ALG acts primarily on the small, long-lived peripheral lymphocytes that circulate between the blood and lymph. With continued administration, “thymus-dependent” (T) lymphocytes from lymphoid follicles also are depleted, as they normally participate in the recirculating pool. As a result of the destruction or inactivation of T cells, an impairment of delayed hypersensitivity and cellular immunity occurs while humoral antibody formation remains relatively intact. ALG and ATG are useful for suppressing certain major compartments (ie, T cells) of the immune system and play a definite role in the management of solid organ and bone marrow transplantation.
Monoclonal antibodies directed against specific cell surface proteins such as CD2, CD3, CD25, or cytokine receptors and various integrins much more selectively influence T-cell subset function. The high specificity of these antibodies improves selectivity and reduces toxicity of the therapy, altering the disease course in several different autoimmune disorders.
In the management of transplants, ALG and monoclonal antibodies can be used in the induction of immunosuppression, in the treatment of initial rejection, and in the treatment of steroid-resistant rejection. There has been some success in the use of ALG and ATG plus cyclosporine to prepare recipients for bone marrow transplantation. In this procedure, the recipient is treated with ALG or ATG in large doses for 7–10 days prior to transplantation of bone marrow cells from the donor. ALG appears to destroy the T cells in the donor marrow graft, and the probability of severe GVH disease is reduced.
The adverse effects of ALG are mostly those associated with injection of a foreign protein. Local pain and erythema often occur at the injection site (type III hypersensitivity). Since the humoral antibody response remains active in the recipient, skin-reactive and precipitating antibodies may be formed against the foreign ALG. Similar reactions occur with monoclonal antibodies of murine origin caused by the release of cytokines by T cells and monocytes.
Anaphylactic and serum sickness reactions to ALG and murine monoclonal antibodies have been observed and usually require cessation of therapy. Complexes of host antibodies with horse ALG may precipitate and localize in the glomeruli of the kidneys causing kidney damage.
A different approach to immunomodulation is the intravenous use of polyclonal human immunoglobulin. This immunoglobulin preparation (usually IgG) is prepared from pools of thousands of healthy donors, and no single, specific antigen is the target of the “therapeutic antibody.” Rather, one expects that the pool of different antibodies will have a normalizing effect upon the patient’s immune networks.
IGIV in high doses (2 g/kg) has proved effective in a variety of different applications ranging from immunoglobulin deficiencies to autoimmune disorders to HIV disease to bone marrow transplantation. In patients with Kawasaki’s disease, it has been shown to be safe and effective, reducing systemic inflammation and preventing coronary artery aneurysms. It has also brought about good clinical responses in systemic lupus erythematosus and refractory idiopathic thrombocytopenic purpura. Possible mechanisms of action of IGIV include a reduction of T helper cells, increase of regulatory T cells, decreased spontaneous immunoglobulin production, Fc receptor blockade, increased antibody catabolism, and idiotypic–anti-idiotypic interactions with “pathologic antibodies.” Although its precise mechanism of action is still unknown, IGIV brings undeniable clinical benefit to many patients with a variety of immune syndromes.