Immune Deviation Research Articles

Effects of Vaccination with Altered Peptide Ligand on Chronic Pain in Experimental Autoimmune Encephalomyelitis, an Animal Model of Multiple Sclerosis

Neuropathic pain is a chronic symptom of multiple sclerosis (MS) and affects nearly half of all MS sufferers. A key instigator of this pain is the pro-inflammatory response in MS. We investigated the behavioral effects of immunization with a mutant peptide of myelin basic protein (MBP), termed altered peptide ligand (APL), known to initiate immune deviation from a pro-inflammatory state to an anti-inflammatory response in experimental autoimmune encephalomyelitis (EAE), an animal model of MS. Male and female Lewis rats were injected with vehicle control or with varying doses of 50 or 100 μg guinea pig MBP in combination with or without APL. APL-treated animals established significantly lower disease severity compared to encephalitogenic MBP-treated animals. Animals with EAE developed mechanical, but not thermal pain hypersensitivity. Mechanical pain sensitivities were either improved or normalized during periods of clinical disease in male and female APL-treated animals as compared to the encephalitogenic group. No significant changes to thermal latency were observed upon co-immunization with APL. Together these data indicate that APL ameliorates disease states and selectively mediates an analgesic effect on EAE animals.

Cytokine status in Ukrainian children with irritable bowel syndrome residing in a radioactive contaminated area.

The effect of low dose radiation on immune system is shown. Ionizing radiation can affect cytokine production and polarization of T helper cells. The current study focused on ionizing radiation in Ukrainian children residing in a contaminated area with clinical irritable bowel syndrome. Our study included 75 rural children population aged 4-18 yrs, who lived in a contaminated area exposed to natural environmental radiation with clinical irritable bowel syndrome (categorized in three groups) and 20 rural children participants aged 5-15 yrs who were living in areas with similar levels of radioactive contamination without clinical irritable bowel syndrome as control group. Internal radiation activity was measured by gamma-ray spectrometry. Serum levels of IL-4 and IFN-γ were measured by enzyme linked immunosorbent assay. A trend towards increased levels of IL-4 was observed in children with clinical irritable bowel syndrome. In these children, IFN-γ levels were lower than that of the control group. The IBS symptoms in Ukrainian children residing in a contaminated area may have stemmed from Th1 to Th2 immune deviation and differential expression of IL-4 and IFN-γ.

Tissue damage and immunity in cutaneous leishmaniasis

Cutaneous leishmaniasis (CL) is caused by parasitic infection of dermal macrophages resulting in intense immune-mediated tissue inflammation and skin ulceration. The severity of the disease is dependent on parasite species as well as the immune responses evoked by the host. Most cases of CL heal spontaneously. In rare cases, the ulcer/s become chronic, and some Leishmania species may induce mucosal leishmaniasis (MCL) leading to severe tissue damage. Due to difficulties in obtaining skin tissue, most human studies of CL have been limited to the analysis of peripheral blood. While systemic responses may be good correlates of immunity, tissue damage and local immune responses at the site of infection is seldom reflected in alterations in the peripheral blood. In this review, we discuss the different forms of CL focusing on the in situ responses in established disease and the mechanisms involved in pathology and healing of Leishmania infection. Great effort has been put into animal models dissecting the immune events behind the evolution of disease, tissue pathology and parasite control. These models of genetically engineered, immune deficient mice or mice given therapy prior to onset of overt disease poorly reflect the clinical situation, where patients seek treatment once infection is well established. Models of established disease are needed to address the clinical challenge of identifying new therapeutic targets in treatment CL. Through understanding immune deviations during CL potential benefits and risks of emerging biological drugs in leishmaniasis can be addressed.

