The Biology of Interleukin-2 (Annual Review of Immunology Book 26)

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Interleukin-2 IL-2 was identified in the supernatants of activated T cells over three decades ago [ 1 , 2 ]. IL-2 is the first cytokine for which receptor component was cloned [ 3 , 4 ].

Prospects of IL-2 in Cancer Immunotherapy

IL-2 possesses potent T cell growth factor action. It can also induce natural killer NK cells and potentiate their cytolytic effect and promote many other immune system components which are required for the removal of autoreactive cells and maintenance of homeostasis [ 10 ]. In the last two decades, the potential of IL-2 to expand T cells without affecting its activity has led to identification of its potential as an immunotherapeutic agent against cancer. The IL-2 administration is reported to induce apparently curative and durable regressions in cancer patients.

Further research also led to evolution of cell transfer therapies having promising response against melanoma cases [ 11 ]. This review discusses scope of IL-2 in the immunotherapy of cancer and major challenge in the development of IL-2 based therapeutic approach as well as perspective on future research. IL-2 is a T cell-derived common cytokine. It plays vital role in growth as well as differentiation of T cells, B cells, natural killer cells, and many other cell types [ 12 ]. The signaling pathway of IL-2 is mediated by a selective receptor family [ 13 ], which includes three classes of cell surface receptors: The activated lymphocytes also express these high affinity receptors.

The low and high affinity IL-2 receptors are expressed in steady state. The transcription of IL-2R is induced by various factors. Transcription of IL-2R is induced by various factors. IL-2R transcription is also induced by intermediate affinity receptors upon binding of IL-2 and as a response to T cell activation.

There is also rapid formation of high affinity receptors and consequent increase in responsiveness to IL This binding also promotes cytolytic activity and cell growth [ 29 ]. However, it should be noted that the affinity with which IL-2 can bind to IL-2R is relatively low with rapid on and off rates. IL-2 binding to IL-2R or IL-2R complex initiates signal transduction for the transcription of target genes through multiple signaling pathways.

All of these three major pathways mediate the effect of IL-2 on cell proliferation, activation, differentiation, survival, and cytokine production in the immune cells [ 31 , 32 ]. It has been long established that the immune system can be harnessed against neoplastic cells.

However, IL-2 was the first cytokines to be successfully used in the treatment of cancer. This was because it can promote T cells as well as NK cells. IL-2 can induce T cell proliferation and differentiation and also cause its activation.

Extensive division was observed in T cell upon treatment of the host animals with IL-2 and anti-IL-2 complexes in the absence of any other stimulation. Further, lymphokine activated killer LAK cells represent a unique and fundamental cytotoxic effector system plays a role in immune surveillance against NK resistant solid tumor cells and has role in the adoptive immunotherapy. LAK cells can recognize and kill human cancer cells as well as cultured tumor cell lines without any need for further in vitro stimulation [ 34 ]. In vitro grown LAK cells have also demonstrated in vivo activity against tumor-bearing mice.

However, in all these studies, the tumors were treated before vascularization [ 35 ]. Further, clinical trials using LAK cells and recombinant LAK cells conducted in 30 patients with advanced cancer did not produce any antitumor response [ 36 ].

Later, studies in murine models showed that in vivo activity of LAK cells was increased by administration of IL Based on this observation, the attempts were made to administer LAK cells in combination with maximum tolerated dose of IL-2 in humans. Recombinant interleukin-2 IL-2 therapy was first tried in and its novel effects in regulating regulatory T cells apart from effector T cells were identified after its FDA approval [ 37 ].

Complete remission was seen in 15 cases for seven months to as long as ninety-one months [ 17 ]. Further, the therapy showed durable effect with ongoing complete responses over a duration of 39 to months [ 38 ]. A few other clinical studies have also demonstrated safety of infusing autologous leukocytes in high-grade glioma patients with local injection of LAK cells. Outcomes of the studies in terms of prolonging disease free survival are also promising.

