Anti-thymocyte globulin
Encyclopedia
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 transplant
ation and therapy of aplastic anemia
.
ATG administration very substantially reduces immune competence in patients with normal immune systems, through a combination of actions, some explicitly understood and some more hypothetical. rATG in particular effects large reductions (through cell lysis) in the number of circulating T-lymphocytes, hence preventing (or at least delaying) the cellular rejection of transplanted organs. However, medical opinion remains divided as to when the benefit of this profound reduction in T-cells outweighs the concomitant increased risks of infection and malignancy.
In the United States
it is frequently given at the time of the transplant to prevent graft-versus-host disease
, although many European centers prefer to reserve its use for the treatment of steroid
-resistant acute rejection, as European centres generally serve more homogeneous populations and rejection tends to be less of a problem.
, and has been thought to increase the risk of post-transplant lymphoproliferative disorder
(PTLD); however, this association may not apply when lower dosing regimens are used. There is some evidence to suggest that inducing immunosuppression with rATG at organ transplantation may create conditions in the patient's immune system favorable to the development of immunological tolerance, but the exact basis for such a development remains largely speculative. Temporary depletion of the T-cell population at the time of the transplant also risks delayed acute rejection, which may be missed and cause severe damage to the graft.
Anti-IL-2Rα receptor antibodies such as basiliximab
and daclizumab
are increasingly being used in place of ATG as an induction therapy, as they do not cause cytokine release syndrome and (theoretically) improve the development of tolerance.
The cytokine release syndrome associated with ATG administration frequently causes high grade fevers (over 39oC), chills, and possibly rigors during administration, for which reason steroids (normally methylprednisolone), diphenhydramine
25–50 mg, and acetaminophen 650 mg are usually co-administered. Such adverse reactions can often be controlled by slowing the infusion rate.
transplants.
While higher doses (15 mg/kg) reduced aGVH this was offset by increased infections. However a long term follow up showed that at both high and low (7.5 mg/kg) doses chronic GVH (cGVH) was reduced.
A similar trial of anti-lymphocyte globulin showed a trend in reduction of aGVH that was not statistically significant, but a reduction in cGVH.
The Canadian Blood and Marrow Transplant Group is currently conducting the first randomised trial in cGVH using an even lower dose of rabbit ATG (4.5 mg/kg) in an attempt to confirm these observations. The endpoint is the reduction in the proportion of patients with cGVH at 1 year, off immunosuppressants.
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...
in organ transplant
Organ transplant
Organ transplantation is the moving of an organ from one body to another or from a donor site on the patient's own body, for the purpose of replacing the recipient's damaged or absent organ. The emerging field of regenerative medicine is allowing scientists and engineers to create organs to be...
ation and therapy of aplastic anemia
Aplastic anemia
Aplastic anemia is a condition where bone marrow does not produce sufficient new cells to replenish blood cells. The condition, per its name, involves both aplasia and anemia...
.
Uses
Two antithymocyte globulin (ATG) agents licensed for clinical use in the United States are Thymoglobulin (rabbit ATG, rATG, Genzyme) and Atgam (equine ATG, eATG, Pfizer). Thymoglobulin and Atgam are currently licensed for use in the treatment of renal allograft rejection; Atgam is additionally licensed for use in the treatment of aplastic anemia. Both drugs are used in off-label applications, especially as immunosuppression induction agents before and/or during kidney transplantation. An rATG product made by Fresenius is marketed outside of the United States.ATG administration very substantially reduces immune competence in patients with normal immune systems, through a combination of actions, some explicitly understood and some more hypothetical. rATG in particular effects large reductions (through cell lysis) in the number of circulating T-lymphocytes, hence preventing (or at least delaying) the cellular rejection of transplanted organs. However, medical opinion remains divided as to when the benefit of this profound reduction in T-cells outweighs the concomitant increased risks of infection and malignancy.
In the United States
United States
The United States of America is a federal constitutional republic comprising fifty states and a federal district...
it is frequently given at the time of the transplant to prevent graft-versus-host disease
Graft-versus-host disease
Graft-versus-host disease is a common complication after a stem cell transplant or bone marrow transplant from another person . Immune cells in the donated marrow or stem cells recognize the recipient as "foreign". The transplanted immune cells then attack the host's body cells...
