This gave us the unique opportunity to compare the phenotype of DCs in the skin to their phenotype in the exactly corresponding SLN after local administration of either recombinant human GM-CSF or saline. The results reported here are consistent with increased migration of large numbers of mature CD83+ LCs through the dermis of GM-CSF-injected skin to the corresponding SLN. CD1a+ myeloid DCs in the SLN were phenotypically mature (ie, CD83+). These data are indicative of migration H100 of small numbers of phenotypically mature DCs to lymph nodes under steady state conditions. Antigen-specific cutaneous immune responses are initiated by epidermal and dermal dendritic cells (DCs).1 The majority of DCs in the skin are Langerhans cells (LCs), residing in the epidermis in an immature state. These immature LCs (iLCs) derive from CD34+ hematopoietic progenitor cells.2 LC precursors home from the bone marrow to the skin, where they differentiate to actively phagocytic LCs. When an antigen is encountered under proinflammatory conditions, LCs are activated and start migrating to regional lymph nodes (LNs), synthesizing new MHC molecules and up-regulating CD80, CD86, and other co-stimulatory and adhesion molecules. On arrival in the LN they have become mature DCs (mDCs). Expression of the chemokine receptor CCR7 facilitates their migration to the paracortical areas where T cells reside and may then be primed. Recently it has been suggested that immature DCs (iDCs) also migrate to the LN to induce peripheral T-cell tolerance in the steady state, this way preventing autoimmunity.3,4 Data that support iDCs migrating to the LN to induce peripheral T-cell tolerance, originate mainly from murine H100 studies.5,6 In humans iLCs were reported in skin-draining LNs only under chronic inflammatory conditions.7 So far, evidence for the presence of iDCs in LNs under normal steady state conditions is lacking. In melanoma, LCs take up and transport tumor-associated antigens to tumor-draining lymph nodes (TDLNs).8,9 To subsequently activate melanoma-specific T cells, the migrated LCs need to become activated.10 DC development and activation can both be frustrated by inhibitory factors commonly associated with melanoma, such as IL-10 or gangliosides.9,11,12 iDCs with ready access to tumor-associated antigens from the tumor may induce specific tolerance through inappropriate or abortive T-cell activation.13,14 DCs in TDLNs were similarly reported to H100 display immature characteristics. 15 The degree of immunosuppression in TDLNs is directly related to their distance to the primary tumor, indicating the causative agents to be tumor-derived. The first LN to directly drain the primary tumor, the so-called sentinel lymph node (SLN), is the preferential site of early metastasis16C18 and shows the most pronounced immunosuppression.19,20 Clearly, this crippling of DC functions in the first line of immunological defense will frustrate specific T-cell activation and increase the chance of tumor immune escape and metastatic spread.20,21 To overcome this suppression, we recently administered intradermal injections of granulocyte/macrophage colony-stimulating factor (GM-CSF) around the excision site of primary melanoma tumors and found increased numbers and activation state of DCs in the paracortical areas of the SLN.22 In the same study, the H100 absence of iDCs in the TDLNs of H100 the saline control group seemed to contrast with the currently dominant school of thought that holds iDCs in the TDLN to be primarily responsible for cancer-associated immune tolerance. Patients included in this study underwent re-excision of the scar of the primary melanoma excision at the same time as the SLN procedure. This gave us the unique opportunity to compare the phenotype of DCs in the skin to their phenotype in the exactly corresponding SLN after local administration of either recombinant human GM-CSF or saline. The results reported here are consistent with increased migration of large numbers of mature CD83+ LCs through the dermis of GM-CSF-injected skin to the corresponding SLN. In contrast, a quiescent steady state prevails in the control group with iLCs scattered throughout the epidermis and only small numbers of isolated CD83+ LCs in the dermis. Rabbit Polyclonal to JAK2 (phospho-Tyr570) Nevertheless, iDCs (CD1a+CD83?) are completely absent in the SLN under both these conditions. We conclude that small numbers of mDCs migrate to LN under steady state conditions and that these are apparently responsible for a maintained state of tolerance under these conditions. Materials and Methods Patients Twelve patients with stage I melanoma according to criteria of the American Joint Committee on Cancer (Breslow thickness, 1.5 mm; patient age, 18 to 70 years) were included in this single-blinded phase II study. All patients were scheduled to undergo a SLN procedure and re-excision of the scar of the primary melanoma excision. Re-excision of the scar of the primary tumor in all cases took place subsequent to SLN excision, during the same operative procedure. An excision margin of 1 1 cm was applied, as routine for melanoma with a Breslow thickness 2.
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