However, comparison of therapy of IL-2 alone with combination of IL-2 with LAK cell has not shown any significant difference in response to renal cell carcinoma in clinical setting [ 39 , 40 ]. The durability of the response which occurs due to development of T cell memory appears to be most important feature of cancer immunotherapy.

Prospects of IL-2 in Cancer Immunotherapy

Recent studies showed that immunization with combination of IL-2 and an altered peptide ligand derived from gp melanoma associated protein has better overall clinical response. In this case, the progression-free survival was of relatively longer duration than IL-2 treatment alone. This observation was in line with the idea that IL-2 can not only maintain but also enhance the tumor reactive T cells. However, as evident from the results, the treatment was effective on fraction of patients [ 19 ]. More recently, better IL-2 based cell transfer therapies with effective response in melanoma have been developed.

Further, genetic modification of T cells with TCRs or chimeric Ag receptors encoding gene and administration of these cells after expansion in IL-2 have opened the scope for use of cell transfer therapy in other cancer types [ 11 ]. The immunotherapy approach causes development of lifelong immunologic memory and consequent durable response. However, the questions that need to be addressed include the evaluation of survival benefits and the scope for possible retreatment. To answer these questions, much larger clinical trials with extended follow-up period should be conducted.

Outcome of trials using combination of IL-2 and interferon have found it to be nonsuperior to high dose IL-2 as a single agent [ 41 — 43 ]. Large trials on biochemotherapy involving combination of chemotherapeutic agent with IL-2 several large trials have consistently shown better overall response rates with early clinical benefit as compared with chemotherapy [ 44 — 47 ]. However, early response and benefit do not affect overall survival due to short duration of response [ 48 , 49 ].

Maintenance biotherapy after induction of biochemotherapy has been tried to extend the response, but with limited success [ 50 ]. The exact mechanism of toxicity due to combination of IL-2 with interferon or chemotherapeutic agents is complex and yet to be fully understood [ 51 ]. Patients sometime require interruption or discontinuation because of toxicity [ 17 , 52 ].

The toxicities due to treatment with IL-2 alone are both predictable and manageable. Further, toxicity in this case tapers off quickly following therapy [ 48 , 53 ]. In spite of this, biochemotherapy remains an option in cases of disease with rapid progression. The major challenge in the development of IL-2 as a therapeutic antitumor agent is that IL-2 can act on both T cells and Tregs. Thus, reports on use of IL-2 have used two different strategies, one to reduce the autoimmune responses and another to augment immune responses against tumor Table 1.

Recently, studies have used IL-2 in low dose, either alone or in combination, to induce preferential activation of Tregs. Tregs having high affinity for IL-2 can compete more effectively for it at low IL-2 levels [ 54 ]. Few studies involving HCV induced vasculitis and Graft-Versus-Host Disease showed improvement in clinical outcome based on the described concept of IL-2 therapy using low doses.

Histamine has a direct effect on the endothelium that increases capillary permeability that causes a transudation process that will aggravate the symptoms of rhinorrhea. Histamine bonding to nociceptic type C receptors in the nasal mucosa derived from Trigeminal nerve causes itching in the nose and stimulates the onset of sneezing.

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The effect of histamine on the gland due to parasympathetic reflex activation has the effect of increasing gland secretion causing serous rhinorrhea symptoms. Furthermore, histamine also causes symptoms of nasal congestion it causes vasodilation of blood vessels, transudation to the interstitial resulting nasal mucosa and especially edema turbinate.

Symptoms that immediately arise after the exposure to allergens are called fast phase reactions or immediate phase reactions. Released histamine from mast cells will be metabolized by histamine N-methyl transferase HMT in both epithelial and endothelial cells [14] [15]. The second stage of the elicitation phase is the effector stage. In the effector stage, the release of cytokine and endothelial activation give a result in slow phase reaction soon after the immediate phase.

Slow-phase reactions is the occurrence of various kinds of inflammatory cells, especially eosinophil cells as major effector cells in chronic allergic reactions such as allergic rhinitis and bronchial asthma.

