Tolerogenic therapy

Tolerogenic therapy aims to induce immune tolerance where there is pathological or undesirable activation of the normal immune response. This can occur, for example, when an allogeneic transplantation patient develops an immune reaction to donor antigens, or when the body responds inappropriately to self antigens implicated in autoimmune diseases.. It must provide absence of specific antibodies for exactly that antigenes. Tolerogenic therapy aims to induce immune tolerance where there is pathological or undesirable activation of the normal immune response. This can occur, for example, when an allogeneic transplantation patient develops an immune reaction to donor antigens, or when the body responds inappropriately to self antigens implicated in autoimmune diseases.. It must provide absence of specific antibodies for exactly that antigenes. Research using animal models in transplantation and autoimmune diseases has led to early-phase human trials of tolerogenic therapy for autoimmune conditions like Type 1 Diabetes. Tolerogenic therapies employ the inbuilt tolerance mechanisms of a class of immune cells called dendritic cells. Dendritic cells are divided into two main subsets: Tolerogenic therapies are based on the principle that inducing the semi-mature phenotype in dendritic cells and then exposing them to the target antigen should allow antigen-specific induction of T-cell tolerance. Tolerogenic dendritic cells induce tolerance through several mechanisms. Once stimulated, the dendritic cells migrate to the draining lymph node and present antigens to T cells via interaction of MHC class II-antigen complexes on the dendritic cell with T cell receptors on the T cell. This can induce T cell clonal deletion, T cell anergy or the proliferation of regulatory T cells (Tregs). Collectively, these mechanisms produce tolerance to specific antigens, which should help to prevent autoimmunity, but could therefore also be used as a therapy to induce tolerance to specific antigens implicated in autoimmune disease, or donor antigens in transplant patients. Several methods of inducing tolerance based on this approach are currently being explored. Ex vivo tolerogenic dendritic cells can be induced through the addition of cytokines, pharmacological agents or genetic engineering techniques after their extraction from the patient. The DCs are then pulsed with the specific antigen to which tolerance is desired and these, now tolerogenic, cells can be injected back into the patient. Alternative methods include the direct injection of an inducing agent to induce semi-mature DCs in vivo. Studies have suggested a role for tolerogenic dendritic cells in the treatment of diseases like type 1 diabetes mellitus and multiple sclerosis. In animal models of Diabetes mellitus (NOD mice), GM-CSF induces resistance by increasing the frequency of regulatory T cells which can suppress T cell proliferation through their T-cell receptors. GM-CSF treated mice were found to have a semi-mature phenotype of dendritic cells which were inefficient at inducing antigen specific cytotoxic T cells compared to controls. In multiple sclerosis research, EAE mice were completely protected from symptoms when injected with dendritic cells matured with TNF-α and antigen specific peptide compared to controls. T regulatory cells of mice treated with TNF-α produced IL-10, a cytokine which is able to inhibit the Th1 response therefore protecting against the Th1 dependent autoimmune EAE.