Studies on antigenicity led to the concept that molecules like the interferons were not immunogenic in homologous systems because antibodies are not normally produced against “self” antigens. However, naturally occuring or therapeutically induced antibodies to cytokines such as interferons, tumor necrosis factors (TNF), interleukins (IL) and various growth factors were found, which are generally thought to inhibit cytokine functions, and the appearance of such antibodies should therefore result in various degrees of cytokine deficiency. It is a common concept that the development of antibodies against any auto-antigen or drug is always undesirable. Such antibodies are crucial for the pathology of autoimmune diseases and inhibit the pharmacological effects of drugs including exogenously administered cytokines. Natural antibodies: Antibodies to IFN-a have been reported in patients with various autoimmune disorders. Antibodies to IFN-a were detected in the serum of patients with systemic lupus erythematosus. There are reports of natural antibodies to IFN-a in patients suffering from herpes zoster infections, and varicella zoster disease. Spontaneous antibodies to IFN-a were shown to occur in sera of various cancer patients. Neutralizing IFN-a antibodies were also found in cerebrospinal fluids and sera of acute aseptic meningitis patients as well as in patients with chronic polyarthritis. There are data from several groups suggesting that elevated levels of antibodies to IFN-a are associated with stages of diseases related to dysbalances of the immune system. Accordingly, antibodies to IFN-a have been found in hemodialysis, kidney transplant patients, and HIV infected patients where the development of such antibodies appears to parallel disease progression. Therapeutically induced antibodies: The immunogenic potential defined as capacity of epitopes to induce antibody formation of the recombinant and natural IFN-a preparations used in human therapy has attracted increasing interest in clinical research. Formation of antibodies against IFN-a has been reported in patients after treatment with all available human IFN preparations regardless of their composition and subtypes. More and more reports indicate that relapses after successful IFN-a therapy coincide the formation of neutralizing antibodies against IFN-a. Antibody formation depends on several factors which include the IFN-a preparation used in therapy, the therapeutic regimen, the duration of treatment and the type of disease. Leukemias/lymphomas: Clinical resistance and IFN-a antibodies have been found in patients with hairy cell leukemia, chronic myeloid leukemia, chronic lymphoid leukemia, multiple myeloma, essential thrombocytemia, preleukemia, and Kaposi's sarcoma. Solid tumors: Treatment of patients with solid tumors may also induce IFN-a antibody formation as shown for: malignant melanoma, renal cell carcinoma, nasopharyngeal carcinoma, breast carcinoma, various advanced carcinomas, urinary bladder carcinoma and genital as well as respiratory papillomatosis. Furthermore there are neutralizing antibodies to IFN-a in response to therapy in chronic hepatitis B and C virus infection.