Thymoglobulin

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Thymoglobulin (manufactured by sanofi) is an anti-human thymocyte immunoglobulin preparation made of purified polyclonal antibodies derived from rabbits. While these antibodies have a variety of specificities, their main mechanism of immunosuppression is through depletion of T cells. Thymoglobulin is currently approved for clinical use in Europe and the United States for renal allograft rejection, prevention of graft-vs.-host disease, and conditions involving bone marrow failure, including aplastic anemia and has additional off-label uses.

Aplastic anaemia is a rare disease in which the bone marrow and the hematopoietic stem cells that reside there are damaged. This causes a deficiency of all three blood cell types (pancytopenia): red blood cells (anemia), white blood cells (leukopenia), and platelets (thrombocytopenia). Aplastic refers to the inability of stem cells to generate mature blood cells.

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History of Antithymocyte globulin

Antithymocyte globulin (ATG) was originally developed as one of various tested preparations of antilymphocyte globulin (ALG) specifically generated against human lymphocytes within the thymus, or thymocytes . The purpose of this research was largely to produce an effective immunosuppressive agent safe for use in humans. Since the discovery of a link between antilymphocyte serum (ALS) and lymphocyte depletion by Metchnikoff in 1899, various studies have demonstrated the immunosuppressive ability of ALG and ATG. Experiments on ALS that confirmed its efficacy in lymphocyte depletion led to testing of different types of preparations including ALG, which were ALS produced against human lymphocytes, and ATG. [1]

Lymphocyte Subtype of white blood cell

A lymphocyte is one of the subtypes of white blood cell in a vertebrate's immune system. Lymphocytes include natural killer cells, T cells, and B cells. They are the main type of cell found in lymph, which prompted the name "lymphocyte".

Thymocytes are hematopoietic progenitor cells present in the thymus. Thymopoiesis is the process in the thymus by which thymocytes differentiate into mature T lymphocytes. The primary function of thymocytes is the generation of T lymphocytes. The thymus provides an inductive environment, which allows for the development and selection of physiologically useful T cells. The processes of beta-selection, positive selection, and negative selection shape the population of thymocytes into a peripheral pool of T cells that are able to respond to foreign pathogens and are immunologically tolerant towards self antigens.

A number of studies conducted in the 1960s, including studies by Starzl et al. and Mathe et al., resulted in promising data for the clinical use of ALG for preserving short-term and long-term kidney function in patients immediately after human kidney transplantation. Use of equine ALG was also found to be efficacious in preventing acute graft-vs.-host-disease in patients’ post-allogeneic bone marrow transplantation. [1] Experimentation with ALG and ATG preparations from different sources followed, leading to testing of ATG derived from rabbit serum. Thymoglobulin was the first commercial rabbit-derived ATG to be introduced in Europe and the US in the 1980s. [1] Due to its demonstrated efficacy as an immunosuppressive agent, it remains a commonly used ATG for induction therapy and treatment of other associated conditions, such as graft-vs.-host disease and aplastic anemia.

Graft-versus-host disease (GvHD) is a medical complication following the receipt of transplanted tissue from a genetically different person. GvHD is commonly associated with stem cell transplants such as those that occur with bone marrow transplants. GvHD also applies to other forms of transplanted tissues such as solid organ transplants.

Mechanism of Immunosuppression

As an rATG, thymoglobulin consists of polyclonal antibodies, which, unlike monoclonal antibodies, target a large variety of immune cell surface proteins, including B and T lymphocyte, natural killer cell, and plasma cell surface antigens. [2] However, its efficacy as an immunosuppressive agent is primarily through rapid induced apoptosis of CD3+ T cells present in the bloodstream. [3] [1] Even at low levels of concentration (up to 1 ug/mL), rATG T-cell depletive ability is still sound, but higher concentrations of ATG can induce lysis of T lymphocytes through the classical complement pathway along with B cell and NK cell depletion as well . [2] Thymoglobulin has also demonstrated the ability to induce expression of a number of regulatory cell markers in vitro, including CD25, GITR, and CTLA-4 (aka CD152, functions as immune checkpoint, downregulates immune response). [2] Recent research has suggested that Thymoglobulin may also contribute to T-cell anergy, in which T-cells remain inactive, though further research must be done to confirm this interaction.

