增加IL-2在治疗黑色素瘤中的功效，5）研究通过使用IL-2静脉素和NK细胞，IL-2对细胞毒性T细胞和天然杀伤细胞的差异作用缺陷NKCD TG小鼠。当前的研究共同为各种各样的研究提供了新的见解 CD44同工型的功能以及如何操纵这些分子以增强基于IL-2 黑色素瘤疗法。拟议的研究还构成了在广泛的EC损伤的基础临床表现。