The generation of research resources designed to uncover novel mechanisms of islet beta-cell interaction with the immune system are vitally important for progress in understanding autoimmune disease onset and progression, enhancing drug development strategies, and other curative endeavors. Intracellular adhesion molecule-1 (ICAM-1) is a critical component in the development of type 1 diabetes (T1D) but the tissue-specific contributions of this protein have not been examined due to lack of available and appropriate model systems. Herein, we outline a strategy to make transgenic mice with conditional deletion of ICAM-1 on both the C57BL/6 and non-obese diabetic (NOD) backgrounds. This R03 project will generate two novel and important mouse lines with which to probe basic mechanisms underlying autoimmune onset and progression of T1D, and importantly, provide insights into how immune cells destroy islet beta cells. These new mouse lines will make it possible to test innovative hypotheses only conceivable with tissue-specific gene deletions, providing important mechanistic insights into events regulating autoimmunity, pancreatic islet inflammation, tissue graft rejection, vascularization events, and T1D onset. We anticipate broad applicability to studies of other diseases with autoimmune and auto-inflammatory components and for general studies on the biology of the ICAM-1 protein.