Clinical Applications

Thymoglobulin is commonly used to prevent and treat acute rejection and increase graft survival in solid organ transplantation, especially kidney, liver, pancreas, and heart transplantation. [1] As multiple studies have demonstrated both its efficacy and safety in a clinical setting, it is also used in different minimization regimens to reduce the application of higher risk immunosuppressive agents such as corticosteroids and calcineurin inhibitors (CNIs) in solid organ transplantation. Because both corticosteroids and CNIs have been found to potentially cause long-term adverse effects in the body, a multitude of studies have been conducted to examine the efficacy of thymoglobulin in SOT either with minimal usage or without the use of either agent. [2] [1] Findings have indicated that use of Thymoglobulin alone minimizes risk of adverse effects and thus improves long-term outcomes for transplant patients. [1]

Organ transplantation moving of an organ from one body or body region to another

Organ transplantation is a medical procedure in which an organ is removed from one body and placed in the body of a recipient, to replace a damaged or missing organ. The donor and recipient may be at the same location, or organs may be transported from a donor site to another location. Organs and/or tissues that are transplanted within the same person's body are called autografts. Transplants that are recently performed between two subjects of the same species are called allografts. Allografts can either be from a living or cadaveric source.

Thymoglobulin is also an effective agent for preventing graft-vs.-host disease in patients receiving haematopoietic stem cell transplantation (HSCT). GVHD is a condition in which immune cells within the graft attack host cells and cause tissue damage. It is considered a major obstacle to successful HSCT. [1] The T-cell depleting activity of thymoglobulin has proved to be useful in preventing GVHD.

Multiple studies have indicated that Thymoglobulin is favored in comparison to other induction agents for patients who have increased risk of developing post-transplant complications, such as elderly patients, patients undergoing a repeat transplantation, and patients in which minimization of use of steroids or CNIs post-operation is recommended. [2]

Related Research Articles

Immunosuppressive drug Agents that suppress immune function by one of several mechanisms of action. Classical cytotoxic immunosuppressants act by inhibiting dna synthesis. Others may act through activation of t-cells or by inhibiting the activation of helper cells. While

Immunosuppressive drugs or immunosuppressive agents or antirejection medications are drugs that inhibit or prevent activity of the immune system.

Transplant rejection

Transplant rejection occurs when transplanted tissue is rejected by the recipient's immune system, which destroys the transplanted tissue. Transplant rejection can be lessened by determining the molecular similitude between donor and recipient and by use of immunosuppressant drugs after transplant.

Post-transplant lymphoproliferative disorder (PTLD) is the name given to a B-cell proliferation due to therapeutic immunosuppression after organ transplantation. These patients may develop infectious mononucleosis-like lesions or polyclonal polymorphic B-cell hyperplasia. Some of these B-cells may undergo mutations which will render them malignant, giving rise to a lymphoma.

Anti-thymocyte globulin (ATG) is an infusion of horse or rabbit-derived antibodies against human T cells, which is used in the prevention and treatment of acute rejection in organ transplantation and therapy of aplastic anemia.

Anti-lymphocyte globulin (ALG) is an infusion of animal- antibodies against human T cells which is used in the treatment of acute rejection in organ transplantation. Its use was first reported by Thomas Starzl in 1966. Its use in transplant was supplanted by thymoglobulin between 1984 and 1999.

Hematopoietic stem cell transplantation

Hematopoietic stem cell transplantation (HSCT) is the transplantation of multipotent hematopoietic stem cells, usually derived from bone marrow, peripheral blood, or umbilical cord blood. It may be autologous, allogeneic or syngeneic.