Effects of human umbilical cord-derived mesenchymal stem cells on anterior chamber-associated immune deviation

Introduction of antigen into anterior chamber (AC) induces a deviant immune response termed anterior chamber-associated immune deviation (ACAID) that protects the eye from inflammatory destruction consequent to a systemic immune response. Mesenchymal stem cells (MSCs) can modulate a variety of immune responses. However, the effects of systemic administration of MSCs on ACAID have not been explored. In this study, C57BL/6 mice were inoculated with ovalbumin in the AC to induce ACAID, control group received AC injection of solvent alone. Immediately after the AC injection, the mice were injected through the tail vein with human Umbilical Cord-derived MSCs (hUC-MSC) or phosphate buffer saline. All animals were subcutaneously immunized with ovalbumin one week later. Delayed-type hypersensitivity assay was performed another week following immunization. The splenic monocytes were then isolated, cultured and stimulated with ovalbumin. Levels of IL-10, TGF-β, and IFN-γ in culture media were measured by ELISA. The frequencies of CD4+CD25+Foxp3+ and CD8+Foxp3+ regulatory T cells (Tregs) were determined by flow cytometry. The results showed that the AC inoculation of ovalbumin induced significantly less ear swelling than controls, confirming the establishment of ACAID. MSCs potentiated IL-10 and TGF-β production, further suppressed IFN-γ secretion from splenic monocytes in ACAID mice, and enhanced expansion of CD4+CD25+Foxp3+ and CD8+Foxp3+ Tregs isolated from the spleen of ACAID mice. Therefore, our study, for the first time, provides clear evidence that systemic administration of MSCs augments cytokine production and Treg expansion from ACAID spleens, which may contribute to promotion and maintenance of ACAID.

Type II Collagen Induces Peripheral Tolerance in BALB/c Mice via the Generation of CD8+ T Regulatory Cells

Antigens introduced into the anterior chamber (AC) of the eye induce a potent form of antigen-specific peripheral immune tolerance termed AC-associated immune deviation (ACAID), which prevents inflammatory immune responses and is characterized by impaired delayed-type hypersensitivity (DTH) responses. Type-II collagen (CII) is a fibrillar protein expressed exclusively in cartilage tissues. Although of its clinical relevance to Rheumatoid arthritis, aging, and osteoarthritis, there have been no studies to date to test if CII has the ability to induce ACAID. We hypothesized that ACAID could be generated via AC injection of CII in BALB/c mice. Using a DTH assay, the hypothesis was supported and led to another hypothesis that CII is capable of inducing specific immune tolerance via CD8+ T regulatory cells (Tregs). Thus, we performed functional local adoptive transfer (LAT) assays to examine the regulatory roles of spleen cells, T cells, and CD8+ T cells in the specific immune regulation induced by CII injection into the AC. Results indicated that CII induced ACAID when injected into the AC. Spleen cells of mice injected with CII in the AC significantly suppressed DTH responses. The T cell compartment of the spleen was capable of expressing this suppression. CD8+ Tregs could solely express this CII-driven suppression and even exerted more noticeable suppression than spleen cells or splenic T cells. This study suggests a crucial role for CD8+ Tregs in mediating CII-driven ACAID-mediated immune tolerance. This could have therapeutic implications in Rheumatoid arthritis, aging, osteoarthritis, and other diseases in which CII is involved.

An Intracameral Injection of Antigen Induces In Situ Chemokines and Cytokines Required for the Generation of Circulating Immunoregulatory Monocytes

Anterior Chamber-Associated Immune Deviation (ACAID) induced by an intracameral injection of antigen generates antigen-specific regulatory splenic T cells that suppress specifically cell-mediated immunity specific for the injected antigen. Circulating F4/80+ cells recovered from mice receiving an intracameral injection of antigen are thought to be ocular in origin and induce the development of thymic and splenic regulatory T cells. We have shown previously that after the intracameral injection of antigen there is a CCR2/CCL2-dependent infiltration of circulating F4/80+ cells into the anterior chamber associated with the generation of circulating, ACAID-inducing F4/80+ monocytes. Here we tested the hypothesis that the intracameral injection of antigen induces events in the anterior chamber that are associated with the induction of circulating immunoregulatory monocytes that induce the suppression of cell-mediated immunity. The intracameral injection of antigen resulted in aqueous humor (i) a time- dependent increase of CCL2 and CCL7, (ii) a transient increase in TNF-α, and (iii) an infiltration of CD11bhi, Gr1hi and F4/80+ as well as F4/80− and Gr1hi peripheral blood cells into the anterior chamber. Further characterization of these F4/80+ cells revealed that they are Ly 6Chi, LY6Glo or negative, 7/4 (LY6B)hi, CD115+, CD45+, CD49B+, and CD62 L+. Antibody-mediated neutralization of TGF-β in situ in the anterior chamber prevented the induction of circulating, ACAID-inducing monocytes and ACAID. These cells did not increase in the irides of ACAID-refractory CCR2–/– and CCL2–/– mice that received an intracameral injection of antigen. Our results extend our suggestion that ACAID is initiated as the result of a mild proinflammatory response to intracameral injection that results in the infiltration of a CCR2+ subset of monocytes into the anterior chamber where there is a TGF-β-dependent induction of an immunosuppressive phenotype in the infiltrated monocytes that recirculate to induce antigen-specific regulatory T cells.

