A monoclonal antibody approach was used to characterize islet cell differentiation antigens involved in autoimmunity related diabetes mellitus. This procedure yielded islet cell monoclonal antibodies (ICMAbs) that demonstrated varying tissue/cellular distribution. The ICMAb I-45 showed a pan-islet reactivity similar to the reactivity of islet cell autoantibodies. The target antigen of the ICMAb I-45 demonstrated a neuroendocrine distribution. Single step immunoaffinity purification of I-45 antigen using I-45 monoclonal antibody immunoaffinity matrix yielded a 68kD protein. The specificity of the immunoaffinity purified 68kD protein was further demonstrated by the lack of binding of this protein to immunoaffinity columns of irrelevant monoclonal antibodies. The neuroendocrine distribution of the I-45 antigen, like that of other differentiation molecules like HISL-19, neuron specific enolase and chromogranin A strengthens the hypothesis of neuroectodermal origin of the islets of Langerhans.