Toward a new generation of vaccines: The anti-cytokine therapeutic vaccines

Pathological conditions, such as cancers, viral infections, and autoimmune diseases, are associated with abnormal cytokine production, and the morbidi ty associated with many medical disorders is often directly a result of cyt okine production. Because of the absence of negative feedback control occur ring in some pathophysiologic situations, a given cytokine may flood and ac cumulate in the extracellular compartment of tissues or tumors thereby impa iring the cytokine network homeostasis and contributing to local pathogenes is. To evaluate whether the rise of anti-cytokine Abs by vaccination is an effective way to treat these pathological conditions without being harmful to the organism, we have analyzed each step of the cytokine process (involv ing cytokine production, target response, and feedback regulation) and have considered them in the local context of effector-target cell microenvironm ent and in the overall context of the macroenvironment of the immune system of the organism. In pathologic tissues, Abs of high affinity, as raised by anti-cytokine vaccination, should neutralize the pool of cytokines ectopic ally accumulated in the extracellular compartment, thus counteracting their pathogenic effects. In contrast, the same Abs should not interfere with cy tokine processes occurring in normal tissues, because under physiologic con ditions cytokine production by effector cells (induced by activation but co ntrolled by negative feedback regulation) does not accumulate in the extrac ellular compartment. These concepts are consistent with results showing tha t following animal and human anti-cytokine vaccination, induction of high-a ffinity Abs has proven to be safe and effective and encourages this approac h as a pioneering avenue of therapy.