CEACAM-1a regulates graft-versus-host-disease after allogeneic HSCT

CEACAM-1a 调节同种异体 HSCT 后的移植物抗宿主病

• 批准号: 7851208
• 负责人: Marcel R M van den Brink
• 金额: $ 87.68万
• 依托单位: SLOAN-KETTERING INST CAN RESEARCH
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-07-01 至 2011-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7851208
• 关键词: Adhesions; Affect; Agonist; Allogeneic Bone Marrow Transplantation; Allogenic; Antibodies; Attenuated; Carcinoembryonic Antigen; Cell Adhesion Molecules; Colitis; Complication; Development; Differentiation and Growth; Disease; Endothelium; Epithelium; Family; Gene Expression Profiling; Glycoproteins; Graft-Versus-Tumor Induction; Hematologic Neoplasms; Hematopoietic Stem Cell Transplantation; Homing; IL2RA gene; Immune response; Infection; Infiltration; Inflammation; Integral Membrane Protein; Integrins; Intestinal Graft Versus Host Disease; Intestines; Large Intestine; Lead; Leukocytes; Malignant - descriptor; Malignant Neoplasms; Mediating; Microarray Analysis; Modeling; Molecular; Mus; Non-Malignant; Organ; Outcome; Prevention strategy; Prophylactic treatment; Publishing; Regulation; Regulatory T-Lymphocyte; Role; SELL gene; Signal Transduction; Small Intestines; T-Lymphocyte; Testing; Transplant Recipients; cancer cell; carcinoembryonic antigen-related cell adhesion molecules; clinically relevant; disorder prevention; efficacy testing; graft vs host disease; imprint; improved; mortality; mouse model; novel strategies; trafficking; tumor growth

Carcinoembryonic antigen related cell adhesion molecule 1 (CEACAM-1) is a transmembrane protein found on leukocytes, endothelium, and epithelium. Its activation can attenuate colitis in murine models. Microarray analysis revealed that CEACAM-1 is increased in the small bowel during intestinal graft-versus-host-disease (GVHD). We studied the role of CEACAM-1 in mouse models for allogeneic bone marrow transplantation. We found that CEACAM-1-/- donor T cells caused significantly more GVHD (p<0.05), while CEACAM-1-Tg donor T cells caused significantly less GVHD (p<0.01). Administration of a CEACAM-1 agonistic antibody CC1 also significantly attenuated GVHD (p<0.01) Histopathological analysis revealed significantly increased GVHD of the large bowel in recipients of CEACAM-1-/- T cells (p<0.05), while recipients of CEACAM-1-Tg T cells had decreased GVHD in all organs (p<0.01). We performed an extensive analysis and found that alloactivated CEACAM-1-/- T cells (a) have increased CD25 and decreased CD62L expression (b) have increased expression of the gut- homing integrin ¿4¿7 (LPAM) and (c) preferentially infiltrate the intestines, while CEACAM-1-Tg T cells (d) have decreased infiltration of all organs. Therefore the major hypothesis of this application is: CEACAM-1 is an important negative regulator of donor T cells during GVHD. We will test the following specific hypotheses: (1) CEACAM-1 regulates tumor growth and the graft-versus-tumor activity; (2) CEACAM-1 regulates alloreactive T cell trafficking and integrin ¿4¿7 expression; (3) CEACAM-1 regulates DC-mediated imprinting of gut-specific homing of alloreactive T cells; (4) CEACAM-1 regulates T cell polarization toward the Th1, Th2, Th17, and regulatory T cells; and (5) the administration of the CEACAM-1 agonist CC1 can ameliorate GVHD.

癌胚抗原相关的细胞粘附分子1（CECAM-1）是一个 在白细胞，内皮和上皮上发现的跨膜蛋白。它的激活可以 在鼠模型中衰减结肠炎。微阵列分析表明，CEACAM-1在 肠道移植物抗疾病（GVHD）期间的小肠。我们研究了 同种异体骨髓移植的小鼠模型中的CEACAM-1。我们发现 CEACAM-1 - / - 供体T细胞引起更大的GVHD（P <0.05），而CEACAM-1-TG 供体T细胞引起的GVHD明显较小（P <0.01）。 CEACAM-1激动剂的管理 抗体CC1还显着减弱了GVHD（P <0.01）的组织病理学分析显示 在CEACAM-1 - / - T细胞受体中，大肠的GVHD显着增加（P <0.05）， 尽管CEACAM-1-TG T细胞的受体在所有器官中均恶化GVHD（p <0.01）。我们 进行了广泛的分析，发现同种活化的CEACAM-1 - / - T细胞（a）具有 CD25增加和CD62L表达增加（B）的表达增加 归居整联蛋白€4¿7（LPAM）和（c）优先渗入肠道，而CEACAM-1-TG T细胞（d）的所有器官浸润改善。 因此，该应用的主要假设是：CEACAM-1是重要的 GVHD期间供体T细胞的负调节剂。我们将测试以下特定 假设：（1）CEACAM-1调节肿瘤生长和移植物肿瘤活性； （2） CEACAM-1调节同种反应性T细胞运输和整联蛋白»4€7表达； （3）CEACAM-1 调节DC介导的同种异体T细胞的肠道特异性归巢的印迹； （4）CEACAM-1 调节T细胞极化向Th1，Th2，Th17和调节性T细胞。 （5） CEACAM-1激动剂CC1的给药可以改善GVHD。