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.

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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]

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.

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 (SOT), 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]

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

Aplastic anemia is a disease in which the body fails to produce blood cells in sufficient numbers. Blood cells are produced in the bone marrow by stem cells that reside there. Aplastic anaemia causes a deficiency of all blood cell types: red blood cells, white blood cells, and platelets.

Immunosuppressive drug

Immunosuppressive drugs, also known as immunosuppressive agents, immunosuppressants and antirejection medications are drugs that inhibit or prevent activity of the immune system.

Transplant rejection Rejection of transplanted tissue by the recipients immune system

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 Medical procedure to replace blood or immune stem cells

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.

Graft-versus-host disease

Graft-versus-host disease (GvHD) is a syndrome, characterized by inflammation in different organs, with the specificity of epithelial cell apoptosis and crypt drop out. GvHD is commonly associated with bone marrow transplants and stem cell transplants. GvHD also applies to other forms of transplanted tissues such as solid organ transplants.

Cyclophosphamide Medication used as chemotherapy and to suppress the immune system

Cyclophosphamide (CP), also known as cytophosphane among other names, is a medication used as chemotherapy and to suppress the immune system. As chemotherapy it is used to treat lymphoma, multiple myeloma, leukemia, ovarian cancer, breast cancer, small cell lung cancer, neuroblastoma, and sarcoma. As an immune suppressor it is used in nephrotic syndrome, granulomatosis with polyangiitis, and following organ transplant, among other conditions. It is taken by mouth or injection into a vein.

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. It is common in cancer patients being treated with radiation and/or chemotherapy.

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.

Primary immunodeficiencies are disorders in which part of the body's immune system is missing or does not function normally. To be considered a primary immunodeficiency (PID), the cause of the immune deficiency must not be secondary in nature. Most primary immunodeficiencies are genetic disorders; the majority are diagnosed in children under the age of one, although milder forms may not be recognized until adulthood. While there are over 430 recognized PIDs as of 2019, most are very rare. About 1 in 500 people in the United States are born with a primary immunodeficiency. Immune deficiencies can result in persistent or recurring infections, auto-inflammatory disorders, tumors, and disorders of various organs. There are currently limited treatments available for these conditions; most are specific to a particular type of PID. Research is currently evaluating the use of stem cell transplants (HSCT) and experimental gene therapies as avenues for treatment in limited subsets of PIDs.

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.

Graft-versus-tumor effect (GvT) appears after allogeneic hematopoietic stem cell transplantation (HSCT). The graft contains donor T cells that can be beneficial for the recipient by eliminating residual malignant cells. GvT might develop after recognizing tumor-specific or recipient-specific alloantigens. It could lead to remission or immune control of hematologic malignancies. This effect applies in myeloma and lymphoid leukemias, lymphoma, multiple myeloma and possibly breast cancer. It is closely linked with graft-versus-host disease (GvHD), as the underlying principle of alloimmunity is the same. CD4+CD25+ regulatory T cells (Treg) can be used to suppress GvHD without loss of beneficial GvT effect. The biology of GvT response still isn't fully understood but it is probable that the reaction with polymorphic minor histocompatibility antigens expressed either specifically on hematopoietic cells or more widely on a number of tissue cells or tumor-associated antigens is involved. This response is mediated largely by cytotoxic T lymphocytes (CTL) but it can be employed by natural killers as separate effectors, particularly in T-cell-depleted HLA-haploidentical HSCT.

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.

Shimon Slavin

Shimon Slavin, M.D., is an Israeli professor of medicine. Slavin pioneered the use of immunotherapy mediated by allogeneic donor lymphocytes and innovative methods for stem cell transplantation for the cure of hematological malignancies and solid tumors, and using hematopoietic stem cells for induction of transplantation tolerance to bone marrow and donor allografts.

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.
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