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| Tolerogenic therapy | |
|---|---|
| Specialty | Immunological |
Tolerogenic therapy aims to induceimmune tolerance where there is pathological or undesirable activation of the normalimmune response. This can occur, for example, when an allogeneictransplantation patient develops an immune reaction to donorantigens, or when the body responds inappropriately to selfantigens implicated inautoimmune diseases.[1] It must provide absence of specificantibodies for exactly that antigenes.
Research using animal models intransplantation and autoimmune diseases has led to early-phase human trials of tolerogenic therapy for autoimmune conditions likeType 1 Diabetes.[2]
Tolerogenic therapies employ the inbuilt tolerance mechanisms of a class of immune cells called dendritic cells.[3] 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.[5]
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 ofMHC class II-antigen complexes on the dendritic cell with T cell receptors on the T cell. This can induce T cellclonal deletion, T cell anergy or the proliferation ofregulatory 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.[4]
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.[6]
Studies have suggested a role for tolerogenic dendritic cells in the treatment of diseases like type 1 diabetes mellitus[7] and multiple sclerosis.[8]
In animal models ofDiabetes mellitus (NOD mice),GM-CSF induces resistance by increasing the frequency ofregulatory T cells which can suppressT cell proliferation through theirT-cell receptors. GM-CSF treated mice were found to have a semi-mature phenotype ofdendritic cells which were inefficient at inducing antigen specificcytotoxic T cells compared to controls.[9]
Inmultiple sclerosis research,EAE mice were completely protected from symptoms when injected with dendritic cells matured withTNF-α and antigen specific peptide compared to controls.[10] T regulatory cells of mice treated with TNF-α producedIL-10, acytokine which is able to inhibit theTh1 response therefore protecting against the Th1 dependentautoimmune EAE.[11]
Mouse models ofautoimmune thyroiditis showed that a semi-mature phenotype of dendritic cells is maintained after mousethyroglobulin immunization in GM-CSF treated but not control mice. IL-10 produced by T regulatory cells was important in suppressing the mouse thyroglobulin specific T cell response and therefore protecting against Experimental autoimmune thyroiditis in mice.[12]
Phase I studies into the safety and efficacy of tolerogenic DC therapy in humans have demonstrated the appropriateness of the therapy for further research. Future research will consider the effectiveness of tolerogenic therapies in a number of planned clinical trials into autoimmune diseases.[13]