Another application of cell therapy: induction of immune tolerance
2020-06-29
As everyone knows, the immune system is the body's guardian. Immune cells are an indispensable part of it. On the one hand, it recognizes and removes foreign invading bacteria, viruses, etc. On the other hand, it also removes tumor cells, senescent cells, apoptotic cells or other harmful components that have undergone mutations in the body. Off. In the maintenance of human health, immune cells have made great contributions!
However, anything in the world is always too late. Abnormal immunity/excessive immunity (such as autoimmune diseases, GVHD, transplant rejection and hypersensitivity), these are problems within the immune system, which greatly affect people's health and quality of life. If you use traditional treatment (long-term or even lifelong use of immunosuppressive agents, etc.), it will lead to a decline in immunity, easy infection and tumors.
If the body can be induced to develop specific immune tolerance, this problem can be overcome and the use of immunosuppressants can be reduced. Cell therapy is one of the new methods.
This article reviews all aspects of current cell therapy for autoimmune diseases, discusses the advantages and disadvantages of different types of cell therapy, and explores new directions and future prospects for these tolerant therapies.
1 Immune imbalance: cancer and autoimmune diseases
In general, a healthy immune system should be in a dynamic balance, and the pro-inflammatory and anti-inflammatory reactions interact to jointly maintain immune homeostasis.
Ideally, the immune system maintains non-responsiveness to self-antigens and environmentally friendly factors (allergens, symbiotic flora, etc.) through central tolerance and peripheral tolerance. During the process of pathogen invasion or mutation of its own cells, the immune system starts and begins to recognize and eliminate these pathogenic factors. After successful elimination, the immune system will return to immune steady state again.
However, if the body cannot effectively achieve immune homeostasis, continuous overactive or suppressed immunity may lead to the occurrence of autoimmune diseases or cancer.
Two types of immune imbalances: cancer and autoimmune diseases
As the saying goes: too much! Immune to recognize its own abnormal ability is too weak to be susceptible to cancer, excessive reaction to self antigens or harmless antigens will lead to autoimmune diseases.
Immune dysfunction is a difficult problem affecting human health. As immune disorders in two different directions-cancer and autoimmune diseases-there may be lessons for each other in the pathogenesis and treatment methods.
For example, malignant tumors are “abnormal tissues”, but are sometimes regarded as “good people” by the immune system and have “good people’s certificates” of normal healthy tissues; while autoimmunity breaks the immune tolerance to self-antigens because “internal "Struggle" leads to tissue damage.
The treatment of autoimmune diseases can refer to how tumor cells immune escape, and the treatment of tumors can refer to autoimmunity to break the immune tolerance to "good people's card".
Autoimmune diseases, excessive inflammation caused by organ transplantation, hypersensitivity, etc. may threaten the lives of patients, and it makes sense to restore immune tolerance (for self-antigens or induction to specific antigens).
Relying on traditional drug induction does not seem to work, so what about cell therapy? The cell therapy that has become popular all over the world has made a revolutionary breakthrough, especially CAR-T cells for the treatment of hematological tumors. But in the fields of autoimmune diseases, organ transplant rejection, GVHD and so on, it is relatively poor.
We can give it a try, cell therapy is expected to achieve long-term remission of the disease, or it may become a key technology in the field of tolerance.
2 Strategy 1: Immunization reconstruction
Just like the discovery of stem cells, we must start with bone marrow transplantation. In the history of science, many important discoveries are accidental discoveries.
In 1977, when bone marrow transplantation was used to treat aplastic anemia (AA), it was unexpectedly found that rheumatoid arthritis (RA) was also relieved, and the prelude to hematopoietic stem cell transplantation (HSCT) treatment of severe autoimmune diseases was opened.
In 1995, hematopoietic stem cell transplantation began to be applied to severe autoimmune diseases that were not effective in conventional treatment. Its purpose is twofold: one is to clear self-reactive immune cells, and the other is to rebuild a self-tolerant immune system.
Clinical studies have shown that for severe autoimmune diseases (such as multiple sclerosis and systemic sclerosis), the effect of autologous hematopoietic stem cell transplantation is better than conventional treatment.
Without long-term use of immunosuppressive agents, hematopoietic stem cell transplantation can achieve long-term relief of autoimmune diseases, although some patients will still relapse after transplantation.
However, at present, hematopoietic stem cell transplantation is still a high-risk treatment method, and transplantation failure and infection and complications may still limit the survival rate of patients. Therefore, hematopoietic stem cell transplantation can currently be used with caution in patients with severe conditions and at risk of death.
3 Strategy 2: Eliminate autoimmune cells
The characteristic of autoimmunity is the presence of autoantibodies or autoreactive T cells.
Clear several common cells of autoimmunity
T cell vaccine
T cell vaccine (TCV) is an individualized cell therapy that uses inactivated self-reactive T cells as an immunogenic drug to induce the body to clear self-reactive T cells.
The concept of TCV was first proposed in 1981. The researchers found that the irradiated MBP+ (human brain myelin basic protein) specific T cells not only did not cause EAE (autoimmune encephalomyelitis), but also induced EAE. resistance.
Past studies have shown that TCV has a role in both autoimmune diseases and GVHD animal models, including experimental autoimmune encephalomyelitis, lupus, autoimmune uveitis, type 1 diabetes, autoimmune thyroiditis, and collagen induction Arthritis, etc.
