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.[1] 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.[2]
Dendritic cells in tolerogenic therapy
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:
Mature
dendritic cells are
immunogenic. Their physiological role is to bridge innate and adaptive immune responses by presenting antigens to
T-lymphocytes. In the presence of an inflammatory environment, which usually accompanies infection or tissue ‘danger’ signals, dendritic cells are activated (mature) and present foreign antigens to the T cells, initiating an appropriate immune response.
Semi-mature dendritic cells are tolerogenic. Conditions including the absence of an inflammatory environment result in the incomplete maturation of dendritic cells. Their influence on T-lymphocytes follows a different mechanism which induces tolerance, rather than immunogenicity.[4]
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 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.[4]
Mechanisms of therapy
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]
Animal models
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
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.[10] 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.[11]
Mouse models of
autoimmune thyroiditis showed that a semi-mature phenotype of dendritic cells is maintained after mouse
thyroglobulin 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]