The immune system removes foreign matter, which makes organ transplantation difficult. Burnet and Medawar demonstrated in mice that if foreign tissue is introduced during fetal or early neonatal life, the animal later accepts it as part of itself and does not reject it. This phenomenon is called acquired, or post-natal, immunological tolerance. Their work laid the groundwork for transplantation medicine, leading to immunosuppressive drugs and HLA matching tests. It also provided clues to understanding autoimmune diseases.

Burnet proposed the clonal selection theory, predicting that immune cells possess genetically fixed diverse receptors and that self-reactive clones are removed during development. Medawar experimentally confirmed, using skin-graft models, that neonatal mice injected with foreign cells later fail to reject grafts from the same donor strain. This phenomenon was later linked to T-cell maturation in the thymus and crystallized into the concept of central tolerance. Their discoveries influenced the development of immunosuppressive drugs such as cyclosporine, clinical protocols for organ and bone-marrow transplantation, and the pathogenesis of autoimmune diseases. Knowledge of tolerance mechanisms is now applied to manage side effects of immune-checkpoint inhibitors as well.

Burnet extended the clonal selection theory to include negative selection of self-reactive clones. Medawar demonstrated, in CBA↔A/J skin-graft systems, that injection of donor cells during fetal life or within 48 h post-partum abolished specific rejection, thus establishing immunological chimerism as a methodological tool. Subsequent thymectomy studies and microchimerism analyses identified T-cell clonal deletion/anergy as the molecular basis of central tolerance. These insights underpin protocols for mixed-chimerism induction, Treg-expansion therapy, and assessment of autoimmunity risks in CAR-T cell platforms, guiding modern transplant and tumor immunology.