Dendritic cells, monocytes and macrophages—key immune cells that patrol the body—are proving difficult to turn into reliable therapies because scientists have been studying the wrong versions of them in the lab. Most of what researchers know about these cells comes from cells grown in a dish, which behave differently from the cells that actually live in human tissues. This mismatch has contributed to disappointing results in cancer treatments that use lab-grown immune cells. The researcher has built a systematic workflow to study these cells directly from human blood and tissue, in both healthy people and those with disease. If successful, this work could improve a melanoma vaccine already in clinical trials, make vaccines more effective by better controlling inflammation, and reveal why the immune system goes awry in atopic dermatitis (eczema). The project is primarily fundamental science—it aims to understand how these cells differ by origin and environment—but that understanding is a prerequisite for designing therapies that harness them reliably, rather than relying on inadequate lab models.
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Dendritic cells (DCs), monocytes and macrophages are a heterogeneous population of mononuclear phagocytes with critical roles in the initiation and regulation of immune responses. Harnessing their immune functions for therapeutic purposes has major implications for a broad range of clinical application. Human mononuclear phagocytes have been challenging to study because i) they are rare in peripheral blood, ii) access to human tissue, where these cells are abundant, is limited and iii) comple x dynamic changes occur in disease which are poorly understood. Our understanding of human mononuclear phagocytes has been primarily derived from studying in vitro monocyte-derived cells, which are not adequate models of in vivo populations. This is further evidenced by the disappointing clinical outcome using in vitro generated cells for cancer therapy. It is clear from murine studies that most DCs and macrophages are not derived from monocytes and that cellular origin impacts on immun e functions. However, the relevance of this to human mononuclear phagocyte biology is unclear. I have developed a systematic workflow to understand the underlying mechanisms for the functional heterogeneity of human mononuclear phagocytes in health and disease. The ultimate aim of my research is to facilitate the development of new therapeutic and vaccination strategies exploiting mononuclear phagocyte function. My key goals in this proposal are to: 1. Inform the design of exist ing blood DC-based melanoma vaccination therapy 2. Guide future manipulation of inflammatory populations during vaccination 3. Understand the immune pathomechanisms of atopic dermatitis
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