**2. Immunomodulation of the T cell response in autoimmunity and cancer**

Autoimmune diseases arise when the immune system recognizes the individual's own tissues or organs as "foreign" and targets them for destruction. Autoimmune diseases can affect virtually all tissues and organ systems and encompass such diverse diseases as Type 1 Diabetes (T1D; pancreas), Idiopathic Thrombocytopenic Purpura (ITP; platelet destruction), Crohn's disease (CD; bowel), Multiple Sclerosis (MS; brain) and Rheumatoid Arthritis (RA; joints). Despite the diversity of tissues affected, extensive research has demonstrated that Treg are downregulated while Teff are upregulated (i.e., leading to a reduced Treg:Teff ratio) leading to a chronic proinflammatory state. Current therapeutic approaches to managing autoimmune diseases are typically focused on symptom relief and the use of immunosuppressive agents capable of inhibiting the proinflammatory response arising from "self-recognition." Most commonly, treatment for chronic autoimmune disease is via administration of systemic steroids (e.g., dexamethasone), cytotoxic anti-proliferative/activation agents (e.g., cyclosporine) that induce a general immunosuppression, and/or IVIG (pooled, polyvalent, IgG purified from the plasma of >1000 blood donors) [2–6]. Other experimental approaches to the treatment of autoimmune diseases include blocking monoclonal antibodies directed against the TCR, CD4, costimulatory ligands and receptors, adhesion molecules, and cytokine receptors [7–9]. A more recent approach has been to interrupt the cytokine signals necessary for the activation and proliferation of autoreactive T cells. The current gold standard for this approach is Enbrel® (etanercept), a solubilized TNF-α receptor fragment that intercepts and sequesters the TNF-α cytokine thereby inhibiting the proliferation of proinflammatory T cells [10–15]. However, Enbrel® has been given a USA FDA "Black Box" warning due to significantly increased risks of serious infections that may lead to hospitalization or death [16–22]. Common to all of these approaches is an attempt to increase the Treg:Teff ratio by either directly increasing Treg or selectively decreasing Teff populations. However, despite their importance in clinical medicine, many of these agents have been plagued by both significant toxicity/adverse events and an inability to adequately eliminate or inhibit reactive T cells [8].

In contrast to autoimmune diseases, an insufficient/inefficient immune response may underlie the proliferation and dissemination of abnormal cells (i.e., cancer cells). While this may occur for a number of reasons, immunosuppression is a known risk factor. Indeed, acquired or inherited T cell defects as well as long-term therapy with immunosuppressive drugs are clearly associated with an increased risk of neoplasia. The impaired immune response to cancer cells can arise, at least in part, from an increase in the Treg:Teff ratio (too many Treg and/or insufficient Teff cell production). To address this imbalance in the Treg:Teff ratio, experimental

therapies are currently focused on the *ex vivo* expansion and subsequent transfusion of autologous Teff capable of killing the cancer cells [23–31]. However, these current immune enhancing methods, while promising, are expensive, complicated to accomplish (e.g., insertion of specific target cancer genes in APC) and requires weeks of tissue culture expansion to meet the threshold for cell infusion.

Perhaps most importantly, current tolerogenic or proinflammatory therapeutic approaches fail to persistently reorient the systemic T cell immune response thus necessitating continual therapy. Moreover, despite the importance of the Treg:Teff ratio, in both autoimmune diseases and cancer, there are a paucity of pharmacologic tools that can directly, and in tandem, target the regulation of both the Treg and Teff subsets. Hence, to diminish or overcome the need for chronic administration of immunotherapeutic agents, new approaches capable of persistently reorienting the endogenous immune (Treg:Teff) response would be of value.