Eosinophil cells in the movement of blood circulation to tissue or location of allergies influenced by chemotactic factors, through several stages such as the migration of the eosinophil cells from the middle to the edge of the blood vessel wall and begin to reversible bend with endothelial inflammation rolling , followed by attachment to blood vessel walls mediated by the interaction of endothelial adhesion molecules such as inter cell adhesion molecule-1 ICAM-1 and vascular cell adhesion molecule-1 VCAM-1 that are specific to the attachment of eosinophil cells because the eosinophil cells express VLA-4 to be administered with VCAM ICAM-1 is also expressed by the nasal mucosal epithelial cells patients with allergic rhinitis who get specific persistent allergen exposure and become the basic concept of minimal persistent inflammation MPI seen in allergic rhinitis to house dust mites HDM in symptom-free [15] [16].

Eosinophil was first reported by Paul Ehrlich on the basis of specific behavior toward painting. The role of eosinophil as pro-inflammatory in chronic allergic disease is the subject of basic research in therapy. Eosinophil in the form of progenitors is derived from the bone marrow, and then the peripheral blood is found in the nasal mucosa of allergic rhinitis patients. In the nasal mucosa of allergic rhinitis patients, eosinophil cells play the important role in the pathophysiological changes of allergic rhinitis.

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This because the content of various chemical mediators such as major basic protein MBP , eosinophil cationic protein ECP , eosinophil derived neurotoxin EDN and eosinophil peroxidase EPO which have the effect of disaggregation and desquamation of the epithelium, cell death, mucosal and mucosal inactivation cell damage due to free radicals [15] [16]. The pathogenesis of Allergic rhinitis can be seen in Figure 1.

Immunologic role in AR is about Th1 and Th2 cells balances. Most individuals do not trigger a strong response of Th2 cells to environmental antigens. In atopic patients, a strong response to Th2 that produces cytokines interleukin-4 IL-4 and interleukin IL stimulates B lymphocytes to transform into plasma cells that then produce IgE [14] [15].

Thus, the basis of AR treatment is aimed at altering the direction of the T cell response apart from the Th2 dominance or the loose antibody response of IgE by triggering tolerance to T cells against specific allergens or stimulating Treg [12]. The concept of immune response is influenced by the balance between activation receptors and inhibition for all lymphocyte populations including natural killer NK cells, B lymphocytes cells and T lymphocytes cells. Treg plays a role in suppressing the immune response and maintaining self-tolerance [12].

Allergic rhinitis patients with atopic history indicate Treg deficiency [17]. Pathophysiology of allergic rhinitis Adapted from Cretios, Treg itself in function and survival requires interleukin-2 [12]. Treg was originally known as suppressor T cells, and known as one of the subpopulation of T cells. Treg morphology does not show a large difference compared to other T cells, but in general Treg has a size slightly smaller than other lymphocytes [18].

Treg is divided into two types namely natural regulatory T cells nTreg and induced T-cell regulator iTreg which acts as an immune tolerant [12]. Natural Treg nTreg is derived from the process of selection of immature T cells in the thymus organ. Immature T cells sustains selection in the thymus in the form of a negative selection of immature T cells that have T cell receptor TCR with high avidity against self-antigen with deletion or apoptosis and positive selection with receptor changes and the formation of nTreg.

A small proportion of immature T cells with high self antigen of TCR passes the negative selection in the thymus entering the peripheral circulation. Treg subsequently played a part in suppressing the escaped portion as a tolerant immune function. Treg has a transcription factor called FoxP3 derived from the forkhead box transcription factor family, an important transcription factor in majority of Treg in development and function [12].

Survival and function of Treg depend on IL-2 cytokines. FoxP3 expression increased significantly in patients with allergic rhinitis who received specific immunotherapy SIT sublingual pollen for 2 years [21]. Treg undergoes the activation directly will suppress B-cell activity, inhibiting proliferation and differentiation of natural killer cells NK. Treg with IL-2R that has a high affinity for IL-2 leads to more consumption and reduces the need for other cells, resulting in decreased proliferation and differentiation of cells whose development requires IL-2 [12].

