The era of the medical application of proteins started at the end of the 19th century when animal sera were introduced for the treatment of serious complications of infections such as diphtheria and tetanus. The high doses used, the general lack of quality controls and a regulatory system, and the impurity of the prepara-tions led to many serious and sometimes even fatal side effects. Many of the problems were caused by the strong immune response these foreign proteins induced, especially when readministered. People who had been treated in general had a warning in their passports or identification cards to alert physi-cians for a possible anaphylactic reaction after rechallenge with an antiserum. Also serum sickness caused by deposits of antigen–antibody complexes was a common complication of the serum therapy.
Also the porcine and bovine insulins introduced after 1922 induced antibodies in many patients. This was also explained by the animal origin of the products, although over the years the immunogeni-city became less because of improvements in the production methods andincreasing purity.
In the second half of the 20th century a number of human proteins from natural sources have introduced such as plasma-derived clotting factors and growth hormone produced from pituitary glands of cadavers. These products were given mainly to children with an innate deficiency who therefore lacked the natural immune tolerance. Therefore, their immune response was also interpreted as a response to foreign proteins. The correlation between the factor VIII gene defect and level of deficiency with the immune response in hemophilia patients confirmed this explanation.
Thus, until the advent of recombinant DNA technology, the immunological response to therapeu-tic proteins could be explained as a classical immune response comparable to that of a vaccine.