1 The Secretariat to ACGM is proposing to review and update the ACGM Compendium of Guidance. In particular, it is proposed that guidance on factors to consider when undertaking risk assessment of genetically modified micro-organisms eliciting altered immune responses will be produced. The wish to design new vaccines and alter the immune response to gene therapy vectors has resulted in an increase in the number of projects notified to the Competent Authority involving these types of organisms. The ACGM and the Competent Authority consider that micro-organisms eliciting altered immune responses require special consideration when the risks are assessed, and therefore have produced interim guidance to aid those carrying out risk assessment of such organisms.
2 Modulation or avoidance of host responses can be achieved in a number of ways, for example:
3 Where projects use these strategies or other methods that have the potential, to alter or modulate the host immune response, special attention must be given to the implications for human health and the environment in the risk assessment and appropriate containment measures and procedures employed. In particular, the risk assessment for organisms employing these strategies for immune modulation should give consideration to:
These points should be specifically detailed in the risk
4 The issue of genetically modified micro-organisms eliciting altered immune responses was also highlighted by a paper on expression of IL-4 in mousepox virus. Ectromelia virus (mousepox) expressing murine IL-4 was found to be lethal to mice normally resistant to the virus. Natural genetic resistance to mousepox infection is characterised by an early activation of a strong CD8+ cytotoxic T-lymphocyte (CTL) response and an effective natural killer (NK) response. Introduction of the IL-4 gene into the mousepox virus resulted in abolition of the CTL response and a reduction in the NK response to the virus. It was also noted that prior vaccination did not completely protect against the lethal effects of the recombinant IL-4 expressing mousepox.
5 While the effects of IL-4 on immune memory may not have been predicted, the reduction of the CTL response to ectromelia virus expressing murine IL-4 might have been considered at the outset as IL-4 is known to promote differentiation of naïve Th cells into Th2 cells. Th2 cells produce cytokines that tend to reduce the Th1 response and thus also reduce the CTL response that is strongly associated with Th1 responses. In fact, where similar experiments were to be carried out in the UK, using vaccinia virus and IL-4, the possibility of an adverse effect on the normal immune response to the virus was identified in the risk assessment. The centre then decided that it would be imprudent to use human IL-4, and inserted bovine IL-4 instead to reduce the risk of serious consequences should a researcher be accidentally infected. In this case, a good knowledge of the immune response to the virus and an understanding of the cross-regulation of Th subsets allowed appropriate risk assessment of the final GMM and a suitable protection measure to be identified.
6 Cross-regulation of Th subsets and the generation of an appropriate type of immune response against a particular pathogen is important since the dominance of an inappropriate response can exacerbate disease and lead to the inability to eradicate the infecting organism. It is therefore important that these effects be considered in the risk assessment for the work.
7 The Th1 type response is central to protection against many other pathogens for example intracellular bacteria such as Mycobacterium tuberculosis (MTB) and almost all viral infections, including respiratory viruses such as respiratory syncytial virus (RSV). The technology to engineer and express foreign genes in MTB and RSV is available and several cytokines have been expressed from vectors based on these organisms. Cytokines and other immune modulators have also been expressed in more established vector systems such as retroviruses, adenoviruses and herpes simplex viruses. In all cases where the normal balance of the immune system could be affected, special attention should be given to the possible effects on the immune response to the GMM.
1. Jackson RJ, Ramsay AJ, Christensen CD, Beaton S, Hall DF,
Ramshaw IA. (2001) J. Virol 75,1205-10