DESCRIPTION (taken from the application) It has been suggested that non-allospecific immune-mediated damage, such as inflammation or the toxicity associated with "cytokine storms," may be responsible for a large proportion of the primary islet graft non-function see in clinical islet transplantation. Although studies in animals have been informative, the species differences in islet biology and immune responses mak it difficult to extrapolate these results to events resulting from the human leukocyte response to human islets. Unfortunately, no proper tools are available to study damage to human islets by inflammation or "cytokine storms" created by human leukocytes. We propose to develop a new model to study non-allogeneic immune-mediated human islet destruction, in NOD/LtSz-scid/scid mice. The Severe Combined ImmunoDeficiency (SCID) phenotype is characterized b a lack of adaptive immunity due to a genetic defect. The human leukocytes injected into these mice will come from the same donor as the human islets and therefore have no adaptive immunity against the islet tissue. By activating th leukocytes before placing them in the mice, where further activation is induce by exposure to mouse tissue, we intensify the release of cytokines, creating a "cytokine storm" with associated upregulation and activation of non-allospecific immunity. We will evaluate the usefulness and limitations of such a model and employ it to investigate the mechanisms of reduced human isle immunogenicity following extended periods of culture. Upon the success of this project, an important new research tool will be available to study and develop techniques that prevent non-allospecific human islet graft destruction.