Alloimmunity is an immune response to nonself antigens from members of the same species, which are called alloantigens or isoantigens. Two major types of alloantigens are blood group antigens and histocompatibility antigens. In alloimmunity, the body creates antibodies against the alloantigens, attacking transfused blood, allotransplanted tissue, and even the fetus in some cases. Alloimmune (isoimmune) response results in graft rejection, which is manifested as deterioration or complete loss of graft function. In contrast, autoimmunity is an immune response to the self's own antigens. Alloimmunization (isoimmunization) is the process of becoming alloimmune, that is, developing the relevant antibodies for the first time.

Cytopenia is a reduction in the number of mature blood cells caused by antibodies that destroy them. This results in a reduction of mature blood cells in the body. It is common in cancer patients being treated with radiation and/or chemotherapy.

Alemtuzumab pharmaceutical drug

Alemtuzumab is a drug used in the treatment of chronic lymphocytic leukemia (CLL), cutaneous T-cell lymphoma (CTCL) and T-cell lymphoma under the trade names Campath, MabCampath and Campath-1H, and in the treatment of multiple sclerosis as Lemtrada. It is also used as an anti-rejection agent in some conditioning regimens for bone marrow transplantation, kidney transplantation and islet cell transplantation.

<i>BK virus</i> species of virus

The BK virus is a member of the polyomavirus family. Past infection with the BK virus is widespread, but significant consequences of infection are uncommon, with the exception of the immunocompromised and the immunosuppressed.

Muromonab-CD3 is an immunosuppressant drug given to reduce acute rejection in patients with organ transplants. It is a monoclonal antibody targeted at the CD3 receptor, a membrane protein on the surface of T cells. It was the first monoclonal antibody to be approved for clinical use in humans.

Gavilimomab is a mouse monoclonal antibody intended for use as an immunosuppressive biologic treatment of glucocorticoid-resistant graft versus host disease. It binds to the antigen CD147. Gavilimomab proved slightly less effective than standard antithymocyte globulin therapy.

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.

TOL101, is a murine-monoclonal antibody specific for the human αβ T cell receptor. In 2010 it was an Investigational New Drug under development by Tolera Therapeutics, Inc.

Guo Mei is a hematologist and associate director of 307th Hospital of Chinese People’s Liberation Army and deputy director of Radiation Research Institute.

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.

T-cell depletion (TCD) is the process of T cell removal or reduction, which alters the immune system and its response. Depletion can occur naturally or be induced for treatment purposes. TCD can reduce the risk of graft-versus-host disease (GVHD), which is a common issue in transplants. The idea that TCD of the allograft can eliminate GVHD was first introduced in 1958. In humans the first TCD was performed in severe combined immunodeficiency patients.

Veto cells are white blood cells that have a selective immunomodulation properties. Veto cells were first described in 1979 as cells that “can prevent generation of cytotoxic lymphocytes by normal spleen cells against self-antigens”. Hence, veto cells delete T cells that recognize the veto cells.

References

  1. 1 2 3 4 5 6 7 8 Gaber, A. Osama; Monaco, Anthony P.; Russell, James A.; Lebranchu, Yvon; Mohty, Mohamad (2012-09-17). "Rabbit Antithymocyte Globulin (Thymoglobulin®)". Drugs. 70 (6): 691–732. doi:10.2165/11315940-000000000-00000. ISSN   0012-6667. PMID   20394456.
  2. 1 2 3 4 5 Mourad, Georges; Morelon, Emmanuel; Noël, Christian; Glotz, Denis; Lebranchu, Yvon (2012-09-01). "The role of Thymoglobulin induction in kidney transplantation: an update". Clinical Transplantation. 26 (5): E450–E464. doi:10.1111/ctr.12021. ISSN   1399-0012. PMID   23061755.
  3. Hardinger, Karen L.; Brennan, Daniel C.; Klein, Christina L. (2013-07-01). "Selection of induction therapy in kidney transplantation". Transplant International. 26 (7): 662–672. doi:10.1111/tri.12043. ISSN   1432-2277. PMID   23279211.