Mast cell protease 6 is required for allograft tolerance.

It has been shown that mast cells (MC) are absolutely required for transplant acceptance. However, only a few of the numerous mediators produced by MC have been proposed as potential mechanisms for the observed immunosuppression. The role of proteases in acquired immune tolerance as such has not yet been addressed. In this study, we have shown the requirement for MC protease 6 (MCP6), an MC-specific tryptase, to establish tolerance toward an allogeneic skin graft. The substrate for MCP6 is interleukin (IL)-6, cytokine generally considered to indicate transplant rejection. Herein we have shown an inverse correlation between MCP6 and IL-6. High expression of MCP6 is accompanied by low levels of IL-6 when the allograft is accepted, whereas low expression of MCP6 in combination with high levels of IL-6 are observed in rejecting grafts. Moreover, tolerance toward an allogeneic graft cannot be induced in MCP6(-/-) mice. Rejection observed in these mice was comparable to that of MC-deficient hosts; it is T-cell mediated. These findings suggest that MCP6 actively depletes the local environment of IL-6 to maintain tolerance.

Mast cell degranulation breaks peripheral tolerance.

Mast cells (MC) have been shown to mediate regulatory T-cell (T(reg))-dependent, peripheral allograft tolerance in both skin and cardiac transplants. Furthermore, T(reg) have been implicated in mitigating IgE-mediated MC degranulation, establishing a dynamic, reciprocal relationship between MC and T(reg) in controlling inflammation. In an allograft tolerance model, it is now shown that intragraft or systemic MC degranulation results in the transient loss of T(reg) suppressor activities with the acute, T-cell dependent rejection of established, tolerant allografts. Upon degranulation, MC mediators can be found in the skin, T(reg) rapidly leave the graft, MC accumulate in the regional lymph node and the T(reg) are impaired in the expression of suppressor molecules. Such a dramatic reversal of T(reg) function and tissue distribution by MC degranulation underscores how allergy may causes the transient breakdown of peripheral tolerance and episodes of acute T-cell inflammation.

Mast cells as regulators of adaptive immunity to tumours.

The observation that mast cells accumulate at the periphery of growing tumours is now well documented, and the loss of mast cells correlates with reduced tumour growth. The role of mast cells as innate regulators of both inflammatory and immunosuppressive responses slowly becomes clear as novel tools become available. This review will address the role of mast cells in tumours and how they can interact with the local immune environment to mediate immune suppression contributing to tumour escape.

Density of dendritic cells in the human tracheal mucosa is age dependent and site specific.

BACKGROUND: The mucosal immune system undergoes extensive changes in early childhood in response to environmental stimuli. Dendritic cells (DC) play a major role in the development of the immune system. However, few data exist on the influence of continuous environmental stimulation on the distribution and phenotype of human airway DC. METHODS: Human tissue samples are mostly paraffin embedded which limits the use of several antibodies, and respiratory tissue for cryopreservation is difficult to obtain. Human frozen post mortem tracheal tissue was therefore used for this study. Only samples with epithelial adherence to the basement membrane were included (n = 34). Immunohistochemical staining and sequential overlay immunofluorescence were performed with DC-SIGN and a panel of leucocyte markers co-expressed by DC. RESULTS: DC detected in the human tracheal mucosa using DC-SIGN correlated with the expression of HLA-DR, co-stimulatory and adhesion molecules. Higher cell densities were found at the ventral tracheal site of patients older than 1 year than in infants in the first year of life. CONCLUSION: The increasing population of mucosal DC with age could reflect immunological maturation.

Cilomilast, tacrolimus and rapamycin modulate dendritic cell function in the elicitation phase of allergic contact dermatitis.

BACKGROUND: Cilomilast and tacrolimus as well as rapamycin are potential drugs for the treatment of allergic skin diseases like atopic dermatitis and allergic contact dermatitis. OBJECTIVES: To compare the in vitro and in vivo immunomodulatory effects of the phosphodiesterase 4 inhibitor cilomilast with those of tacrolimus and rapamycin. METHODS: The in vitro action of cilomilast, tacrolimus and rapamycin were tested in a mixed leucocyte reaction (MLR). In vivo, the inhibitory action of the immunomodulatory drugs was compared in the toluene-2,4-diisocyanate (TDI)-induced allergic inflammatory response with particular focus on dendritic cell (DC) function. RESULTS: Cilomilast, tacrolimus and rapamycin were all able to inhibit DC-mediated T-cell activation in a MLR. But it was demonstrated for cilomilast that the target cells are T cells rather than DC. In vivo, a combination of systemic and topical administration of each of these three substances significantly inhibited swelling in the murine ear 16 h after TDI challenge. There was also a reduction in the weight of the draining auricular lymph node, in lymphocyte cell count, and in the number of emigrated DC. The density of Langerhans cells in the epidermis was correspondingly higher in mice treated with cilomilast, tacrolimus and rapamycin than in those treated with vehicle. All three substances were found to inhibit DC migration ex vivo in a skin DC migration assay performed on ear tissue after TDI challenge. CONCLUSIONS: DC migration into the draining lymph node also takes place in the elicitation phase of allergic contact dermatitis and this migration can be influenced by tacrolimus and rapamycin, and, to a lesser extent, by cilomilast.

Differential capacity of CD8+ alpha or CD8- alpha dendritic cell subsets to prime for eosinophilic airway inflammation in the T-helper type 2-prone milieu of the lung.

BACKGROUND: Different subsets of dendritic cells (DCs), identified in mouse spleen by their differential expression of CD8 alpha, can induce different T-helper (Th) responses after systemic administration. CD8 alpha(-) DCs have been shown to preferentially induce Th type 2 (Th2) responses whereas CD8 alpha(+) DCs induce Th1 responses. OBJECTIVE: To study if these DC subsets can still induce different Th responses in the Th2-prone milieu of the lung and differentially prime for eosinophilic airway inflammation, typical of asthma. METHODS: Donor mice first received daily Flt3L injections to expand DC numbers. Purified CD8 alpha(+) or CD8 alpha(-) splenic DCs were pulsed with ovalbumin (OVA) or phosphate-buffered saline and injected intratracheally into recipient mice in which carboxyfluorescein diacetate succinimidyl ester-labelled OVA-specific T cell receptor transgenic T cells had been injected intravenously 2 days earlier. T cell proliferation and cytokine production of Ag-specific T cells were evaluated in the mediastinal lymph nodes (MLNs) 4 days later. The capacity of both subsets of DCs, to prime for eosinophilic airway inflammation was determined by challenging the mice with OVA aerosol 10 days later. RESULTS: CD8 alpha(-) DCs migrated to the MLN and induced a vigorous proliferative T cell response accompanied by high-level production of IL-4, IL-5, IL-10 and also IFN-gamma during the primary response and during challenge with aerosol, leading to eosinophilic airway inflammation. In the absence of migration to the MLN, CD8 alpha(+) DCs still induced a proliferative response with identical levels of IFN-gamma but reduced Th2 cytokines compared with CD8 alpha(-) DCs, which led to weak eosinophilic airway inflammation upon OVA aerosol challenge. Unpulsed DCs did not induce proliferation or cytokine production in Ag-specific T cells. CONCLUSION: CD8 alpha(-) DCs are superior compared with CD8 alpha(+) DCs in inducing Th2 responses and eosinophilic airway inflammation in the Th2-prone environment of the lung.