Khachatryan A, Guerder S, Palluault F, Cote G, Solimena M, Valentijn K, Millet I, Flavell R A, Vignery A
Yale University School of Medicine, Department of Orthopaedics and Rehabilitation, New Haven, CT 06510, USA.
J Immunol. 1997 Feb 1;158(3):1409-16.
To investigate whether the immunosuppressive neuropeptide calcitonin gene-related peptide (CGRP) was a potential candidate for tissue-specific gene therapy, we engineered nonobese diabetic (NOD) mice to produce CGRP in beta cells by placing the modified calcitonin gene under the control of the rat insulin promoter. CGRP inhibits CD4 T cell production of the cytokines that have been implicated in the pathogeny of type I diabetes. Three transgene-positive mouse lines were obtained, two of which expressed immunoreactive CGRP in beta cells (NOD-CGRP mice). Isolated islets from one of these two transgene-positive founders produced active CGRP, whereas islets from transgene-negative littermates did not. The production of CGRP by beta cells prevented insulin-dependent diabetes mellitus in male and reduced its incidence by 63% in female mice. This prevention was due to a local immunosuppressive effect of CGRP as no difference was detected between NOD-CGRP and NOD littermate lymph node, spleen, and thymus cells by either FACS analysis or proliferative response to stimulation by Ag, alloantigen or anti-CD3. These data suggest that CGRP is a potential therapeutic molecule to prevent or treat diabetes and possibly other diseases and conditions in which immune cells are involved. These data also suggest that endogenous CGRP concentrated in sensory nerve endings may regulate locally the immune response, further strengthening the importance of the functional neuroimmune link.
为了研究免疫抑制性神经肽降钙素基因相关肽（CGRP）是否是组织特异性基因治疗的潜在候选物，我们通过将修饰的降钙素基因置于大鼠胰岛素启动子的控制下，对非肥胖糖尿病（NOD）小鼠进行基因工程改造，使其β细胞产生CGRP。CGRP可抑制与I型糖尿病发病机制有关的细胞因子的CD4 T细胞产生。获得了三个转基因阳性小鼠品系，其中两个在β细胞中表达免疫反应性CGRP（NOD-CGRP小鼠）。这两个转基因阳性奠基者之一分离出的胰岛产生活性CGRP，而转基因阴性同窝小鼠的胰岛则不产生。β细胞产生CGRP可预防雄性小鼠的胰岛素依赖型糖尿病，并使雌性小鼠的发病率降低63%。这种预防是由于CGRP的局部免疫抑制作用，通过FACS分析或对Ag、同种异体抗原或抗CD3刺激的增殖反应，在NOD-CGRP和NOD同窝小鼠的淋巴结、脾脏和胸腺细胞之间未检测到差异。这些数据表明，CGRP是预防或治疗糖尿病以及可能涉及免疫细胞的其他疾病和病症的潜在治疗分子。这些数据还表明，集中在感觉神经末梢的内源性CGRP可能局部调节免疫反应，进一步强化了功能性神经免疫联系的重要性。
