Abstracts (complete list) - Wissenschaft Online

Nicolas Sabarth, Louise Chamberlain, John Tite, Sara Brett, Craigen Jenny
Two-sided effect of T cell help in tolerance breaking and
immunodominance
To develop a successful cancer vaccine it is necessary to break immunological tolerance
to self-antigens expressed on tumour cells. Broken immunological tolerance results in a
functional CD8 T cell response, the development of which is known to be dependent on
provision of CD4 help. In the transgenic RIP OVALOW mouse model which is
hyporesponsive, ergo immunological tolerant, to ovalbumin, DNA vaccination with
ovalbumin in combination with GM-CSF and the TLR7 agonist Imiquimod provided a
strong synergistic adjuvant effect on CD4 cells resulting in broken tolerance in both the
CD4 and CD8 compartments. Compared to wildtype mice RIP OVALOW mice had CD8 T
cells of lower avidity, but functional CD8 T cell responses were evident by induction of
tumour protection and correlating autoimmunity which served as a surrogate of efficient
target cell killing. Heterologous CD4 help has been shown to improve functional CD8
responses and we confirmed that inclusion of the T helper epitope PADRE enhanced CD8
responses compared to self antigen alone both in RIP OVALOW mice and their wildtype
counterpart although no autoimmunity was induced. Addition of GM-CSF and Imiquimod
however resulted in dominance of the PADRE response over the ovalbumin specific CD4
responses in both mouse strains. The effect of the PADRE on the CD8 T cell response
was depended on the state of tolerance of the animals: PADRE specific CD4 help
compensated for the lack of ovalbumin specific CD4 help and the CD8 T cell response
was little affected in wildtype mice. In contrast, in tolerant RIP OVALOW mice the
combination of PADRE and GM-CSF & Imiquimod decreased ovalbumin specific CD8
numbers and function, abrogating diabetes development. Only the limited use of PADRE
together with adjuvant enhanced DNA immunisation provided some benefit evident by
accelerated autoimmunity in RIP OVALOW mice, i.e. target cell killing.
Hence, Imiquimod/GM-CSF enhanced DNA immunisation has good potential as
therapeutic cancer vaccine but the use of heterologous T cell help has to be handled
with care and needs further investigation.