Granulocyte-macrophage colony stimulating factor (GM-CSF) and interleukin-3 (IL-3) demonstrate many overlapping activities on the proliferation, differentiation, and activation of hematopoietic cells. This apparent redundancy of function is attributed in part to the common signalling pathways mediated by the shared beta chain of the heterodimeric receptor for each cytokine. The two factors also demonstrate several distinct activities of hematopoietic cells, and this is attributed in part to the divergent expression of the unique alpha chain of each receptor. Delineating the precise functions of these cytokines in vivo is complicated, however, by the multiplicity of activities ascribed to each factor and the uncertainty regarding the sites and circumstances of expression of each molecule. We have shown that vaccination with irradiated tumor cells engineered to secrete GM-CSF stimulates potent, specific, and long-lasting anti-tumor immunity. Vaccination with irradiated tumor cells expressing IL-3 also stimulates anti-tumor immunity, albeit less efficiently. The mechanism underlying the ability of the two cytokines to enhance anti-tumor immunity appears to involved improved tumor antigen presentation by host antigen presenting cells. In order to further explore the functions of these molecules in anti-tumor immunity and to provide additional insight into their roles in hematopoiesis and inflammation, we have generated GM-CSF and IL-3 deficient mice by gene targeting in embryonic stem cells. Although steady state hematopoiesis is unperturbed in both strains of mice, GM- CSF deficient, but not IL-3 deficient animals demonstrate impaired vaccination responses to immunization with irradiated, immunogenic tumor cells. In contrast, both IL-3 and GM-CSF deficient mice manifest impaired contact sensitivity responses. Since the generation of contact sensitivity is closely related to the development of T cell mediated anti-tumor immunity, these findings reveal essential and non-overlapping roles for GM-CSF and IL-3 in vaccination responses. More detailed investigation of immunization in these animals should provide important insights into the pathways underlying the development of anti-tumor immunity and reveal new information regarding the physiologic functions of GM-CSF and IL-3.
The specific aims of this proposal are: 1. To delineate the mechanisms underlying defective vaccination responses in GM-CSF and IL-3 deficient mice. 2. To evaluate the ability of GM-CSF and IL-3 deficient mice to process exogenous antigens for MHC class I presentation. 3. To evaluate the functions of GM-CSF and IL-3 in promising cancer vaccination strategies.
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