? for Dr. Furman

[Guest guest]

Could you briefly tell me what this means and whether or not it has

application for CLL?

Thanks in advance.

Ann Macklin

Abstract (provisional)

Background

Granulocyte-macrophage colony-stimulating factor (GM-CSF) has shown

promising results as a cytokine adjuvant for antiviral vaccines and

in various models of tumor gene therapy. To explore whether the

targeting of antigens to GM-CSF receptors on antigen-presenting cells

enhances antigen-specific CD8 T-cell responses, fusion proteins of GM-

CSF and ovalbumin (OVA) were expressed by DNA and adenoviral vector

vaccines. In addition, bicistronic vectors allowing independent

expression of the antigen and the cytokine were tested in parallel.

Results

In vitro, the GM-CSF ovalbumin fusion protein (GM-OVA) led to the

better stimulation of OVA-specific CD8+ T cells by antigen-presenting

cells than OVA and GM-CSF given as two separate proteins. However,

prime-boost immunizations of mice with DNA and adenoviral vector

vaccines encoding GM-OVA suppressed CD8+ T-cell responses to OVA. OVA-

specific IgG2a antibody levels were also reduced, while the IgG1

antibody response was enhanced. Suppression of CD8+ T cell responses

by GM-OVA vaccines was associated with the induction of neutralizing

antibodies to GM-CSF. In contrast, the coexpression of GM-CSF and

antigens in DNA prime adenoviral boost immunizations led to a

striking expansion of polyfunctional OVA-specific CD8+ T cells

without the induction of autoantibodies.

Conclusions

The induction of autoantibodies suggests a general note of caution

regarding the use of highly immunogenic viral vector vaccines

encoding fusion proteins between antigens and host proteins. In

contrast, the expansion of polyfunctional OVA-specific CD8+ T cells

after immunizations with bicistronic vectors further support a

potential application of GM-CSF as an adjuvant for heterologous prime-

boost regimens with genetic vaccines. Since DNA prime adenoviral

vector boost regimenes are presently considered as one of the most

efficient ways to induce CD8+ T cell responses in mice, non-human

primates and humans, further enhancement of this response by GM-CSF

is a striking observation.