TARGETED EXPRESSION OF THE NEUROPEPTIDE CALCITONIN-GENE-RELATED PEPTIDE TO BETA-CELLS PREVENTS DIABETES IN NOD MICE

To investigate whether the immunosuppressive neuropeptide calcitonin g ene-related peptide (CGRP) was a potential candidate for tissue-specif ic 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 producti on of the cytokines that have been implicated in the pathogeny of type I diabetes, Three transgene-positive mouse lines were obtained, two o f which expressed immunoreactive CGRP in beta cells (NOD-CG RP mice), Isolated islets from one of these two transgene-positive founders prod uced active CGRP, whereas islets from transgene-negative littermates d id not, The production of CGRP by beta cells prevented insulin-depende nt diabetes mellitus in male and reduced its incidence by 63% in femal e mice, This prevention was due to a local immunosuppressive effect of CGRP as no difference was detected between NOD-CGRP and NOD littermat e lymph node, spleen, and thymus cells by either FAGS analysis or prol iferative response to stimulation by Ag, alloantigen or anti-CD3, Thes e data suggest that CGRP is a potential therapeutic molecule to preven t or treat diabetes and possibly other diseases and conditions in whic h immune cells ape involved, These data also suggest that endogenous C GRP concentrated in sensory nerve endings may regulate locally the imm une response, further strengthening the importance of the functional n euroimmune link.