Tolerance, Immunological

the absence or attenuation of immunological response to a given antigen without impairment of immunological reactivity to all other antigens. The term was introduced in 1953 by the English immunologist P. Medawar to designate tolerance toward transplanted foreign tissues by the body’s immunity system. The terms “immunological paralysis, ” “areactivity, ” and “antigenic overload” denote various forms of tolerance.

Tolerance to its own antigens in a healthy body’s immunity system prevents the formation of antibodies that could harm the body’s cells and tissues. A physiological state of tolerance to alloantigens produced by the fetus may arise during pregnancy. Mutual physiological tolerance to blood-group antigens may also result from the intrauterine exchange of hematopoietic cells in dizygotic twins. Tolerance to bacterial and viral antigens is observed in cases of latent infection, such as serum hepatitis in humans and brucellosis in goats. The successful transplantation of organs or tissues depends on how complete and long-lasting is the recipient’s acquired tolerance to the histocompatibility antigens of the donor. Impairment of the body’s tolerance to its own antigens leads to autoimmune diseases. Tolerance may be complete or it may be manifested as a form of immune response; for example, retention of cellular immunity may be coupled with loss of the ability to form antibodies.

The complex nature of tolerance is revealed in experiments. It has been shown that complete removal or suppression of the vital activity of a given clone of immunocompetent cells leads to irreversible tolerance; such tolerance arises most readily when large doses of antigens are introduced before the immunity system has reached maturity—namely, during intrauterine development or in early postnatal life. In adult individuals, tolerance may be created by general suppression of the immunocompetent cells through ionizing radiation or immunodepressants. Reversible tolerance, on the other hand, may be produced by injecting small doses of soluble (monomeric) disaggregated antigens. The molecules of such antigens apparently combine with and block the immunoglobulin molecules (with individually specific receptors) that are built into the membranes of lymphocytes. Reversible tolerance is also produced by antigen-antibody complexes. There are special T-lymphocytes that actively suppress the immune responses of other T- and B-lymphocytes, as well as of phagocytes. Such T-lymphocytes, called suppressors, probably maintain a physiological tolerance to their own antigens.

Tolerance may occur in a form in which antibodies are produced normally, but in which all the antibodies without exception are bound to the unmetabolizable antigen retained in the tissues. Tolerance may also be induced by injecting large doses of antibodies that either intercept the antigen molecules in their course toward the individually specific lymphacytes or shield the antigen from the immunocompetent cells.

In toxicology and pharmacology, the term “tolerance” denotes a decrease in sensitivity to toxic or pharmacological preparations—for example, to narcotics. Repeated and prolonged injection of strong poisons in small doses may result in the acquisition of immunity—also called mithridatism (after Mithridates VI Eupator, king of Pontus).