Tolerogenic therapy

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Tolerogenic therapy
Specialty immunological

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.

Contents

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:

  1. 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.
  2. 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 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. [9]

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]

See also

Related Research Articles

Autoimmunity is the system of immune responses of an organism against its own healthy cells, tissues and other body normal constituents. Any disease that results from such an aberrant immune response is termed an "autoimmune disease". Prominent examples include celiac disease, post-infectious IBS, diabetes mellitus type 1, Henloch Scholein Pupura (HSP) sarcoidosis, systemic lupus erythematosus (SLE), Sjögren syndrome, eosinophilic granulomatosis with polyangiitis, Hashimoto's thyroiditis, Graves' disease, idiopathic thrombocytopenic purpura, Addison's disease, rheumatoid arthritis (RA), ankylosing spondylitis, polymyositis (PM), dermatomyositis (DM) and multiple sclerosis (MS). Autoimmune diseases are very often treated with steroids.

Dendritic cell

Dendritic cells (DCs) are antigen-presenting cells of the mammalian immune system. Their main function is to process antigen material and present it on the cell surface to the T cells of the immune system. They act as messengers between the innate and the adaptive immune systems.

Immunotherapy or biological therapy is the treatment of disease by activating or suppressing the immune system. Immunotherapies designed to elicit or amplify an immune response are classified as activation immunotherapies, while immunotherapies that reduce or suppress are classified as suppression immunotherapies.

The regulatory T cells, formerly known as suppressor T cells, are a subpopulation of T cells that modulate the immune system, maintain tolerance to self-antigens, and prevent autoimmune disease. Tregs are immunosuppressive and generally suppress or downregulate induction and proliferation of effector T cells. Tregs express the biomarkers CD4, FOXP3, and CD25 and are thought to be derived from the same lineage as naïve CD4 cells. Because effector T cells also express CD4 and CD25, Tregs are very difficult to effectively discern from effector CD4+, making them difficult to study. Recent research has found that the cytokine TGFβ is essential for Tregs to differentiate from naïve CD4+ cells and is important in maintaining Treg homeostasis.

FOXP3 Immune response protein

FOXP3, also known as scurfin, is a protein involved in immune system responses. A member of the FOX protein family, FOXP3 appears to function as a master regulator of the regulatory pathway in the development and function of regulatory T cells. Regulatory T cells generally turn the immune response down. In cancer, an excess of regulatory T cell activity can prevent the immune system from destroying cancer cells. In autoimmune disease, a deficiency of regulatory T cell activity can allow other autoimmune cells to attack the body's own tissues.

CTLA-4

CTLA4 or CTLA-4, also known as CD152, is a protein receptor that functions as an immune checkpoint and downregulates immune responses. CTLA4 is constitutively expressed in regulatory T cells but only upregulated in conventional T cells after activation – a phenomenon which is particularly notable in cancers. It acts as an "off" switch when bound to CD80 or CD86 on the surface of antigen-presenting cells.

Immune tolerance, or immunological tolerance, or immunotolerance, is a state of unresponsiveness of the immune system to substances or tissue that have the capacity to elicit an immune response in a given organism. It is induced by prior exposure to that specific antigen and contrasts with conventional immune-mediated elimination of foreign antigens. Tolerance is classified into central tolerance or peripheral tolerance depending on where the state is originally induced—in the thymus and bone marrow (central) or in other tissues and lymph nodes (peripheral). The mechanisms by which these forms of tolerance are established are distinct, but the resulting effect is similar.

Certain sites of the human body have immune privilege, meaning they are able to tolerate the introduction of antigens without eliciting an inflammatory immune response. Tissue grafts are normally recognised as foreign antigen by the body and attacked by the immune system. However, in immune privileged sites, tissue grafts can survive for extended periods of time without rejection occurring. Immunologically privileged sites include:

Peripheral tolerance is the second branch of immunological tolerance, after central tolerance. It takes place in the immune periphery. Its main purpose is to ensure that self-reactive T and B cells which escaped central tolerance do not cause autoimmune disease.

Gamma delta T cells are T cells that have a distinctive T-cell receptor (TCR) on their surface. Most T cells are αβ T cells with TCR composed of two glycoprotein chains called α (alpha) and β (beta) TCR chains. In contrast, gamma delta (γδ) T cells have a TCR that is made up of one γ (gamma) chain and one δ (delta) chain. This group of T cells is usually less common than αβ T cells, but are at their highest abundance in the gut mucosa, within a population of lymphocytes known as intraepithelial lymphocytes (IELs).

LAG3

Lymphocyte-activation gene 3, also known as LAG-3, is a protein which in humans is encoded by the LAG3 gene. LAG3, which was discovered in 1990 and was designated CD223 after the Seventh Human Leucocyte Differentiation Antigen Workshop in 2000, is a cell surface molecule with diverse biologic effects on T cell function. It is an immune checkpoint receptor and as such is the target of various drug development programs by pharmaceutical companies seeking to develop new treatments for cancer and autoimmune disorders. In soluble form it is also being developed as a cancer drug in its own right.

