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.

癌胚抗原相关细胞粘附分子1（CEACAM-1）是一种细胞粘附分子， 在白细胞、内皮细胞和上皮细胞上发现的跨膜蛋白。它的激活可以 减轻小鼠模型中的结肠炎。微阵列分析显示，CEACAM-1增加， 小肠移植物抗宿主病（GVHD）。我们研究了 CEACAM-1在同种异体骨髓移植小鼠模型中的应用我们发现 CEACAM-1-/-供体T细胞引起显著更多的GVHD（p<0.05），而CEACAM-1-Tg 供体T细胞引起的GVHD显著减少（p<0.01）。CEACAM-1激动剂的施用 抗体CC 1也显著减弱GVHD（p<0.01）。 在CEACAM-1-/- T细胞的接受者中显著增加大肠的GVHD（p<0.05）， 而CEACAM-1-Tg T细胞的受体在所有器官中均降低了GVHD（p<0.01）。我们 进行了广泛的分析，发现同种激活的CEACAM-1-/- T细胞（a） 增加的CD 25和减少的CD 62 L表达（B）具有增加的肠- 归巢整联蛋白<$4 <$7（LPAM）和（c）优先浸润肠，而CEACAM-1-Tg T细胞（d）在所有器官中的浸润减少。 因此，本申请的主要假设是： GVHD期间供体T细胞的负调节因子。我们将测试以下具体 假设：（1）CEACAM-1调节肿瘤生长和移植物抗肿瘤活性;（2） CEACAM-1调节同种异体反应性T细胞运输和整合素<$4 <$7表达;（3）CEACAM-1 调节DC介导的同种异体反应性T细胞肠道特异性归巢的印记;（4）CEACAM-1 调节T细胞向Th 1、Th 2、Th 17和调节性T细胞的极化;和（5） 给予CEACAM-1激动剂CC 1可以改善GVHD。