immunosuppression

Immunosuppression

The natural or induced active suppression of the immune response, as contrasted with deficiency or absence of components of the immune system. Like many other complex biological processes, the immune response is controlled by a series of regulatory factors. A variety of suppressor cells play a role in essentially all of the known immunoregulatory mechanisms, such as maintenance of immunological tolerance; limitation of antibody response to antigens of both thymic-dependent and thymic-independent types, as well as to antigens that stimulate reaginic antibody (antibodies involved in allergic reactions); genetic control of the immune response; idiotype suppression; control of contact and delayed hypersensitivity; and antigenic competition. All of the major cell types involved in the positive side of cellular interactions required for an immune response have also been found capable of functioning as suppressors in different regulatory systems. See Immunological deficiency

Suppressor cells

Some suppressor functions are antigen- or carrier-specific. (A carrier is a molecule that can be chemically bound to another small molecule, called a hapten, in such a way that the combination induces an immune response that the hapten alone would not induce.) Others may not be carrier-specific, but may be specific for the type of response, such as immunoglobulin production but not delayed hypersensitivity. In the case of immunoglobulin production, the suppressor T cell may regulate the production of all immunoglobulin classes, a single class of immunoglobulins, or molecules that bind only a given antigen. Other suppressors may affect only cellular immunity and not humoral immunity. See Cellular immunology, Immunoglobulin

Suppressor cells are critical in the regulation of the normal immune response. Immunological tolerance refers to the ability of an individual's immune system to distinguish between its own and foreign antigens and to mount a response only to foreign antigens. A major role has been established for suppressor T lymphocytes in this phenomenon. Suppressor cells also play a role in regulating the magnitude and duration of the specific antibody response to an antigenic challenge.

Reagin, or IgE, is the class of immunoglobulin that mediates allergic reactions such as asthma and urticaria. The reaginic antibody response depends heavily on nonspecific cooperator T cells and specific helper T cells as well as the B cells that produce the antibody. In a negative direction, IgG-blocking antibodies regulate the response, but antigen-specific and antigen-nonspecific suppressor T cells also play a critical role in regulating this response. See Allergy

T cells are the major cells involved in immunosuppression, although activated phagocytic mononuclear cells are also significant as nonspecific suppressors in many systems. Helper T cells and suppressor T cells are different cell populations that are distinguished to a considerable extent by surface antigens that react with monoclonal antibodies or receptors for specific substances such as histamine.

No single model explains the entire array of cellular suppressor phenomena. In different systems, other T cells, macrophages, or even B cells may be the immediate targets of the suppressor cells and their secretions. Some suppression requires direct cell-cell interaction, whereas other suppression may be mediated by suppressor lymphokines. Both antigen-specific and antigen-nonspecific factors are known, and they may be secreted to act upon other cells, or especially in the case of antigen-specific factors, they may be integral parts of the cell membrane. The soluble immune-response suppressor factor, produced by activated T cells and then activated by monocytes, inhibits B-cell proliferation and immunoglobulin production in response to antigens. Macrophages also secrete suppressor factors, including prostaglandins that act on T cells and other soluble factors that are B-cell-specific.

There is a variety of disorders of immunoglobulin production in humans. In many cases these involve intrinsic defects in the bone marrow stem cells that normally mature into immunoglobulin-producing plasma cells. Defects in cell-mediated immunity occur in individuals who are infected with various fungal organisms. Suppressor T cells have been implicated, although it is not clear whether the appearance of suppressor cells is the initial event allowing development of the fungal infection or whether they develop secondarily after infection. Those individuals found to have suppressor T cells are at high risk for dissemination of the fungal infection and relapse following therapy. Although probably only one of many mechanisms, suppressor cells interfere with the host tumor-growth-inhibiting immune response to the foreign tumor-specific transplantation antigens that occur on malignant cells, thus allowing the tumors to progress. Both animal and human studies indicate a major role for both an activation of immunoglobulin-producing B cells as well as the absence or reduced numbers or function of suppressor T cells in autoimmune disorders such as Coombs-positive hemolytic anemia, systemic lupus erythematosus, rheumatoid disorders, and thyroid disorders in which antithyroid antibodies appear in the serum. See Autoimmunity

Immunosuppressors

Suppression of the immune response may be specific to a particular antigen or may be a response to a wide range of antigens encountered. The whole immune response may be depressed, or a particular population of immunologically active lymphocytes may be selectively affected. In some cases, the effect may be preferentially on T cells rather than B cells. If B cells are affected, it may be on a specific subclass of antibody-producing cells. Antigen-specific immunosuppression may be the result of deletion or suppression of a particular clone of antigen-specific cells, or the result of enhanced regulation of the immune response by antigen-specific suppressor cells. It can also be the result of increased production of antiidiotypic antibody.

Nonspecific suppression of the immune response occurs in a number of rare immunological deficiency diseases of childhood. Acquired deficiency states affecting mainly T-cell function occur in states of malnutrition and in the presence of tumors, particularly those of the lymphoreticular system. Acquired deficiencies may also occur secondary to a number of infectious diseases. The acquired immune deficiency syndrome (AIDS) is probably of similar origin; its manifestations are similar although more severe and more dramatic. See Acquired immune deficiency syndrome (AIDS), Immune complex disease

There are a number of compounds capable of suppressing the immune response. The main stimulus for studies designed to identify these substances has been to devise means for controlling organ graft rejection. However, there has also been considerable activity in looking for compounds that will suppress the immune response and reduce the inflammatory process in experimental models of rheumatoid arthritis. The ideal immunosuppressive drug should fulfill five main requirements: (1) There should be a wide margin of safety between a toxic and a therapeutic dose. (2) The drug should have a selective effect on lymphoid cells and not cause damage to the rest of the body. (3) If possible, this effect should be only on those cells which are involved in the specific immune process to be suppressed. (4) The drug should need to be administered for only a limited period until the immunological processes become familiar with the foreign antigen and begin to recognize it as part of “self.’’ (5) The drug should be effective against immune processes once they have developed. See Transplantation biology

The result of any immune response is a balance between the action of effector cells mediating the phenomenon and suppressor cells regulating the response. Anything that reduces the regulatory function of suppressor cells will functionally increase the immune response. As suppressor cells are derived from rapidly turning-over precursor cells, and effector cells of T-cell-mediated immunity are derived from slowly dividing precursors, it is possible preferentially to depress the action of suppressor cells without affecting effector cells. This may be done by the use of alkylating agents such as cyclophosphamide given before immunization. Cyclophosphamide used in this way can increase a normal cell-mediated immune response, reverse immunological tolerance caused by increased regulatory activity of suppressor cells, and even reverse antigenic competition. It is likely that the chemotherapeutic effect of alkylating agents which are used extensively in the treatment of cancer in humans is partially due to these agents modifying the biological response to the tumor, producing an immunopotentiating action. See Immunity, Immunology