This issue of immune stimulation by pharmaceuticals came into the forefront when biotechnology-derived products, especially recombinant proteins, moved toward clinical trials. Today it is evident that the immune system can effectively recognize biological therapeutics as foreign substances and build up a multi-level immune response against them. A number of factors result in the immune system responding to the administration of a pharmacological product, such as structure, formulation, folding architecture, but also degradation byproducts.170 In addition, the route of administration and the dosage were shown to influence the staging and the amplitude of the immune system's response. In general, immune responses to biological products could be classified as benign in the sense that they affect only the pharmacological efficacy of the administered compound. The greatest concern is the robust immune response to certain biotechnology-derived products that are fraught with serious clinical consequences that may even result in a fatal outcome due to specific recognition and elimination of the patient's endogenous growth factors critical for survival.171-173 For example, in the case of thrombopoietin, the immune response may result in the production of neutralizing antibodies, causing inhibition of the endogenous thrombopoietin with subsequent development of thrombocytopenia.173 The patient's immune response to recombinant erythropoietin product Eprex® has been reported to induce pure red cell aplasia.171,172,174 In the latter example, cross-reactivity tests indicated that antibodies generated against Eprex® could also neutralize other forms of erythropoietin products such as Epogen®, NeoRecormon®, and Aranesp® and suggested that antibodies are directed against some specific conformation of the erythropoietin active site.170 Although incidence of the acute pure red cell aplasia remains relatively rare, the long-term implications are of great concern, as over half of patients who developed the auto-antibody remained transfusion dependent. The potential of using multifunctional nanoparticles for medical applications raises a key question of whether nanoparticle materials by themselves can induce an anti-nanopar-ticle immune response, stimulate allergic reactions, or trigger synthesis of nanopreparation-specific IgE. One can expect that the generation of antibodies to nanoparticles will ultimately affect only efficacy of the particle-based product. Of greatest concern will be the immune response to particles functionalized with growth factors, receptors or other biological molecules, which would result in the formation of antibodies, neutralizing the effect of these biological molecules and leading to potential exclusion of both particle-linked and endogenous proteins, akin to similar effects observed with biotechnology-derived pharmaceuticals. There are a limited number of studies on immunogenicity of nanomaterials. A few of them have shown that nanoparticles may both induce nanoparticles specific immune response and act as adjuvants.175-178 Although preclinical animal studies may not be predictive to human immune response, available data described above do suggest that the immune system can recognize and build an immune response against some nanoparticles. Therefore, evaluation of nanoparticle antigenicity is seen as an important step during preclinical development. Other immunogenicity characterization should include evaluation of a nanoparticles' ability to act as an adjuvant and to induce allergic reactions.

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