Antilymphocyte globulin

When injected, azathioprine (Imuran) is rapidly converted to 6-mercaptopurine. The half-life of azathioprine after intravenous injection is 10 to 20 min, and that of 6-mercaptopurine is somewhat longer. The cytotoxic activity of these thiopurines is due to the conversion of mercaptopurine to 6-thiouric acid, a noncarcinostatic metabolite. This action is thought to block the excess synthesis of inosinic acid from its precursors, glutamine and phosphoribosylpyrophosphate. In addition, unlike cyclophosphamide, azathioprine is a potent anti-inflammatory substance that can cause a reduction in the number of monocytes and neutrophils at inflammatory sites. Antibody responses are also inhibited by azathioprine. Studies in humans have shown that azathioprine decreases the y-globulin and antibody levels, thus influencing IgG rather than IgM production. This makes azathioprine an effective immunosuppressant in the early phases of immune responses. It is less effective or completely ineffective in altering either the effector phase or already established reactivities. 

Azathioprine is an effective agent in suppressing the immune system in patients undergoing renal transplantation and in patients suffering from acute glomerulonephritis, the renal component of systemic lupus erythematosus, prednisone-resistant idiopathic thrombocytopenic purpura, and functioning autoimmune hemolytic anemia. Azathioprine depresses bone marrow functioning, which is its chief side effect. 

Cyclosporin A, a fungal metabolite, is a cyclic polypeptide that consists of 11 amino acids. It has a biologic half-life of 4 to 6 h and displays a preferential T cell cytotoxic property, in that it inhibits the factors that stimulate T lymphocyte proliferation. Cyclosporin A has been used as the sole immunosuppressant (without prednisone or other drugs) for cadaveric transplants of the kidney, pancreas, and liver. Cyclosporin A has been observed to cause reversible hepatic toxicity and nephrotoxicity. 

Dihydrocyclosporin C, another fungal metabolite, is even more selective than cyclosporin A, in that it suppresses T lymphocyte production with only marginal effects on the antibody response. 

The antilymphocyte globulin is obtained through the immunization of horses with human lymphoid cells or with fetal thymus cells. The antilymphocyte antibody destroys the T cells and impairs delayed hypersensitivity and cellular immunity without altering humoral antibody formation. The pattern of immunosuppression obtained with antilymphocyte globulin is identical to that brought about following thoracic duct drainage that depletes the numbers of small lymphocytes. 

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Both globulins exert their effect by depletion of circulating lymphocytes either by complement-dependent lysis or by phagocytosis after opsonization. However, antilymphocyte globulin (ALG) and antithymocyte globulin (ATG) are nonhuman polyclonal antibodies. To prevent sensitization application is restricted to a time period of several days only. 

ADA Adenosine deaminase ALG Antilymphocyte globulin APC Antigen-presenting cell ATG Antithymocyte globulin CD Cluster of differentiation CSF Colony-stimulating factor CTL Cytotoxic T lymphocyte DC Dendritic cell... 

Antisera directed against lymphocytes have been prepared sporadically for over 100 years. With the advent of human organ transplantation as a therapeutic option, heterologous antilymphocyte globulin (ALG) took on new importance. ALG and antithymocyte globulin (ATG) are now in clinical use in many medical centers, especially in transplantation programs. The antiserum is usually obtained by immunization of large animals such as horses or sheep with human lymphoid cells. 

Kreis H. 1992. Antilymphocytic globulins in kidney transplantation. Kidney Int. 42 S188-S192. 

A 16-year-old with severe aplastic anemia failed to respond to treatment with corticosteroids plus an androgen and to antilymphocyte globulin, but had a strikingly positive response to the combination of lithium and an androgen derivative (41). Leukopenia and thrombocytopenia recurred 2 months after lithium was withdrawn and responded to reintroduction of the drug. 

After he had failed to respond to combined treatment with corticosteroids and androgens and to antilymphocyte globulin, a 16-year-old with aplastic anemia responded to lithium combined with an androgen derivative, relapsed when lithium was stopped, and responded again when it was restarted (41). 

Immunosuppression is used in patients who are not candidates for bone marrow transplantation due to age or to the lack of a donor (up to 70%). Horse antithymocyte globulin (ATG) or rabbit antilymphocyte globulin (ALG) induce haematological responses (transfusion-independence and freedom from infection) in 40-50%. The addition of ciclosporin to ATG or ALG improves response rates to 70-80% and survival rates in responders to 90%. Adverse effects of ATG and ALG include anaphylaxis, exacerbation of cytopenias and serum sickness. Ciclosporin is nephrotoxic. In refractory patients G-CSF and erythropoetin can improve blood counts, as can androgens in some patients. 

The risk of reactions to antilymphocyte globulin is increased in patients with autoimmune disease (126). Fever and chills, sometimes with extreme hyperpyrexia, nausea and vomiting, urticaria, and reduced platelet and granulocyte counts were reported after the administration of horse antithymocyte globulin. 

Kawano Y, Nissen C, Gratwohl A, Wursch A, Speck B. Cytotoxic and stimulatory effects of antilymphocyte globulin (ALG) on hematopoiesis. Blut 1990 60(5) 297-300. 

Barlow, C.W. Moon, M.R. Green, G.R. Gamberg, P. Theodore, J. Reitz, B.A. Robbins, R.C. Rabbit antilymphocyte globulin versus OKT3 induction therapy after heart-lung and lung transplantation effect on survival, rejection, infection, and obliterative bronchiolitis. Transplant Int. 2001, 14, 234-239. 

Frickhofen N, Kaltwasser J, Schrezenmeier H, et al. Treatment of aplastic anemia with antilymphocyte globulin and methylprednisolone with or without cyclosporine. N Engl J Med 1991 324 1297-1304. 

Young N, Speck B. Antithymocyte and antilymphocyte globulins CUnical trials and mecUanism of action. In Young S, et al, eds. Aplastic Anemia. Stem Cell Biology and Advances in Treatment. New York, AlanRLiss, 1984 221-226. 

Induction therapy with polyclonal and monoclonal antibodies (mAbs) has been an important component of inunu-nosupression when the beneficial effect of antilymphocyte globulin (ALG) in the prophylaxis of rejection in renal transplant recipients was demonstrated. Over the past 40 years, several polycolonal antilymphocyte preparations have been used in renal transplantation however, only two preparations are currently FDA approved lymphocyte immune globulin (ATGAM) and antithymocyte globulin (Thymoglobulin). 

Antilymphocyte globulin and monoclonal anti-T cell antibodies 1,2, 3... 

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