**1. Introduction**

Biologically, and clinically, the concept of "self" is of crucial importance in protection against foreign biologicals (e.g., viruses and bacteria), abnormal autologous cells (e.g., cancers) and more recently developed "diseases" (i.e., the purposeful introduction of "nonself") such as enzyme-replacement therapy and transfusion

#### *Cells of the Immune System*

and transplantation medicine. The immune system is tasked with preserving "self" and rejecting "nonself" and has multiple components-any of which will be of variable importance depending on the context of the immunological assault. Immunological "self" of most tissues is imparted by the major histocompatibility complex (MHC) which encodes a variety of proteins that provide a means for identifying, targeting, and eliminating foreign invaders and diseased cells while preserving normal "self" tissue. The MHC proteins themselves consist of three classes. MHC Class I molecules are expressed on virtually all nucleated cells while Class II molecules are expressed exclusively on antigen presenting cells (APC; e.g., monocytes, macrophages, dendritic cell, B lymphocytes, and endothelial cells) and activated T lymphocytes. MHC Class III genes encode components of the complement system. The human MHC is referred to as the Human Leukocyte Antigen (HLA) complex while the murine equivalent is referred to as the Histocompatibility-2 (H2) complex. In the context of MHC-mediated immune recognition, the T lymphocyte (T cell) is of particular importance. T cells themselves consist of a diverse array of subsets that fall into two general categories: 1) Regulatory T cells (Treg) which modulate the strength of an immune response and maintain "self"; and effector T

#### **Figure 1.**

*Immune modulation via pharmacologic and immunocamouflage therapy. (A) Current pharmacologic therapy almost exclusively targets T cell activation and proliferation consequent to allorecognition. Response to nonself is in large part mediated by cell-cell interactions between antigen presenting cells (APC; e.g., dendritic cells) and naive T cells. This cell-cell interaction is characterized by essential adhesion, allorecognition and co-stimulation events. Consequent to allorecognition, a proliferation of proinflammatory T cells (e.g., cytotoxic T lymphocyte, CTL; Th17, IL-17+ ; Th1, IFN-γ + ; and IL-2+ populations) and decrease in regulatory T cells (Treg, Foxp3+ and CD25+ ) is observed. Current therapeutic agents are primarily cytotoxic agents preventing T cell activation (e.g., cyclosporine and rapamycin) or T cell proliferation (e.g., methotrexate, corticosteroids and azathioprine). Additionally, blocking antibodies have been investigated. Gray text indicates current techniques to prevent/ limit alloimmune responses. (B) In contrast, immunocamouflage of donor cells by methoxy(polyethylene) glycol (mPEG) results in the disruption of the essential cell-cell interactions decreasing T cell proliferation and altering differentiation patterns (decreased Th17 and increased Treg). In aggregate, the polymer induced changes induces a tolerogenic/anergic state both* in vitro *and* in vivo*. Size of T cell population denotes increase or decrease in number. Size of B cell indicates antibody response. Blue text represents the consequences of polymer-mediated immunocamouflage of the alloresponse. (C) As shown in photomicrographs, in a control mixed lymphocyte reaction (MLR), significant and persistent interactions (black arrows) occur between allogeneic lymphocytes (LYM) and dendritic cells (APC). The lymphocyte adhesion and antigen presentation interactions typically occur at pseudopodal extensions from the APC (white arrows). PEGylation of either allogeneic PBMC population decreases the stability and duration of initial cell:cell interactions between lymphocytes due to the global charge and steric camouflage of membrane proteins. (D) Importantly, the secretomes derived from the MLR and mPEG-MLR exert potent effects on a secondary MLR encompassing fresh PBMC from the same or different donors. The key component of the secretome are soluble (free and exosome) miRNA. Data derived from Refs [32–43].*

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*Modulating the T Lymphocyte Immune Response via Secretome Produced…*

cells (Teff) that mediate the inflammatory response and consists, in part, of Th1, Th17 and Th2 subsets. Hence, the functional ratio of Treg to Teff (Treg:Teff) cells is critical and an imbalance of this ratio from the norm can induce either an autoimmune (excess Teff or decreased Treg) state or impaired response to "nonself" (e.g., cancer) consequent to biologically ill-advised tolerance (too many Treg or weak Teff response). Indeed, the T cell response plays a (the) central role in autoimmune diseases, transplant rejection, graft versus host disease (GVHD), graft versus leukemia (GVL), cancer and, more recently, cancer therapy. Hence, consequent to the central role of T cells as a key cellular component in the development of autoimmune diseases, graft tolerance or rejection, and the anticancer response, the T cell response has been a major focus in the development of clinical therapies (**Figure 1A**) [1].

