Conlan, TJ; (2015) Mechanisms of graft-versus-host-disease: a role for Langerhans cells in regulating skin GVHD. Doctoral thesis , UCL (University College London).

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Abstract

Allogeneic bone marrow transplantation (BMT) is an important and commonly used treatment for a variety of haematological malignancies. Central to the therapeutic benefits of allogeneic BMT is the role of donor T cells, which mediate a potent anti-neoplastic effect against tumours in the recipient. However, the presence of donor T cells is also tightly associated with the development of the life-threatening condition graft-versus-host-disease (GVHD), a disorder where alloreactive donor T cells recognise the recipient as ‘non-self’ and elicit a potent anti-host immune response. Antigen presenting cells (APC) are critical to the induction of acute GVHD. However, recent studies have questioned whether any particular subset of APC has a non-redundant role in the priming of an alloreactive donor T cell response. One of the most commonly affected organs in acute GVHD is the skin, which contains a diverse array of professional APC subsets capable of initiating potent immune responses. One such subset is Langerhans cells (LC), a population of radioresistant dendritic cells (DC) that form a dense interlacing network within the epidermis. Using an in vivo mouse model of acute GVHD where host LC can be conditionally depleted, LC were found to play an important role in the development of acute GVHD in the skin. The depletion of host LC significantly reduced the severity of cutaneous GVHD that developed following allogeneic BMT. Host LC were required in situ in the epidermis for both the accumulation and function of alloreactive donor CD8 T cells in the skin. A role for host Langerin+ dDC, a population shown to be critical for CD8-mediated T cell responses in the skin, was also ruled out. These findings describe a novel role for host LC in the regulation of cutaneous GVHD in situ, which could identify a novel target for organ specific immunosuppression following allogeneic BMT.

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