Immune tolerance, or immunological tolerance, or immunotolerance, is a state of unresponsiveness of the immune system to substances or tissue that have the capacity to elicit an immune response in a given organism. It is induced by prior exposure to that specific antigen and contrasts with conventional immune-mediated elimination of foreign antigens. Tolerance is classified into central tolerance or peripheral tolerance depending on where the state is originally induced—in the thymus and bone marrow (central) or in other tissues and lymph nodes (peripheral). The mechanisms by which these forms of tolerance are established are distinct, but the resulting effect is similar.

Immune tolerance is important for normal physiology. Central tolerance is the main way the immune system learns to discriminate self from non-self. Peripheral tolerance is key to preventing over-reactivity of the immune system to various environmental entities (allergens, gut microbes, etc.). Deficits in central or peripheral tolerance also cause autoimmune disease, resulting in syndromes such as systemic lupus erythematosus, rheumatoid arthritis, type 1 diabetes, autoimmune polyendocrine syndrome type 1 (APS-1), and immunodysregulation polyendocrinopathy enteropathy X-linked syndrome (IPEX), and potentially contribute to asthma, allergy, and inflammatory bowel disease. And immune tolerance in pregnancy is what allows a mother animal to gestate a genetically distinct offspring with an alloimmune response muted enough to prevent miscarriage.

Tolerance, however, also has its negative trade-offs. It allows for some pathogenic microbes to successfully infect a host and avoid elimination. In addition, inducing peripheral tolerance in the local microenvironment is a common survival strategy for a number of tumours that prevents their elimination by the host immune system.

The phenomenon of immune tolerance was first described by Ray D. Owen in 1945, who noted that dizygotic twin cattle sharing a common placenta also shared a stable mixture of each other's red blood cells and retained that mixture throughout life. Although Owen did not use the term immune tolerance, his study showed the body could be tolerant of these foreign tissues. This observation was experimentally validated by Leslie Brent, Rupert E. Billingham and Peter Medawar in 1953, which showed by injecting foreign cells into fetal or neonatal mice, they could become accepting of future grafts from the same foreign donor. However, they were not thinking of the immunological consequences of their work at the time: as Medawar explains: "We did not set out with the idea in mind of studying the immunological consequences of the phenomenon described by Owen; on the contrary, we had been goaded by Dr. H.P. Donald into trying to devise a fool proof method of distinguishing monozygotic from dizygotic twins."

However, these discoveries, and the host of allograft experiments and observations of twin chimerism they inspired, were seminal for the theories of immune tolerance formulated by Sir Frank McFarlane Burnet and Frank Fenner, who were the first to propose the deletion of self-reactive lymphocytes to establish tolerance, now termed clonal deletion. Burnet and Medawar were ultimately credited for "the discovery of acquired immune tolerance" and shared the Nobel Prize in Physiology or Medicine in 1960.

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