Cellular interaction and activation is controlled by the local microenvironment. A good balance of moderate perfusion and diffusion limitation ensures the formation of local microgradients in the CCS. As with many hormones, cytokines and growth factors have both autocrine and paracrine effects [105], but in contrast to hormones most of them function on a short track in the cellular neighborhood, or by direct cell-cell contact only. An overlay of different metabolite and factor microgradients forms distinct niches for cell differentiation, activation or energy. The differentiation and activation of hematopoietic stem cells and mature lymphocytes is biased by distinct levels of factors, such as glucose, lactate, dissolved oxygen, and pH [96, 97, 100-102].

APC immobilized in the ECM form a cellular network and secrete chemokines for the attraction of highly migrational T lymphocytes [109-111]. The communication ofAPC and T cell, and the formation of immunological synapses, is driven by a set of cytokines [103, 104]. Activated T lymphocytes are key players in antigen-specific co-stimulation ofB cells to ensure sustained B-cell activation and antibody rearrangement and secretion.

The T-cell activation can switch into a humoral, antibody-driven or a cellular immune response, and is strongly influenced by interleukin (IL)-4, IL-10, tumor necrosis factor (TNF)-a and interferon (IFN)-y. In addition to the given local microenvironment, immune responses can also be guided by additional supplementation.

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