EPO and Autoimmunity: Second, cross-reactivity resulting in autoimmunity occurs when there is an antibody produced to a biologic agent that cross-reacts to a native protein (breaking tolerance), which has occurred in erythropoietin, IFN-γ, and Factor VIII trials.16,17 Antibody responses such as these generally occur after months of long-term treatment and usually by routes of administration involving parenteral administration.