, although many European centers prefer to reserve its use for the treatment of steroid
Steroid
A steroid is a type of organic compound that contains a characteristic arrangement of four cycloalkane rings that are joined to each other. Examples of steroids include the dietary fat cholesterol, the sex hormones estradiol and testosterone, and the anti-inflammatory drug dexamethasone.The core...
-resistant acute rejection, as European centres generally serve more homogeneous populations and rejection tends to be less of a problem.
Complications and alternatives
ATG use can induce cytokine release syndromeCytokine release syndrome
Cytokine release syndrome is a common immediate complication occurring with the use of anti-T cell antibody infusions such as ATG, OKT3 and TGN1412. Severe cases are known as cytokine storms....
, and has been thought to increase the risk of post-transplant lymphoproliferative disorder
Post-transplant lymphoproliferative disorder
Post-transplant lymphoproliferative disorder is the name given to a B-cell proliferation due to therapeutic immunosupression after organ transplantation. These patients may develop infectious mononucleosis-like lesions or polyclonal polymorphic B-cell hyperplasia...
(PTLD); however, this association may not apply when lower dosing regimens are used. There is some evidence to suggest that inducing immunosuppression with rATG at organ transplantation may create conditions in the patient's immune system favorable to the development of immunological tolerance, but the exact basis for such a development remains largely speculative. Temporary depletion of the T-cell population at the time of the transplant also risks delayed acute rejection, which may be missed and cause severe damage to the graft.
Anti-IL-2Rα receptor antibodies such as basiliximab
Basiliximab
Basiliximab is a chimeric mouse-human monoclonal antibody to the α chain of the IL-2 receptor of T cells. It is used to prevent rejection in organ transplantation, especially in kidney transplants...
and daclizumab
Daclizumab
Daclizumab is a therapeutic humanized monoclonal antibody to the alpha subunit of the IL-2 receptor of T cells. It is used to prevent rejection in organ transplantation, especially in kidney transplants....
are increasingly being used in place of ATG as an induction therapy, as they do not cause cytokine release syndrome and (theoretically) improve the development of tolerance.
The cytokine release syndrome associated with ATG administration frequently causes high grade fevers (over 39oC), chills, and possibly rigors during administration, for which reason steroids (normally methylprednisolone), diphenhydramine
Diphenhydramine
Diphenhydramine hydrochloride is a first-generation antihistamine possessing anticholinergic, antitussive, antiemetic, and sedative properties which is mainly used to treat allergies. Like most other first-generation antihistamines, the drug also has a powerful hypnotic effect, and for this reason...
25–50 mg, and acetaminophen 650 mg are usually co-administered. Such adverse reactions can often be controlled by slowing the infusion rate.
History
The first report of immunizing an animal of one species (Guinea pig) against the immune cells of another species (mouse lymphocytes) was by Metchnikoff in 1899. He reported injecting cells recovered from mouse lymph nodes into Guinea pigs and waiting for the immunization to result in the accumulation of anti-mouse antibodies in the Guinea pig blood. When he subsequently collected serum from these Guinea pigs and injected it into normal mice he observed a marked depletion in the number of circulating mouse lymphocytes.Status in graft-versus-host disease
Rabbit ATG has been used in two randomised trials to reduce acute Graft versus Host (aGVH) disease in recipients receiving progenitor cellProgenitor cell
A progenitor cell is a biological cell that, like a stem cell, has a tendency to differentiate into a specific type of cell, but is already more specific than a stem cell and is pushed to differentiate into its "target" cell...
transplants.
While higher doses (15 mg/kg) reduced aGVH this was offset by increased infections. However a long term follow up showed that at both high and low (7.5 mg/kg) doses chronic GVH (cGVH) was reduced.
A similar trial of anti-lymphocyte globulin showed a trend in reduction of aGVH that was not statistically significant, but a reduction in cGVH.
The Canadian Blood and Marrow Transplant Group is currently conducting the first randomised trial in cGVH using an even lower dose of rabbit ATG (4.5 mg/kg) in an attempt to confirm these observations. The endpoint is the reduction in the proportion of patients with cGVH at 1 year, off immunosuppressants.