Expression of immunomodulatory proteins in genetically modified, replication-competent microorganisms

Currently there are about 60 Cytokines and approx. 50 Chemokines known that have an immunomodulatory effect. Due to their pleiotropic and redundant functioning as well as the strong context-dependence of their properties, the various representatives of these immunomodulatory proteins can either stimulate or suppress the defense against a pathogen. For example, the overexpression of interleukin 4 (IL-4) alters the immune response by shifting the cellular immune response towards the humoral immune response. The administration of tumor cells that express IL-4 can induce a systemic T cell-dependent immune response against the tumor cells. However, it has been found that IL-4 can significantly suppress the cellular immune response against the Ectromelia virus (ECTV). After infection of mice with a recombinant, replication-competent ECTV into whose genome the murine IL-4 gene had been inserted, existing immunity was undermined. The insertion of the murine IL-4 gene thus significantly increased the risk potential of ECTV. The expression of chemokines by a replication-competent microorganism can also lead to an increased risk potential. Infection with an otherwise attenuated Rabies lyssavirus strain into whose genome the gene for the chemokine IP-10 (CXCL10) had been integrated led to severe weight loss, neurological deficits, and death in mice. In contrast, infection with the original strain was associated with only minor and temporary symptoms in a few experimental animals.

Recommendation of the ZKBS For genetic engineering work in which immunomodulating proteins are expressed by replication-competent microorganisms, a statement about the mode of action of these modulators can only be made for each individual case. This work is therefore fundamentally not to be regarded as comparable within the meaning of the Genetic Engineering Act. A case-by-case assessment by the ZKBS is therefore generally required. However, this does not apply to genetic engineering work in which • recipient organisms are used that pose no risk to humans or animals and cannot permanently colonize or infect them • combinations of recipient organisms and immunomodulating genes are used that have already been assessed by the ZKBS (e.g. transfer of the gene for the human TRAIL protein to human mastadenovirus C).

There is no list of genes for immunomodulatory proteins that do not require individual review by the ZKBS.

The updated ZKBS statement can be found at File number 6790-03-05 can be retrieved.