Immune Responses

The use of modified viruses as gene transfer vectors always raises questions about the safety of gene therapy in humans. AdVs are destroyed in the body by the immune system and neutralising antibodies are produced towards the vector to prevent further transduction [24]. Deletions of the viral elements in the vector and modification of the viral capsid can help to lower the immune responses. The gutless AdVs are an example of this kind of an approach [14]. However, immune responses are not only the problem of AdVs. Any non-human material put into the human body is identified by the immune system as foreign and will be destroyed. Long-term expression vectors, such as AAV and lentiviruses are also known to induce immune responses [29, 30] similar to AdVs. Also, it might be possible that the immune response is lengthened in cases where the immune response is directed towards cells containing the long-term expressed transgene (Karvinen H, unpublished 2007).

Impurities in vector preparations can cause severe toxic reactions and immune responses [21, 31]. Therefore, the production of vectors should be well controlled. In fact, in most cases inflammation induced by appropriate doses of highly purified GMP-grade adenoviruses has been only moderate and has not caused any significant tissue damages [13, 16, 21, 23]. Importantly, in angiogenic gene therapy, immune responses towards impure virus preparations have to be avoided since formation of granulation tissue and up-regulation of several pro-inflammatory factors can result in false positive results especially in preclinical models where less purified vectors are often used. Subsequently, such findings can lead to disappointments in clinical trials where full GMP viruses have to be used. High viral amounts are often the reason for inflammatory reactions after gene transfer. Importantly, since the transduction efficacy of AdVs is very high, low AdV doses can be used to reduce inflammatory reactions.

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