Protective autoimmunity is a condition in which cells of the adaptive immune system contribute to maintenance of the functional integrity of a tissue, or facilitate its repair following an insult. The term ‘protective autoimmunity’ was coined by Prof. Michal Schwartz of the Weizmann Institute of Science (Israel), whose pioneering studies were the first to demonstrate that autoimmune T lymphocytes can have a beneficial role in repair, following an injury to the central nervous system (CNS). Most of the studies on the phenomenon of protective autoimmunity were conducted in experimental settings of various CNS pathologies and thus reside within the scientific discipline of neuroimmunology.

Autoimmune disease Abnormal immune response to a normal body part

An autoimmune disease is a condition arising from an abnormal immune response to a functioning body part. There are at least 80 types of autoimmune diseases. Nearly any body part can be involved. Common symptoms include low grade fever and feeling tired. Often symptoms come and go.

T helper 3 cells (Th3) are a subset of T lymphocytes with immunoregulary and immunosupressive functions, that can be induced by administration of foreign oral antigen. Th3 cells act mainly through the secretion of anti-inflammatory cytokine transforming growth factor beta (TGF-β). Th3 have been described both in mice and human as CD4+FoxP3- regulatory T cells. Th3 cells were first described in research focusing on oral tolerance in the experimental autoimmune encephalitis (EAE) mouse model and later described as CD4+CD25-FoxP3-LAP+ cells, that can be induced in the gut by oral antigen through T cell receptor (TCR) signalling.

Short Course Immune Induction Therapy or SCIIT, is a therapeutic strategy employing rapid, specific, short term-modulation of the immune system using a therapeutic agent to induce T-cell non-responsiveness, also known as operational tolerance. As an alternative strategy to immunosuppression and antigen-specific tolerance inducing therapies, the primary goal of SCIIT is to re-establish or induce peripheral immune tolerance in the context of autoimmune disease and transplant rejection through the use of biological agents. In recent years, SCIIT has received increasing attention in clinical and research settings as an alternative to immunosuppressive drugs currently used in the clinic, drugs which put the patients at risk of developing infection, cancer, and cardiovascular disease.

Regulatory B cells represent a small population of B cells which participates in immunomodulations and in suppression of immune responses. These cells regulate the immune system by different mechanisms. The main mechanism is a production of anti-inflammatory cytokine interleukin 10 (IL-10). The regulatory effects of Bregs were described in various models of inflammation, autoimmune diseases, transplantation reactions and in anti-tumor immunity.

Type 1 regulatory cells or Tr1 (TR1) cells are a class of regulatory T cells participating in peripheral immunity as a subsets of CD4+ T cells. Tr1 cells regulate tolerance towards antigens of any origin. Tr1 cells are self or non-self antigen specific and their key role is to induce and maintain peripheral tolerance and suppress tissue inflammation in autoimmunity and graft vs. host disease.

Infectious tolerance is a term referring to a phenomenon where a tolerance-inducing state is transferred from one cell population to another. It can be induced in many ways; although it is often artificially induced, it is a natural in vivo process. A number of research deal with the development of a strategy utilizing this phenomenon in transplantation immunology. The goal is to achieve long-term tolerance of the transplant through short-term therapy.

Dendritic cells (DCs) are powerful antigen presenting cells for the induction of antigen specific T cell response. DC vaccine has been introduced as a new therapeutic strategy in cancer patients. DC-based immunotherapy is safe and can promote antitumor immune responses and prolonged survival of cancer patients.

Tolerogenic dendritic cells are heterogenous pool of dendritic cells with immuno-suppressive properties, priming immune system into tolerogenic state against various antigens. These tolerogenic effects are mostly mediated through regulation of T cells such as inducing T cell anergy, T cell apoptosis and induction of Tregs. Tol-DCs also affect local micro-environment toward tolerogenic state by producing anti-inflammatory cytokines.

References

  1. ↑ 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. S2CID   10713893.
  2. ↑ 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   3161299 . PMID   21680720.
  3. ↑ 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.
  4. 1 2 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   2860031 . PMID   20055808.
  5. ↑ 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.
  6. ↑ 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. S2CID   6587584.
  7. ↑ 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   3628318 . PMID   23574312.
  8. ↑ Mannie MD, Curtis AD (May 2013). "Tolerogenic vaccines for Multiple sclerosis". Human Vaccines & Immunotherapeutics. 9 (5): 1032–8. doi:10.4161/hv.23685. PMC   3899137 . PMID   23357858.
  9. ↑ 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.
  10. ↑ 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   2196016 . PMID   11781361.
  11. ↑ 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. S2CID   4403803.
  12. ↑ 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.
  13. ↑ 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 . PMC   3414843 . PMID   22908013.
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