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

癌胚抗原相关细胞黏附分子1(CEACAM-1)是一种 存在于白细胞、内皮细胞和上皮细胞上的跨膜蛋白。它的激活可以 减轻小鼠结肠炎模型。基因芯片分析显示CEACAM-1在 肠道移植物抗宿主病(GVHD)期间的小肠。我们研究了它的作用 CEACAM-1在小鼠异基因骨髓移植模型中的应用。我们发现 CEACAM-1-/-供者T细胞引起的移植物抗宿主病显著增加(p&lt；0.05)，而CEACAM-1-TG 供者T细胞引起的移植物抗宿主病显著减少(p&lt；0.01)。CEACAM-1激动剂的给药 组织病理学分析显示，抗体CC1也可显著减轻移植物抗宿主病(P&lt；0.01) CEACAM-1-/-T细胞受者的大肠移植物抗宿主病显著增加(p&lt；0.05)， 而接受CEACAM-1-TGT细胞移植的小鼠各脏器GVHD均显著降低(p&lt；0.01)。我们 进行了广泛的分析，发现同种异体激活的CEACAM-1-/-T细胞(A)具有 CD25增加和CD62L表达减少(B)增加了肠道- 归巢整合素(LPAM)和(C)优先侵入肠道，而CEACAM-1-TG T细胞(D)对各脏器的浸润性减少。 因此，这一应用的主要假设是：CEACAM-1是一种重要的 移植物抗宿主病中供者T细胞的负性调节。我们将测试以下特定的 假设：(1)CEACAM-1调节肿瘤生长和移植物抗肿瘤活性；(2) CEACAM-1调节同种反应性T细胞运输和整合素4？7的表达； 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迹；(4)CEACAM-1 调节T细胞向Th1、Th2、Th17和调节性T细胞的极化；和(5) 应用CEACAM-1激动剂CC1可改善GVHD。

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.