Methods and compositions for modulating an immune response to an immunogenic therapeutic agent are disclosed. One of the disclosed methods comprises administering an effective amount of CTLA-4 to decrease the incidence of an immune reaction in conjunction with the administration of a potentially immunogenic substance. Another method contemplates tolerizing a subject to a therapeutic molecule that is or is capable of being immunogenic by the administration of CTLA-4. Various embodiments of CTLA-4 are also disclosed.