Inflammation and adaptive immune responses to adenoviral vectors injected into the brain: peculiarities, mechanisms, and consequences

Viral vectors for in vivo gene transfer in Parkinson's disease: Properties and clinical grade production

“…Thus, in vivo, expression of these wt Ad genes leads to a host inflammatory response which hinders the use of this vector for clinical purposes outside cancer therapy (Byrnes et al, 1995;Byrnes et al, 1996;Dewey et al, 1999;Lowenstein and Castro, 2003;Thomas et al, 2001a;Thomas et al, 2001b;Wood et al, 1996). Moreover, rAd infection induces well characterized innate and adaptive immune responses in the brain (Byrnes et al, 1995;Byrnes et al, 1996;Dewey et al, 1999;Lowenstein and Castro, 2003;Thomas et al, 2001a;Thomas et al, 2001b;Wood et al, 1996). Newer Ad vectors have been designed that retain only the inverted terminal repeats, i.e., with all viral genes removed; the so-called gutless vectors or high-capacity vectors (Hardy et al, 1997;Parks et al, 1996;Thomas et al, 2001b).…”

Virology and immunology of gene therapy, or virology and immunology of high MOI infection with defective viruses

“…The only viral nucleic acid remaining represents sequences required for genome replication and packaging into virions. 5,6 Further, capsids have been engineered to reduce viron binding to endogenous viral receptors, and to retarget infection of predetermined cell types. 7 Transcriptional regulatory systems facilitate directed expression of transgenes in a cell-type-specific fashion.…”

“…5,12,13 Of further importance to the field, this issue explores how inflammatory and immune responses will vary, even for the same vector, depending on the target organ being injected and transduced. 6,11,13 Thus, this special issue examines immune responses to vectors infecting different tissues, that is, muscle, 9 liver, 10 eye, 11 and brain. 6 Main themes of this issue include early inflammatory responses and signaling pathways activated by viral vectors; 4 how viral vectors stimulate the release of inflammatory mediators, cytokines, and 9 the mechanisms by which the innate and/or adaptive arm of the immune response can inhibit transgene expression (or eliminate transduced cells).…”

“…6,11,13 Thus, this special issue examines immune responses to vectors infecting different tissues, that is, muscle, 9 liver, 10 eye, 11 and brain. 6 Main themes of this issue include early inflammatory responses and signaling pathways activated by viral vectors; 4 how viral vectors stimulate the release of inflammatory mediators, cytokines, and 9 the mechanisms by which the innate and/or adaptive arm of the immune response can inhibit transgene expression (or eliminate transduced cells). 6,12,13 Clinical immune responses have not been discussed, since they were reviewed (at least those concerning adenoviral vectors) in detail elsewhere.…”

“…6 Main themes of this issue include early inflammatory responses and signaling pathways activated by viral vectors; 4 how viral vectors stimulate the release of inflammatory mediators, cytokines, and 9 the mechanisms by which the innate and/or adaptive arm of the immune response can inhibit transgene expression (or eliminate transduced cells). 6,12,13 Clinical immune responses have not been discussed, since they were reviewed (at least those concerning adenoviral vectors) in detail elsewhere. 14 While the astute reader will find no quick answers on how to 'get away with it', that is, forgetting the immune response continues to impose a major theoretical and practical hurdle to the safe implementation of clinical gene therapy, the goal is to share with the larger gene therapy community, the possibility that by understanding the molecular and cellular mechanisms underlying the activation of immune responses by viral vectors, and the elucidation of the pathways by which activated arms of the inflammatory and immune pathways interact with transduced cells, the field will be on the high ground to design better and safer vectors, and implement more effective and compelling clinical trials.…”