Retinal Laser Burn-Induced Neuropathy Leads to Substance P-Dependent Loss of Ocular Immune Privilege

Inflammation in the eye is tightly regulated by multiple mechanisms that together contribute to ocular immune privilege. Many studies have shown that it is very difficult to abrogate the immune privileged mechanism called anterior chamber-associated immune deviation (ACAID). Previously, we showed that retinal laser burn (RLB) to one eye abrogated immune privilege (ACAID) bilaterally for an extended period of time. In an effort to explain the inflammation in the nonburned eye, we postulated that neuronal signals initiated inflammation in the contralateral eye. In this study, we test the role of substance P, a neuroinflamatory peptide, in RLB-induced loss of ACAID. Histological examination of the retina with and without RLB revealed an increase of the substance P-inducible neurokinin 1 receptor (NK1-R) in the retina of first, the burned eye, and then the contralateral eye. Specific antagonists for NK1-R, given locally with Ag within 24 h, but not 3, 5, or 7 d post-RLB treatment, prevented the bilateral loss of ACAID. Substance P knockout (KO) mice retained their ability to develop ACAID post-RLB. These data support the postulate that substance P transmits early inflammatory signals from the RLB eye to the contralateral eye to induce changes to ocular immune privilege and has a central role in the bilateral loss of ACAID. The possibility is raised that blocking of the substance P pathway with NK1-R antagonists postocular trauma may prevent unwanted and perhaps extended consequences of trauma-induced inflammation in the eye.

Neonatal antigen-presenting cells are functionally more quiescent in children born under traditional compared with modern environmental conditions

One explanation for the high burden of allergic and autoimmune diseases in industrialized countries is inappropriate immune development under modern environmental conditions. There is increasing evidence that the process of immune deviation already begins in utero, but the underlying immunologic mechanisms are not clear. We sought to identify differences in the function of neonatal antigen-presenting cells (APCs) in children born in settings that are more traditional versus those of modern societies. Cord blood mononuclear cells were collected from newborns from Papua New Guinea (PNG; traditional) and Australia (modern) and compared for differences in APCs and T-cell phenotype and function. Australian cord naive T cells (CD4(+)CD25(-)CD127(+) cells) showed an enhanced and more rapid proliferative response in an autologous, APC-dependent culture system, a result of differences in neonatal APCs rather than T-cell function. This included an increased capacity to process antigen and to upregulate activation markers after stimulation. In contrast, resting PNG APCs exhibited higher baseline levels of activation and inhibitory markers and were less responsive or nonresponsive to stimulation in vitro. This study supports the hypothesis that prenatal environments can influence the developing immune system in utero. Children born under modern environmental conditions exhibit increased APC reactivity at birth compared with children born under traditional environmental conditions. The functionally more quiescent nature of PNG neonatal APCs might protect against the development of harmful inflammatory responses in early life.

Is HOT a Cool Treatment for Type 1 Diabetes?

