Acute Inflammation by Human Leukocytes in Human Skin Xenografts

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P/F #60 - "Acute Inflammation by Human Leukocytes in Human Skin Xenografts" Stephen Malawista, MD (Rheumatology), Nancy Kirkiles-Smith, PhD (Pathology) Eligibility Category Established Investigator, new skin-related research project. Abstract: In this proposal an expert in neutrophil biology, Dr. Stephen Malawista, is turning his attention to the recruitment to and function of neutrophils in skin, taking advantage of human skin xenograph models in the YSDRC core laboratory operated by Drs. Jordan Pober and Nancy Kirkiles-Smith. Our aim is to create a model of acute human skin inflammation. In SCID/beige mice engrafted with human skin, it has been difficult to adoptively transfer whole human neutrophils. Their recruitment to human xenografts stimulated by agents injected intradermally will depend in part on their persistence in the circulation, and the study of longer-term effects may require repeated administration of neutrophils. To address this potential difficulty we will explore the use of human neutrophil cytoplasts, which are heat-induced membrane-bound fragments from neutrophils that maintain the locomotory and phagocytic capacity of the parent cell, and which in a dog model have been shown to home to inflammatory skin lesions with generally equal facility to that of intact neutrophils. Lacking lysosomal granules and the respiratory burst, they may be more robust in "foreign territory" than the intact cells. Thus a key aim will be to compare whole neutrophils and cytoplasts for lifetime in the circulation, biodistribution into mouse tissues, and homing into human skin grafts at baseline and following local activation, e.g. with LPS or with cytokines. Once the model is established, we will examine the capacity of cytoplasts to perform specific neutrophil functions such as clearance of bacteria. Relevance to public health Acute inflammation and its control are of great importance in Medicine - in infection, autoimmune disorders, and elsewhere. A good model for studying acute inflammation in human skin will be useful to workers in the field.