Mechanisms of immune toxicity associated with immunotherapy. (1) The delivery of exogenous antibody specific for TAA expressed on both tumor and normal tissue can result in damage to normal tissue mediated by complement or ADCC mediated by innate immune cells, such as macrophages. (2) Similarly, transfer of TAA-specific T cells can lead to destruction of normal tissue if the TAA is also expressed on cells of normal tissue. (3) Alternate ways of inducing immune reactivity toward normal tissue include dysregulation of normal immune homeostasis using anti–CTLA-4, resulting in expansion of self-reactive T cells. (4) It is also possible that induction of immunity to tumor cells could lead to epitope spreading whereby T cells reactive with self-antigens are generated.