Type 1 diabetes (T1D) is an organ-specific autoimmune disease characterized by immune-mediated destruction of the insulin-producing β-cells of the islets of Langerhans that results in life-long insulin dependence (1). Given the immunological nature of the disease, numerous antigen-specific as well as nonantigen-specific tolerance induction or immune deviation strategies have been developed as treatments for T1D. Although successful in experimental models, results of studies to translate these strategies to humans have been discouraging (2–5). This has prompted researchers to explore safer, broader, and more effective immunotherapeutic approaches to prevent, treat, and/or revert T1D. In this issue of Diabetes , Faleo et al. (6) show compelling data regarding use of hyperbaric oxygen therapy in autoimmune diabetes using nonobese diabetic (NOD) mice. This model spontaneously develops T1D, a feature that closely mimics human disease. Faleo et al. (6) show that hyperbaric oxygen therapy (HOT) significantly protects from T1D when initiated early in the disease course, but not after its onset, suggesting that this approach could be useful in high-risk individuals. According to the Undersea and Hyperbaric Medical Society, HOT is a process wherein patients breathe 100% oxygen (atmospheric air contains ~21% oxygen) while inside a treatment chamber at a pressure higher than at sea level (usually 2.5 times greater pressure). In 1662, Henshaw, a British clergyman, first used pressurized atmospheric air to treat certain ailments. Since that time, HOT has been used to treat various conditions such as decompression sickness, arterial gas embolism, and carbon monoxide poisoning (with or without …

Effects of Sublingual Immunotherapy on Allergic Inflammation: An Update

The most common allergic diseases, and especially the respiratory disorders such as rhinitis and asthma, are closely related to the allergic inflammation elicited by the causative allergen. This makes inflammation the main target of anti-allergic therapies. Among the available treatments, allergen specific immunotherapy (AIT) has a patent effect on allergic inflammation, which persists also after its discontinuation, and is the only therapy able to modify the natural history of allergy. The traditional, subcutaneous route of administration was demonstrated to modify the allergen presentation by dendritic cells (DCs) that in turn correct the phenotype of allergen-specific T cells, switching from the Th2-type response, typical of allergic inflammation and characterized by the production of IL-4, IL-5, IL-13, IL-17, and IL-32 cytokines to a Th1-type response. This immune deviation is related to an increased IFN-gamma and IL-2 production as well as to the anergy of Th2 or to tolerance, the latter being related to the generation of allergen-specific T regulatory (Treg) cells, which produce cytokines such as IL-10 and TGF-beta. Anti-inflammatory mechanisms observed during sublingual AIT with high allergen doses proved to be similar to subcutaneous immunotherapy. Data obtained from biopsies clearly indicate that the pathophysiology of the oral mucosa, with particular importance for mucosal DCs, plays a crucial role in inducing tolerance to the administered allergen.

Allergen Immunotherapy in Allergic Respiratory Diseases: From Mechanisms to Meta-analyses

Allergen-specific immunotherapy (SIT) involves the repeated administration of allergenic extracts to atopic individuals over a period of 3 to 5 years either subcutaneously (SCIT) or sublingually (SLIT) for the treatment of allergic respiratory diseases, including asthma and allergic rhinitis (AR). In studies, SCIT and SLIT have been shown to improve existing symptoms of asthma and AR and to also have the capability to cause disease-modifying changes of the underlying atopic condition so as to prevent new allergic sensitization as well as arrest progression of AR to asthma. Recent evidence suggests that immunotherapy brings about these effects through actions that use T-regulatory cells and blocking antibodies such as IgG4 and IgA2, which can then result in an “immune deviation” from a T-helper (Th) 2 cell pattern to a Th1 cell pattern. Numerous meta-analyses and studies have been performed to evaluate the existing data among these studies, with the consensus recommendation favoring the use of immunotherapy because of its potential to modify existing diseases. Significant adverse reactions can occur with immunotherapy, including anaphylaxis and, very rarely, death. A primary factor in considering SIT is its potential to provide long-lasting effects that are able to be sustained well after its discontinuation. Given the significant burden these allergic diseases impose on the health-care system, SIT appears to be a cost-effective adjunctive treatment in modifying the existing disease state. Allergen-specific immunotherapy (SIT) involves the repeated administration of allergenic extracts to atopic individuals over a period of 3 to 5 years either subcutaneously (SCIT) or sublingually (SLIT) for the treatment of allergic respiratory diseases, including asthma and allergic rhinitis (AR). In studies, SCIT and SLIT have been shown to improve existing symptoms of asthma and AR and to also have the capability to cause disease-modifying changes of the underlying atopic condition so as to prevent new allergic sensitization as well as arrest progression of AR to asthma. Recent evidence suggests that immunotherapy brings about these effects through actions that use T-regulatory cells and blocking antibodies such as IgG4 and IgA2, which can then result in an “immune deviation” from a T-helper (Th) 2 cell pattern to a Th1 cell pattern. Numerous meta-analyses and studies have been performed to evaluate the existing data among these studies, with the consensus recommendation favoring the use of immunotherapy because of its potential to modify existing diseases. Significant adverse reactions can occur with immunotherapy, including anaphylaxis and, very rarely, death. A primary factor in considering SIT is its potential to provide long-lasting effects that are able to be sustained well after its discontinuation. Given the significant burden these allergic diseases impose on the health-care system, SIT appears to be a cost-effective adjunctive treatment in modifying the existing disease state.