In addition, TCV has also shown certain safety and effectiveness in multiple clinical trials, including multiple sclerosis, rheumatoid arthritis, systemic lupus erythematosus, and amyotrophic lateral sclerosis (ALS, gradual freezing disease).
CAR-T cells
The existence of autoantibodies is a feature of many autoimmune diseases and has been widely used in disease diagnosis, and B cells are one of the important targets for the treatment of autoimmune diseases.
At present, antibody drugs targeting B cells are in clinical use or are under development, including monoclonal antibodies to CD19, CD20 and CD22. However, it is particularly inadequate and requires repeated administration, and drug resistance may also occur.
CAR-T therapy has made breakthrough progress in the treatment of B-cell hematoma, which can exert an effect in the body to eliminate B cells for a long time. CD19+CAR-T cells can eradicate the autoantibodies produced by B cells in the mouse lupus model and prolong the life of mice.
However, targeting B-cell antigens will kill normal B-cells and weaken the body's resistance. Patients need to continue to be injected with immunoglobulins.
Therefore, CAR-T therapy is unlikely to be used to treat autoimmune diseases.
CAAR-T cells
Since CAR-T therapy is not suitable for the treatment of autoimmune diseases, researchers have developed chimeric autoantibody receptor (CAAR) therapy. Speaking of CAAR, it is actually similar to a typical CAR, except that its antigen-binding domain can target self-reactive B cell receptors.
The researchers constructed Dsg3+CAAR-T cells through desmosome sugar egg 3, which can effectively eliminate anti-Dsg3 specific B cells. Compared with other B-cell therapies, CAAR technology only eliminates self-reactive B cells, avoiding the complete elimination of B cells, and the risk of immunoglobulin decline and opportunistic infections.
4 Strategy 3: Inducing autoimmune tolerance
Clinical application of various tolAPC methods
Antigen-presenting cells (APCs), including DC cells and monocytes/macrophages, play an important role in regulating innate immunity and acquired immunity, as well as the two-way regulation of immunity, which can induce both immune activation and immune tolerance. Note: tolerogenic antigen-presenting cell, tolAPC
tolDC cell therapy
In autoimmunity, DC cells can produce pro-inflammatory factors and promote the activation of self-reactive T cells. DC cells promote immune response or promote immune tolerance, which is related to the maturation state of DC cells. Both iDC (immature dendritic cells) and smDC (semi-mature dendritic cells) are pro-tolerant.
TolDC cells (tolerogenic dendritic cells) can be iDC or smDC. Among them, dexamethasone and vitamin A/vitamin D3 can stabilize the function of tolDC cells, and induction of semi-maturity can make tolDC have more powerful antigen presentation and homing ability.
TolDC cells induce immune tolerance by inducing T/B cell incompetence or regulatory lymphocytes. TolAPC cells, represented by tolDC cells, have shown certain efficacy in the clinical studies of treating Crohn's disease and rheumatoid arthritis.
TolDC therapy generally uses autologous cells.
Mreg cell therapy
Mreg cells (regulatory macrophages) are generally used to induce allogeneic tolerance during organ transplantation. Transplant acceptance inducing cells (TAIC) are mainly a class of macrophages with immunomodulatory activity. Researchers using TAIC therapy can eliminate some allogeneic reactions.
TAIC can come from the donated spleen or the peripheral blood of healthy donors, but its effectiveness remains to be studied.
Treg and CAR-Treg cell therapy
Regulatory T cells (Treg) are important regulator cells for maintaining peripheral immune tolerance.
Treg cells have shown certain effectiveness in clinical trials such as GVHD and type 1 diabetes. However, Treg cells require relatively high doses, which can cause widespread immunosuppression, leading to increased infection or tumor susceptibility.
In recent years, CAR-Treg (chimeric antigen receptor regulatory T cells) has made great progress in anti-inflammatory and immune tolerance. Antigen-specific Treg is more efficient than Treg, which means fewer cells are needed to obtain the desired therapeutic effect.
CAR-Treg therapy is very likely to be the next hot spot in the development of anti-inflammatory and tolerant therapies.
CAR-Treg can target different antigens
Mesenchymal stem cell therapy
Mesenchymal stromal/stem cells (MSCs) are widely present in various connective tissues, have multi-directional differentiation potential, and have powerful immune regulation and tissue repair functions.
Therefore, MSCs have become a research hotspot in the fields of autoimmune diseases, organ transplantation, GVHD, etc. There are many clinical trials related to MSCs, including the treatment of diabetes, rheumatoid arthritis, Behcet's disease, organ transplantation, systemic lupus erythematosus and other diseases.
5 Summary
At present, there are many problems with induced tolerance cell therapy, such as autologous cells may have genetic defects, allogeneic cells have rejection and short survival period, which affects the treatment effect. After input, the regulatory cells become effector cells is also a very troublesome problem. All these issues are for us to study. In addition to cell therapy, cell-like materials based on immune checkpoints may also be an effective strategy. Existing scholars have explored the induction of immune tolerance through nanomaterials, and induced the apoptosis of self-reactive immune cells by synthesizing cell-like materials with personalized and regulatory functions, which is expected to achieve the restoration of immune tolerance and is more conducive to industrialization.
In any case, cell therapy or biological material induced immune tolerance technology will undoubtedly play an increasingly important role in future medical technology.
