As restricted by airplane R&D circle, aircraft tooling design is desired to comply with airplane product design and subsequent portions. However, cooperative design for aircraft tooling, especially large-sized one, is difficult and the reasons are as follows: ①The quantity for Aircraft tooling parts is enormously large, the size is large, and the structure is complex. ②Tooling design procedure is complicated with many portions to be coordinated. ③Airplane product amendments are frequent and hard to trace. Aircraft tooling design tends to proceed without effective mechanism to evaluate and optimize manufacturing process, scheduling and etc. With these difficulties considered, an aircraft tooling cooperative design model based on Neuron-Endocrine-Immunity working principle is presented in this paper. Resorting to shared chemical information molecules, Neuron-Endocrine-Immunity system forms an extensive and complicated regulating network which regulates all cells and tissues in human body. Referring to this principle, aircraft tooling design system involves controller and controlled objects. With adaptive and self-organized tooling design procedure, rapid adjustment or reconfiguration can be realized. Meanwhile, the feasibility and validity of adjusting task plans and tooling design schedules are ensured. To implement this model, a multi-agent-based framework for aircraft tooling cooperative design is proposed. This framework incorporates PDM and united structure for effective collaboration in terms of unified data sharing, convenient tool wrapping and decentralized control. A pilot system has been developed and testified in an aircraft manufacturing enterprise, thus lessening repetitive modifying workload, ensuring design quality and project schedule.