Immune deviations significance for complications risk in IVF and natural pregnancy

Immune deviations significance for complications risk in IVF and natural pregnancy

Seeing Eye to Eye With Gene Therapy

Seeing Eye to Eye With Gene Therapy

Prophylactic injection of non-citrullinated α-enolase has immunomodulatory effects in collagen-induced arthritis mice

BackgroundIdentification of autoantibodies associated with rheumatoid arthritis (RA) has been of major interest. In this context, the authors have previously identified for the first time α-enolase as a new auto-antigen...

489 Does Sublingual Immunotherapy Work with an Immune Deviation Mechanism?

BackgroundWe aimed at finding out the immunological mechanisms of SLIT by studying the activity of IgE specific for the epitopes of Phleum in patients treated with SLIT for grass allergen and in a control group.Methods30 patients allergic to grass were included in the study:15 patients carried out a pre-seasonal SLIT for 2 years with the 5 grass mix extract from Stallergenes.15 patients were not treated with SLIT.Eligible patientsClear symptoms of seasonal rhinoconjunctivitis during the past year, positivity to Phleum skin prick tests (+++-) and specific IgE (3.5 kU/L). Prick tests were performed with extracts from Stallergenes; serum specific IgE for Phleum and rPhlp1, rPhlp2, rPhlp5, rPhlp6, rPhlp7, and rPhlp12 were determined through the Unicap system 100 IgE FEIA (Phadia Usala, Sweden). Wilkoxon and Fischer method were performed. Rast Inibition rpPhlp1/rpPhlp1, rpPhlp1/rpPhlp2 and rpPhlp1/rpPhlp4 were evaluated.ResultsIgE for rPhlp7 and rPhlp12 present only in some patients did not show significant modifications. Most patients treated with SLIT for 2 years, and all those showing improvement in symptoms, showed a less evident increase of specific IgE for rPhlp1 and rPhlp5 if compared with that of minor allergens, ie, rPhlp2, rPhlp4, rPhlp6. This difference was absent in control patients and in patients not showing clinical improvement. In patients showing clinical improvement the IgE ratio rPhlp5/rPhlp2 was significantly decreased (P = 0.02). A RAST inhibition study showed no cross-reactivity between rPhlp1/rPhlp2 and rPhlp1/rPhlp4.ConclusionsAfter 1 and 2 years of SLIT, the data show the following results:a significant increase of specific IgE for minor allergens and a less evident increase of specific IgE for major allergens in patients showing a clinical response to SLITa drastic decrease in IgE ratio for rPhlp5/rPhlp2. These results suggest that SLIT not only induces a TH2-TH1 isotypic switch, but also can act with a mechanism of immunological replacement. In fact, the production of specific IgE for minor allergens (rPhlp2, rPhlp4, rPhlp6) tends to replace the production of specific IgE for major allergens (rPhlp1, rPhlp5).

Evidence for Quantitative and Functional Immune Deviation in Pediatric Patients with Sickle Cell Disease

Evidence for Quantitative and Functional Immune Deviation in Pediatric Patients with Sickle Cell Disease

Tolerance-Inducing Strategies in Islet Transplantation

Allogeneic islet transplantation is a promising approach for restoring normoglycemia in type 1 diabetic patients. Current use of immunosuppressive therapies for management of islet transplant recipients can be counterintuitive to islet function and can lead to complications in the long term. The induction of donor-specific tolerance eliminates the dependency on immunosuppression and allows recipients to retain responses to foreign antigens. The mechanisms by which tolerance is achieved involve the deletion of donor-reactive T cells, induction of T-cell anergy, immune deviation, and generation of regulatory T cells. This review will outline the various methods used for inducing donor-specific tolerance in islet transplantation and will highlight the previously unforeseen potential of tissue stromal cells in promoting islet engraftment.

