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IL-2 / Interleukin 2 & Receptor

IL-2 / Interleukin 2

Interleukin 2 (IL-2) is a type of interleukin that induces the proliferation of responsive T-cells. In addition, it acts on some B-cells, via receptor-specific binding, as a growth factor and antibody production stimulant. Interleukin 2 is the only drug approved in the US for the treatment of metastatic RCC. It is also approved in many other countries. But Interleukin 2 isn't just a drug. IL-2 is a natural part of your immune system, a messenger protein called a cytokine which activates parts of your immune system. IL-2 does not kill tumor cells directly like classical chemotherapy. Instead, IL-2 activates and stimulates the growth of immune cells, most importantly T-Cells, but also Natural Killer Cells (NK Cells), both of which are capable of destroying cancer cells directly.

IL-2 Receptor / Interleukin 2 Receptor

Crystal Structure of Human Interleukin-2

Interleukin 2 can be used by cells expressing either the intermediate-affinity receptor dimer of Interleukin 2Rβ (CD122) and the common γ chain (γc; CD132), or the high-affinity trimeric Interleukin 2R comprising Interleukin 2Rα (CD25), Interleukin 2Rβ, and γc. The intermediate-affinity Interleukin 2R is more broadly expressed on T cells, natural killer (NK) cells, and monocytes, whereas the high-affinity Interleukin 2R is only constitutively expressed on regulatory T-cells (Tregs). IL-2 binding initiates signal transduction following cross-phosphorylation of tyrosine residues in Janus-activated kinases (JAKs), leading to downstream phosphatidylinositol 3-kinase/Akt, mitogen-activated protein kinase/extracellular signal–related kinase, and signal transducer and activator of transcription (STAT5) activation.

The Interleukin 2 receptor is often modeled as a stand-alone structure consisting of the individual α/β/γc subunits complexed with Interleukin 2. In fact, high-resolution microscopy studies suggest clustering of receptors and signaling complexes adjacent to immunological synapses. Furthermore, a careful analysis of the X-ray crystallographic structure of the IL-2 tetrameric complex suggests that CD25/IL-2Rβ may interact with the γc chain on a neighboring receptor, allowing for assembly of a cell surface network of receptor complexes and increased responsiveness to Interleukin 2. This theory is supported by the observation of an extensive interaction between γc and IL-2Rα in the crystal structure, featuring high shape complementarity as well as hydrogen bonding.

Interleukin 2 Therapy

Interleukin 2 therapy has a long clinical history in humans, which can provide invaluable insight to future therapeutic design. The use of cyclosporine to suppress IL-2–mediated autoreactive T-cell activation in new-onset type 1 diabetes patients marked the advent of clinical immunotherapy in type 1 diabetes. This effort initially succeeded in halting T cell–mediated β-cell destruction, but the beneficial effect was only temporary because of concerns over drug toxicity and the effects of long-term immunosuppression.

Low-dose Interleukin 2 was recently used in a clinical trial for the therapy of graft versus host disease in patients after allogeneic hematopoietic stem cell transplantation with the notion of bolstering the Treg pool to prevent alloreactive T cell expansion. Patients treated with IL-2 exhibited increased Treg frequency, suggesting there may have been a preferential binding of IL-2 for the high-affinity IL-2R expressed on Tregs. Combination therapy using hematopoietic stem cell transplantation, low-dose IL-2, and donor CD4+ lymphocyte infusion provided greater Treg increases than either IL-2 or lymphocyte infusion alone. Given these findings in graft versus host disease, IL-2–based therapeutic interventions in autoimmunity will require the identification of biomarkers of response in each cell subset, allowing for optimal and targeted trial design. A currently enrolling clinical trial of low-dose IL-2 should provide a wealth of information.

Interleukin 2 therapy in humans has been used in the past for severe metastatic melanoma and renal carcinoma and has undergone several unsuccessful clinical trials for patients with HIV/AIDS. The use of large, toxic doses of Interleukin 2 given every 6-8 weeks in HIV therapy, similar to its use in cancer therapy, has been found recently to be ineffective in preventing progression to an AIDS diagnosis in two large clinical trials. However, that does not mean that the drug is ineffective in improving T-cell count. Many persons who underwent Interleukin 2 therapy enjoyed dramatic improvement in T-cell count, as well as overall health. But the FDA determined that the risks and costs (experience of side-effects) outweighed those benefits.

Interleukin 2 Cancer Treatment

Recent increases in knowledge of cellular immunology, combined with developments in biotechnology, have provided new opportunities for the development of immunotherapies for the treatment of cancer in humans. One approach to therapy is that of adoptive immunotherapy, that is, the transfer to the tumor bearing host of lymphoid cells with antitumor reactivity that can mediate antitumor responses. Several lymphocyte subpopulations have now been identified that may be suitable for use in adoptive immunotherapy. Resting lymphocytes incubated in interleukin-2 (IL-2) give rise to lymphokine activated killer (LAK) cells that can lyse malignant cells, but not normal cells. Clinical studies in patients with advanced cancer have revealed that treatment with high dose IL-2 alone or in combination with LAK cells can mediate the complete or partial regression of cancer in selected patients. Other approaches are currently undergoing investigation, including the adoptive transfer of tumor infiltrating lymphocytes, which, in animal models, have antitumor reactivity 50-100 times more potent than do LAK cells. Other new approaches to immunotherapy include the use of combination of lymphokines, such as the use of tumor necrosis factor or alpha interferon in conjunction with IL-2. The availability of recombinant lymphokines that provide large amounts of biologically active materials can hopefully lead to the development of effective new therapies for cancer in humans.

Interleukin 2 Side Effects

Although the Interleukin 2 therapy rarely causes serious permanent damage, it's more or less miserable while you're getting it, and often more rather than less. Most importantly, only a small minority of patients get the kind of long term relief that is the reason to try it. In the end whether it's worth it to endure the side effects of Interleukin 2 for a small (but the best known unless surgery is also an option) chance at a great result is strictly a personal decision.

Two unusual side effects have been noted: bowel perforation and hypothyroidism. In at least some patients the perforation was at the site of an unresected tumour, and histological examinationhas shown tumour necrosis. Most of the patients who became hypothyroid had pre-existing antithyroid antibodies. It may be that the activation of natural killer cells provides effector cells for antibody dependent cellular cytotoxicity or that coexisting autoreactive T cells have also been activated.

Despite this wide array of side effects in most patients they are predictable and may therefore be handled effectively. It is almost always possible for the patient to be treated in an ordinary hospital ward, and already reports have appeared of the successful use of interleukin 2 in outpatient departments. Fear of the side effects of anticancer drugs inhibits their use and drives patients who could benefit from them into the arms of alternative practitioners. Oncologists should learn how to learn new drugs-even if the side effects are strange-so that their patients are not deprived from effective treatment.

References

    1. Maigan A. et al. (2012) Central Role for Interleukin-2 in Type 1 Diabetes. Diabetes. 61(1): 14–22.
    2. S A Rosenberg. (1988) The development of new immunotherapies for the treatment of cancer using interleukin-2. A review. Ann Surg. 208(2): 121–135.
    3. Malek TR. et al. (2010) Interleukin-2 receptor signaling: at the interface between tolerance and immunity. Immunity. 33:153–165.
    4. Bachmann MF. et al. (2007) Differential role of IL-2R signaling for CD8+ T cell responses in acute and chronic viral infections. Eur J Immunol. 37:1502–1512.
    5. Malek TR. et al. (2004) Bayer AL. Tolerance, not immunity, crucially depends on IL-2. Nat Rev Immunol. 4:665–674.
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