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

Abstract

Pathological conditions, such as cancers, viral infections, and autoimmune diseases, are associated with abnormal cytokine production, and the morbidity associated with many medical disorders is often directly a result of cytokine production. Because of the absence of negative feedback control occurring in some pathophysiologic situations, a given cytokine may flood and accumulate in the extracellular compartment of tissues or tumors thereby impairing the cytokine network homeostasis and contributing to local pathogenesis. 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 (involving cytokine production, target response, and feedback regulation) and have considered them in the local context of effector--target cell microenvironment 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 ectopically accumulated in the extracellular compartment, thus counteracting their pathogenic effects. In contrast, the same Abs should not interfere with cytokine processes occurring in normal tissues, because under physiologic conditions cytokine production by effector cells (induced by activation but controlled by negative feedback regulation) does not accumulate in the extracellular compartment. These concepts are consistent with results showing that following animal and human anti-cytokine vaccination, induction of high-affinity Abs has proven to be safe and effective and encourages this approach as a pioneering avenue of therapy.

Figures

Figure 1

Cytokine process in normal (A) and vaccinated (B) subjects under physiological condition. Cytokines (●) produced by E cells after activation (↘) initially may form immune complexes with ECM Abs (t1) and trigger a target cell (T; t2 and t'2). After T-cell response (✖), negative feedback down-regulates the cytokine process (cytokine synthesis and target receptor expression; t3 and t'3). Note that natural Abs (Y) or vaccine-induced Abs of high affinity (YY), complexed with the cytokine, delay the process for only a few minutes.

Figure 2

Effects of vaccination against immunosuppressive cytokines on tumor cell growth. Cancer cells may constitutively release immunosuppressive cytokines (●), including TGF-β (–36) or IL-10 (39), which accumulate in the extracellular compartment. (A) Natural Abs (Y) present in ECM cannot contain the accumulated cytokine (no. 1), stromal T lymphocytes are anergized, (no. 2), and cancer cell growth occurs (no. 3). (B) High-titer and high-affinity Abs (YY), triggered by an appropriate anti-cytokine vaccine, neutralize the suppressive signal and block its effects (no. 1). T lymphocytes may be activated spontaneously by either a tumor cell antigen or better by a conventional anti-tumor vaccine (no. 2). As a result, effector cytotoxic T lymphocytes (CTLs) directed against cancer cells control tumor growth (no. 3).