Diabetes Mellitus (DM) is a metabolic disorder characterized by the occurance of chronic hyperglycemia accompanied by greater or lesser impairment in the metabolism of carbohydrates, lipids and proteins. DM is probably one of the oldest diseases known to man. It was first appeared in Egyptian manuscript about 3000 years ago.(1)
The prevalence of diabetes is increasing rapidly worldwide and has predicted that by 2030 the number of adults with diabetes would have almost raised worldwide from 177 million in 2000 to 370 million. Project done by expert found that the incidence of diabetes is set to soar by 64% by 2025 meaning that 53.1 million citizens will be affected by the disease. (2) In Egypt, the prevalence rate of type 1 DM among school children in Heliopolis citizens in cairo was 1.09/1000 with male predominance and in El Manyal citizens the prevalence was 1.12/1000 with school children with female predominance.(3)
In humans, diabetes mellitus is one of the most prevalent conditions with spontaneous manifestation. In animals, it can be induced by the administration of diabetogenic drugs such as alloxan, streptozotocin, ditizona and anti-insulin serum.(4) These agents selectively destroy the Langerhans islet ?-cells. The autoimmune destruction of pancreatic ?-cells, leads to a deficiency of insulin secretion which results in the metabolic derangements associated with IDDM. (5,6)
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Type 1 diabetes (T1D) is an autoimmune disease whereby antigen-specific T cells selectively destroy insulin-producing pancreatic ? cells .(7) In 1965, Gepts et al. first found inflammatory infiltrates in pancreatic islets, which have since then become a hallmark of T1D termed ‘insulitis’.(8) Current evidence suggests that initiation of T1D requires both CD4+ and CD8+ T cells; that autoreactive T cells differentiate into effectors by engaging ?-cell antigens on local antigen-presenting cells (APCs); that initiating CD4+ T cells are insulin reactive; and that CD8+ T cells play a major role as ?-cell killers .(9) A significant number of other immune cell types including B cells, NK cells, natural killer T cell (NKT), ??T and macrophages have been implicated in T1D progression.
Tregs, suppressors of antigen-activated immune responses to self and non-self antigens, were first described in1975.(10) Tregs play an indispensable role in maintaining immunological unresponsiveness and in suppressing excessive immune responses through cell contact-dependent mechanisms, by secretion of cytokines such as transforming growth factor (TGF)-?, IL-10 and IL-35.(11) Several markers for Tregs, such as human transcription factor forkhead box P3 (FoxP3), CTLA-4, CD25high and CD127low, have been clarified .(51) Of these molecules, FoxP3 could be most essential for Tregs, which is not only for the development of Tregs, but also for the maintenance of their suppressive function .(12)
FOXP3 (forkhead box P3), also known as scurfin, is a protein involved in immune system responses.(13) A member of the FOX protein family, FOXP3 appears to function as a master regulator of the regulatory pathway in the development and function of regulatory T cells.(14) Regulatory T cells generally turn the immune response down. Mutations or disruptions of the Foxp3 regulatory pathway can lead to organ-specific autoimmune diseases such as autoimmune thyroiditis and type 1 diabetes mellitus.(15) Adoptive transfer of Tregs has been shown to offer protection from T1D, whereas their experimental depletion or genetic deficiency in their numbers or activity promotes a more aggressive disease.(16) In addition, IL-2 administration has been shown to expand and activate Tregs in mice, while a short course of low-dose IL-2 administration at diabetes onset can reverse established disease .(17)
It is generally believed that NK cells are important players in innate immunity and are involved in direct killing of target cells that are transformed or infected by certain microorganisms without previous sensitization by recognizing class I HLA molecules on target cells through their membrane receptors .(18) Researchers have observed NK cells infiltrate islets of NOD mouse long ago, non-invasive islet inflammation is mainly mediated by NK cells .(19) Pancreatic NK cells, localized to the endocrine and exocrine parts, were present before T cells during disease development and did not require T cells for their infiltration .(20)
The natural cytotoxicity receptors, which include NKp30, NKp44 and NKp46, are expressed almost exclusively on NK cells .(21) NKp46 is considered as the most specific NK cell marker, and the activating receptor NKp46 recognizes mouse and human ligands on pancreatic ? cells leading to degranulation of NK cells .(21) NKp46-deficient mice had less development of T1D induced by injection of a low dose of streptozotocin .(22) The previous studies have shown a reduction in the frequency of NK cells in the peripheral blood in patients with T1D, and a reduced surface expression of the activating receptors NKp30 and NKp46 as well as lower mRNA levels of IFN-? and perforin in NK cells of patients with long-standing T1D, when compared to controls without T1D .(23)
NK cells appeared in the pancreas when insulitis progressed to type 1 diabetes, and NKp46 engagement by beta cells led to degranulation of NK cells. NKp46-deficient mice had less development of type 1 diabetes induced by injection of a low dose of streptozotocin. Injection of soluble NKp46 proteins into nonobese diabetic mice during the early phase of insulitis and the prediabetic stage prevented the development of type 1 diabetes. Our findings demonstrate that NKp46 is essential for the development of type 1 diabetes and highlight potential new therapeutic modalities for this disease.
