This article relies too much on references to primary sources. (November 2014) (Learn how and when to remove this template message)
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.
Dendritic cells in tolerogenic therapy
Tolerogenic therapies employ the inbuilt tolerance mechanisms of a class of immune cells called dendritic cells. 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.
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.
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.
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.
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.
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.
- Bluestone JA, Thomson AW, Shevach EM, Weiner HL (August 2007). "What does the future hold for cell-based tolerogenic therapy?". Nature Reviews. Immunology. 7 (8): 650–4. doi:10.1038/nri2137. PMID 17653127.
- Giannoukakis N, Phillips B, Finegold D, Harnaha J, Trucco M (September 2011). "Phase I (safety) study of autologous tolerogenic dendritic cells in type 1 diabetic patients". Diabetes Care. 34 (9): 2026–32. doi:10.2337/dc11-0472. PMC . PMID 21680720.
- Rutella S, Danese S, Leone G (September 2006). "Tolerogenic dendritic cells: cytokine modulation comes of age". Blood. 108 (5): 1435–40. doi:10.1182/blood-2006-03-006403. PMID 16684955.
- Thomson AW (February 2010). "Tolerogenic dendritic cells: all present and correct?". American Journal of Transplantation. 10 (2): 214–9. doi:10.1111/j.1600-6143.2009.02955.x. PMC . PMID 20055808.
- Morelli AE, Hackstein H, Thomson AW (October 2001). "Potential of tolerogenic dendritic cells for transplantation". Seminars in Immunology. 13 (5): 323–35. doi:10.1006/smim.2001.0328. PMID 11502167.
- Morelli AE, Thomson AW (August 2007). "Tolerogenic dendritic cells and the quest for transplant tolerance". Nature Reviews. Immunology. 7 (8): 610–21. doi:10.1038/nri2132. PMID 17627284.
- Hilkens CM, Isaacs JD (May 2013). "Tolerogenic dendritic cell therapy for rheumatoid arthritis: where are we now?". Clinical and Experimental Immunology. 172 (2): 148–57. doi:10.1111/cei.12038. PMC . PMID 23574312.
- Mannie MD, Curtis AD (May 2013). "Tolerogenic vaccines for Multiple sclerosis". Human Vaccines & Immunotherapeutics. 9 (5): 1032–8. doi:10.4161/hv.23685. PMC . PMID 23357858.
- Gaudreau S, Guindi C, Ménard M, Besin G, Dupuis G, Amrani A (September 2007). "Granulocyte-macrophage colony-stimulating factor prevents diabetes development in NOD mice by inducing tolerogenic dendritic cells that sustain the suppressive function of CD4+CD25+ regulatory T cells". Journal of Immunology. 179 (6): 3638–47. doi:10.4049/jimmunol.179.6.3638. PMID 17785799.
- Menges M, Rössner S, Voigtländer C, Schindler H, Kukutsch NA, Bogdan C, Erb K, Schuler G, Lutz MB (January 2002). "Repetitive injections of dendritic cells matured with tumor necrosis factor alpha induce antigen-specific protection of mice from autoimmunity". The Journal of Experimental Medicine. 195 (1): 15–21. doi:10.1084/jem.20011341. PMC . PMID 11781361.
- Monney L, Sabatos CA, Gaglia JL, Ryu A, Waldner H, Chernova T, Manning S, Greenfield EA, Coyle AJ, Sobel RA, Freeman GJ, Kuchroo VK (January 2002). "Th1-specific cell surface protein Tim-3 regulates macrophage activation and severity of an autoimmune disease". Nature. 415 (6871): 536–41. doi:10.1038/415536a. PMID 11823861.
- Gangi E, Vasu C, Cheatem D, Prabhakar BS (June 2005). "IL-10-producing CD4+CD25+ regulatory T cells play a critical role in granulocyte-macrophage colony-stimulating factor-induced suppression of experimental autoimmune thyroiditis". Journal of Immunology. 174 (11): 7006–13. doi:10.4049/jimmunol.174.11.7006. PMID 15905543.
- Moreau A, Varey E, Bériou G, Hill M, Bouchet-Delbos L, Segovia M, Cuturi MC (2012). "Tolerogenic dendritic cells and negative vaccination in transplantation: from rodents to clinical trials". Frontiers in Immunology. 3: 218. doi:10.3389/fimmu.2012.00218. PMID 22908013.