Regulatory dendritic cells: there is more than just immune activation

The immune system exists in a delicate equilibrium between inflammatory responses and tolerance. This unique feature allows the immune system to recognize and respond to potential threats in a controlled but normally limited fashion thereby preventing a destructive overreaction against healthy tissues. While the adaptive immune system was the major research focus concerning activation vs. tolerance in the immune system more recent findings suggest that cells of the innate immune system are important players in the decision between effective immunity and induction of tolerance or immune inhibition. Among immune cells of the innate immune system dendritic cells (DCs) have a special function linking innate immune functions with the induction of adaptive immunity. DCs are the primary professional antigen presenting cells (APCs) initiating adaptive immune responses. They belong to the hematopoietic system and arise from CD34+ stem cells in the bone marrow. Particularly in the murine system two major subgroups of DCs, namely myeloid DCs (mDCs) and plasmacytoid DCs (pDCs) can be distinguished. DCs are important mediators of innate and adaptive immunity mostly due to their remarkable capacity to present processed antigens via major histocompatibility complexes (MHC) to T cells and B cells in secondary lymphoid organs. A large body of literature has been accumulated during the last two decades describing which role DCs play during activation of T cell responses but also during the establishment and maintenance of central tolerance (Steinman et al., 2003). While the concept of peripheral tolerance has been clearly established during the last years, the role of different sets of DCs and their particular molecular mechanisms of immune deviation has not yet fully been appreciated. In this review we summarize accumulating evidence about the role of regulatory DCs in situations where the balance between tolerance and immunogenicity has been altered leading to pathologic conditions such as chronic inflammation or malignancies.

FasL and TRAIL signaling in the skin during cutaneous leishmaniasis - implications for tissue immunopathology and infectious control

Cutaneous leishmaniasis (CL) is associated with chronic inflammation and ulceration of the skin. Tissue macrophages serve as host cells and immune activation is necessary for parasite clearance. The balance between immune-mediated tissue destruction and successful clearance of infection is delicate and ulceration has been proposed to be a result of infiltration of activated immune cells into the skin. FasL and TRAIL play a dual role in skin homeostasis through induction of apoptosis as well as proinflammatory signaling. During leishmaniasis, dysregulation of both FasL and TRAIL has been described by us and others but the resulting pathogenic effects in the skin during human leishmaniasis are not fully elucidated. Targeting disease specific immune deviations has proven to be a promising new approach for the therapy of autoimmune diseases. Potentially, targeting FasL or TRAIL in combination with microcidals could offer a future treatment strategy to reduce the disfiguring immunopathology associated with CL. In this mini review we will discuss how FasL and TRAIL-induced signaling may influence on the extent of tissue inflammation and the efficacy of parasite clearance in leishmaniasis.

Immune modulation by Lacto-N-fucopentaose III in experimental autoimmune encephalomyelitis

Parasitic infections frequently lead to immune deviation or suppression. However, the application of specific parasitic molecules in regulating autoimmune responses remains to be explored. Here we report on the immune modulatory function of Lacto-N-fucopentaose III (LNFPIII), a schistosome glycan, in an animal model for multiple sclerosis. We found that LNFPIII treatment significantly reduced the severity of experimental autoimmune encephalomyelitis (EAE) and CNS inflammation, and skewed peripheral immune response to a Th2 dominant profile. Inflammatory monocytes (IMCs) purified from LNFPIII-treated mice had increased expression of nitric oxide synthase 2, and mediated T cell suppression. LNFPIII treatment also significantly increased mRNA expression of arginase-1, aldehyde dehydrogenase 1 subfamily A2, indoleamine 2,3-dioxygenase and heme oxygenase 1 in splenic IMCs. Furthermore, LNFPIII treatment significantly reduced trafficking of dendritic cells across brain endothelium in vitro. In summary, our study demonstrates that LNFPIII glycan treatment suppresses EAE by modulating both innate and T cell immune response.