IL-2, also named T-cell growth factor, was first discovered in 1976 and was characterized as a soluble factor with the unique ability to promote clonal expansion of T cells in vitro.(24) IL-2 is a 15.5?kDa four-bundle, ?-helical protein member of the common cytokine receptor ?-chain family of cytokines First cloned in 1983, it has been the most highly investigated IL with a diverse role in the regulation of the immune system.(25) IL-2 is predominantly produced by activated CD4+ T cells and, to a lesser extent by activated CD8+ T cells, activated dendritic cells, natural killer (NK) cells, NKT cells, as well as B cells.(26)
IL-2 is a pleiotropic cytokine with myriad functions. Where Tregs are concerned, it supports their development in the thymus (27), is a key survival factor for them in the periphery, and is required for their functional competence and stability.(28) Chitosan is an interesting polymer that has been used extensively in the medical field. It is either partially or fully deacetylated chitin. Chitosan has been investigated extensively as a potential drug carrier, due to it’s biocompatible properties. Some studies have suggested using chitosan to coat nanoparticles made of other materials, in order to reduce their impact on the body and increase their bioavailability.
Successful protection against islet ?-cell destruction has also been observed with a combination therapy of rapamycin and LD IL-2 .(29) Treatment with human recombinant IL-2 alone (4?ng/day) in NOD mice between the ages of 10–25?weeks made a dose-dependent decline in diabetes incidence in NOD mice treated with rapamycin alone (0.1 and 1.0?mg/kg/day) at the age of 10–33?weeks was seen. However, a synergistic effect was achieved using combination therapy with rapamycin plus human recombinant IL-2 that significantly decreased diabetes incidence in NOD mice compared to the vehicle-treated group. Disease (29) The use of LD IL-2 in combination with an autoantigen like insulin or an insulin peptide (discussed below) be used as potential safe and efficacious therapy to prevent or reverse disease, in part by remedying the dysregulation of Treg and Teff cells, without impairing the immune response .(30, 31) CD25 is constitutively expressed on Tregs, whereas its expression on other T cells is induced only after activation. Therefore, Tregs can better respond to IL-2 than other T cells in the steady state, prompting the consideration of using IL-2 therapeutically to expand Tregs for restoration of immune homeostasis.
T cells and natural killer (NK) cells constitutively express CD122 and CD132 that can respond to high-dose IL-2, leading to their activation and tissue destruction. In fact, the current U.S. Food and Drug Administration–approved use of IL-2 is for enhancing immunity in patients with metastatic renal cell carcinoma and melanoma. Proleukin, a prescription form of IL-2, has an explicit warning for exacerbation of a variety of autoimmune and inflammatory diseases. In mouse models, high-dose IL-2 precipitated diabetes in a few days in prediabetic mice .(32) As Tregs constitutively express high-affinity receptors for IL-2, low-dose IL-2, in theory, should preferentially boost Tregs without causing global immune activation. While this is shown to be true in mouse models (33), many issues remain in applying IL-2 therapy to humans.
Malek and colleagues (34) report their investigation of the cellular basis of Treg responsiveness to IL-2 and their findings help to address many of these crucial issues in applying IL-2 therapy for treatment of T1D. The investigators found that Tregs from normal individuals were invariably better responders to IL-2, followed by CD56hi NK cells and memory T cells. By calculating the half-maximal concentrations (EC50) for each cell type, the group was able to quantitatively measure the differences in IL-2 responsiveness and found that Tregs were 7 to 10 times more sensitive to IL-2 than NK cells and memory T cells. Overall, this new report by Malek and colleagues (34) lends strong support for low-dose IL-2 therapy for boosting Tregs in patients with T1D. Future study is needed to determine heterogeneity of responsiveness to low-dose IL-2 in Tregs as well as other IL-2–responsive cells, especially NK cells.