Editorial [Hot Topic:Gene Therapy and the Immune System (Guest Editor: Roland W. Herzog)]

While based on a simple concept of introducing a functional gene to replace a non-functional sequence of a person's genome or to otherwise add a therapeutically beneficial gene, gene therapy is faced with a complex set of interactions between the gene transfer vector, the transgene, and the recipient of gene transfer. Following tremendous advances in vector development, cures have been reported in numerous animal models of human diseases, and gene therapy now holds much promise as a novel form of molecular medicine. However, complications of treatment related to insertional mutagenesis following integration of vector DNA into host chromosomes and to untoward immune responses against vectors and transgene products have merged as serious obstacles for successful translation to humans. This issue of Current Gene Therapy is dedicated to an in-depth assessment of immune responses in gene transfer. The importance of the topic is further highlighted by the recent meeting of the NIH's Recombinant DNA Advisory Committee (RAC), which discussed vector-specific T cell responses in a gene therapy trial for hemophilia on 19 June 2007, and by reports on complications of gene therapy for severe inflammatory disease. The immune system has evolved to differentiate between self and foreign molecular structures and sequences and to respond to activation signals that indicate danger to the body. Consequently, the immune system may fight off “invading” gene transfer vectors or foreign protein and nucleic acid sequences. Innate immunity provides a rapid defense system that responds to exogenous signals (e.g. pathogen-associated molecular patterns such as bacterial or viral nucleic acids) and to endogenous signals that, for example, may be derived from tissue damage during vector administration, cellular stress, or viral infection. The adaptive immune response is delayed but more specific (involving presentation of antigen to highly specific T and B cell receptors) and also generated memory B and T cells. Cytotoxic T cell and antibody responses may block gene transfer or eliminate therapeutic gene expression. The articles in this issue reflect that the potential for any of these immune responses in gene transfer depends on many factors, including the gene transfer vector (type of vector, specifics of the construct such as promoters, envelope/capsid, purity, etc.), vector dose, route of administration (ex vivo, in vivo, target organ, method of delivery), age and genetic factors of the recipient of gene therapy, and the nature of the transgene product (self, non-self, cellular localization, etc.). Nonetheless, research is well under way to overcome these hurdles. We have just begun to understand the interactions between vectors and the immune system of specific target tissues (organ-specific immunity). For example, recent research demonstrates the importance of interactions with bone marrow-derived professional antigen presenting cells. Similar to research in transplantation biology, gene therapists have uncovered strategies to manipulate the immune system, leading to sustained transgene expression in animal models. At the same time, we can take advantage of mechanisms of immune tolerance and regulation mechanisms, which have evolved to prevent autoimmunity and destructive immune responses.