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

to adequately eliminate or inhibit reactive T cells [8].

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

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

*DOI: http://dx.doi.org/10.5772/intechopen.86598*

**cancer**

*Modulating the T Lymphocyte Immune Response via Secretome Produced… DOI: http://dx.doi.org/10.5772/intechopen.86598*

*Cells of the Immune System*

**74**

**Figure 1.**

*CD25+*

*CTL; Th17, IL-17+*

*; Th1, IFN-γ*

*exosome) miRNA. Data derived from Refs [32–43].*

*+ ; and IL-2+*

*Immune modulation via pharmacologic and immunocamouflage therapy. (A) Current pharmacologic therapy almost exclusively targets T cell activation and proliferation consequent to allorecognition. Response to nonself is in large part mediated by cell-cell interactions between antigen presenting cells (APC; e.g., dendritic cells) and naive T cells. This cell-cell interaction is characterized by essential adhesion, allorecognition and co-stimulation events. Consequent to allorecognition, a proliferation of proinflammatory T cells (e.g., cytotoxic T lymphocyte,* 

and transplantation medicine. The immune system is tasked with preserving "self" and rejecting "nonself" and has multiple components-any of which will be of variable importance depending on the context of the immunological assault. Immunological "self" of most tissues is imparted by the major histocompatibility complex (MHC) which encodes a variety of proteins that provide a means for identifying, targeting, and eliminating foreign invaders and diseased cells while preserving normal "self" tissue. The MHC proteins themselves consist of three classes. MHC Class I molecules are expressed on virtually all nucleated cells while Class II molecules are expressed exclusively on antigen presenting cells (APC; e.g., monocytes, macrophages, dendritic cell, B lymphocytes, and endothelial cells) and activated T lymphocytes. MHC Class III genes encode components of the complement system. The human MHC is referred to as the Human Leukocyte Antigen (HLA) complex while the murine equivalent is referred to as the Histocompatibility-2 (H2) complex. In the context of MHC-mediated immune recognition, the T lymphocyte (T cell) is of particular importance. T cells themselves consist of a diverse array of subsets that fall into two general categories: 1) Regulatory T cells (Treg) which modulate the strength of an immune response and maintain "self"; and effector T

*) is observed. Current therapeutic agents are primarily cytotoxic agents preventing T cell activation (e.g., cyclosporine and rapamycin) or T cell proliferation (e.g., methotrexate, corticosteroids and azathioprine). Additionally, blocking antibodies have been investigated. Gray text indicates current techniques to prevent/ limit alloimmune responses. (B) In contrast, immunocamouflage of donor cells by methoxy(polyethylene) glycol (mPEG) results in the disruption of the essential cell-cell interactions decreasing T cell proliferation and altering differentiation patterns (decreased Th17 and increased Treg). In aggregate, the polymer induced changes induces a tolerogenic/anergic state both* in vitro *and* in vivo*. Size of T cell population denotes increase or decrease in number. Size of B cell indicates antibody response. Blue text represents the consequences of polymer-mediated immunocamouflage of the alloresponse. (C) As shown in photomicrographs, in a control mixed lymphocyte reaction (MLR), significant and persistent interactions (black arrows) occur between allogeneic lymphocytes (LYM) and dendritic cells (APC). The lymphocyte adhesion and antigen presentation interactions typically occur at pseudopodal extensions from the APC (white arrows). PEGylation of either allogeneic PBMC population decreases the stability and duration of initial cell:cell interactions between lymphocytes due to the global charge and steric camouflage of membrane proteins. (D) Importantly, the secretomes derived from the MLR and mPEG-MLR exert potent effects on a secondary MLR encompassing fresh PBMC from the same or different donors. The key component of the secretome are soluble (free and* 

 *populations) and decrease in regulatory T cells (Treg, Foxp3+*

 *and* 

cells (Teff) that mediate the inflammatory response and consists, in part, of Th1, Th17 and Th2 subsets. Hence, the functional ratio of Treg to Teff (Treg:Teff) cells is critical and an imbalance of this ratio from the norm can induce either an autoimmune (excess Teff or decreased Treg) state or impaired response to "nonself" (e.g., cancer) consequent to biologically ill-advised tolerance (too many Treg or weak Teff response). Indeed, the T cell response plays a (the) central role in autoimmune diseases, transplant rejection, graft versus host disease (GVHD), graft versus leukemia (GVL), cancer and, more recently, cancer therapy. Hence, consequent to the central role of T cells as a key cellular component in the development of autoimmune diseases, graft tolerance or rejection, and the anticancer response, the T cell response has been a major focus in the development of clinical therapies (**Figure 1A**) [1].