Treg found no difference in the amount of allergen dust mite atopic and non-atopic patients. The atopic diseases are cause only by a deficiency of Treg [17]. Treg deficiency can lead to autoimmune and inflammatory diseases [22]. In a genetic-based study, there was an association of AR with FoxP3 genetic polymorphisms in the homozygous allele [23]. This protein is produced by activated T cells by antigen signals, co-stimulators and cytokines.

The signals continue and stimulate the transcription of the IL-2 gene through the transcription factor nuclear factor of activated T cell NFAT. Interleukin-2 is rapidly excreted within 1 to 2 hours after the recognize antigen, peaks at approximately 8 to 12 hours and decreases within 24 hours. IL-2 production occurs in multiple signaling pathways and each channel plays an important role for the activation of multiple signaling pathways [12]. The biological activity of IL-2 is to grow, maintain survival, and as a differentiation factor of T cells that play an important role in responding and controlling the immune response.

The activity occurs in the cell itself that secretes IL-2 and other adjacent cells or functions can be referred to as autocrine and paracrine [12]. The survival function of IL-2 is by stimulating Bcl-2 protein which is an anti-apoptotic protein [12]. The increasing secretion of IL-2, IL-2R expression, cyclin, decreased cell cyclin inhibitors result in cell proliferation, and with multiple mechanism T-cell differentiation [12]. The function of IL-2 is maintains the survival and function of Treg to suppress the immune response.

In the deficiency condition levels of IL-2 and IL-2R do to proliferation and uncontrolled T cells and B cells, causing autoimmune disease [12]. In a study of low-dose IL-2 therapy for chronic graft Versus host disease patients occurred the increasing level of Treg [24]. Low-dose IL-2 therapy is also used as a clinical trial concept as specific therapy activates Treg and can control autoimmune and inflammatory diseases [22].

Interleukin has a heterodimer structure with a molecular weight of IL is produced from populations of some activated immune cells such as dendritic cells, Th1 cells, Th2 cells, macrophages, B cells and Tregs. Because IL has properties inhibiting macrophages and dendritic cells it is called negative feedback regulator [12]. The biological activity of IL inhibits the function of macrophages and dendritic cells. A rare inherited autoimmune disease has been described in which mutations in the IL receptor cause severe colitis that develops early in life, before 1 year of age.

Knockout mice are lacking IL ether in all cells or only in Treg also develop colitis, probably as a result of uncontrolled activation of lymphocyte and macrophage reacting to enteric microbes. Because of these findings, we believe that this cytokine is especially importance for controlling inflammatory reaction in mucosal tissue, particularly in gastrointestinal tract [13].

Potensial mechanism of conventional allergen immunotherapy. J Clin Invest ; Immunoglobulin A is the antibody required for mucosal defence. The following figure is explaining the role of interleukin-2 and FoxP3 in the pathogenesis of allergic rhinitis in Figure 3. Interleukin-2 IL-2 plays an important role in the pathogenesis of allergic rhinitis through Treg activation.

Schematic of conceptual framework. Increased levels of IL-2 will increase Treg activation. Treg has a transcription factor FoxP3 is an important transcription factor in the development and function of the majority of Treg. Rhinitis allergy occurs Treg deficiency. Severe AR is an indication of immunotherapy [2]. Immunotherapy can produce tolerance to allergens with various mechanisms. Several studies of immunotherapy noted a shift in the profile of cytokines that produced Th2 to Th1 by producing IL both local and systemic, and proving locally elevated only in the nose [30] [31] [32].

Tolerance occurs as a result of an increase from a specific allergen suppressor T cell, and Treg after immunotherapy [33]. A new perspective of the therapeutic approach focuses on administering IL-2 to inflamed tissue in autoimmune and allergic-induced inflammatory cases. Low-dose IL-2 therapy in chronic graft versus host disease increased Treg [24].

However, low-dose IL-2 therapy requires further clinical studies to optimize the dose, time and schedule of IL-2 administration to minimize the adverse effects of IL-2 [34]. Low-dose IL-2 therapy is a clinical trial concept as specific therapy activates Treg and can control autoimmune disease and inflammation [22].

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