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1.  Comparison of Immunity in Mice Cured of Primary/Metastatic Growth of EMT6 or 4THM Breast Cancer by Chemotherapy or Immunotherapy 
PLoS ONE  2014;9(11):e113597.
Purpose
We have compared cure from local/metastatic tumor growth in BALB/c mice receiving EMT6 or the poorly immunogenic, highly metastatic 4THM, breast cancer cells following manipulation of immunosuppressive CD200:CD200R interactions or conventional chemotherapy.
Methods
We reported previously that EMT6 tumors are cured in CD200R1KO mice following surgical resection and immunization with irradiated EMT6 cells and CpG oligodeoxynucleotide (CpG), while wild-type (WT) animals developed pulmonary and liver metastases within 30 days of surgery. We report growth and metastasis of both EMT6 and a highly metastatic 4THM tumor in WT mice receiving iv infusions of Fab anti-CD200R1 along with CpG/tumor cell immunization. Metastasis was followed both macroscopically (lung/liver nodules) and microscopically by cloning tumor cells at limiting dilution in vitro from draining lymph nodes (DLN) harvested at surgery. We compared these results with local/metastatic tumor growth in mice receiving 4 courses of combination treatment with anti-VEGF and paclitaxel.
Results
In WT mice receiving Fab anti-CD200R, no tumor cells are detectable following immunotherapy, and CD4+ cells produced increased TNFα/IL-2/IFNγ on stimulation with EMT6 in vitro. No long-term cure was seen following surgery/immunotherapy of 4THM, with both microscopic (tumors in DLN at limiting dilution) and macroscopic metastases present within 14 d of surgery. Chemotherapy attenuated growth/metastases in 4THM tumor-bearers and produced a decline in lung/liver metastases, with no detectable DLN metastases in EMT6 tumor-bearing mice-these latter mice nevertheless showed no significantly increased cytokine production after restimulation with EMT6 in vitro. EMT6 mice receiving immunotherapy were resistant to subsequent re-challenge with EMT6 tumor cells, but not those receiving curative chemotherapy. Anti-CD4 treatment caused tumor recurrence after immunotherapy, but produced no apparent effect in either EMT6 or 4THM tumor bearers after chemotherapy treatment.
Conclusion
Immunotherapy, but not chemotherapy, enhances CD4+ immunity and affords long-term control of breast cancer growth and resistance to new tumor foci.
doi:10.1371/journal.pone.0113597
PMCID: PMC4237434  PMID: 25409195
2.  Cure of metastatic growth of EMT6 tumor cells in mice following manipulation of CD200:CD200R signaling 
In previous studies, we observed that regulation of expression of CD200, both on cells of a transplantable breast cancer, EMT6, and of the host, as well as of the receptor, CD200R in host mice, regulated local tumor growth and metastasis in immunocompetent animals. This in turn led to an improved ability to document immunity to EMT6 in CD200R1KO mice. In the current study, we have explored the ability to cure BALB/c CD200KO or CD200R1KO mice of tumors ≤1 cm3 in size by surgical resection of localized tumor, followed by immunization with irradiated EMT6 cells along with CpG as adjuvant. While control animals treated in this fashion developed significant pulmonary and liver metastases within 30 days of surgery, significant protection was seen in both CD200KO or CD200R1KO mice, with no macroscopic lung/liver metastases observed in CD200R1KO mice on sacrifice at day 300. Following surgical resection and immunization, draining lymph nodes from control mice contained tumor cells cloned at limiting dilution in vitro even before pulmonary and hepatic metastasis was seen. In contrast, within the limits of detection of the assay used (sensitivity ~1 in 107 cells), no tumor cells were detected at limiting dilution in similarly treated CD200R1KO mice, and significant reductions were seen in CD200KO mice. Infusion of anti-CD4, but less so anti-CD8, mAb into surgically treated and immunized CD200R1KO mice attenuated protection from both macroscopic (liver/lung) and microscopic (assayed by limiting dilution of DLN) metastasis. Adoptive transfer of lymphocytes from treated CD200R1KO mice to surgically treated control mice also attenuated metastatic growth of tumor, which was abolished by pretreatment of transferred cells with anti-CD4 mAb. Our data suggest that CD200:CD200R attenuates a potentially tumor-protective CD4 host response to breast cancer.
Electronic supplementary material
The online version of this article (doi:10.1007/s10549-013-2735-3) contains supplementary material, which is available to authorized users.
doi:10.1007/s10549-013-2735-3
PMCID: PMC3832754  PMID: 24166280
Breast cancer; Metastasis; CD200R1KO; CD200R1KO; Immunotherapy
3.  Pollen aero allergens and the climate in mediterranean region and allergen sensitivity in allergic rhinoconjunctivitis and allergic asthma patients 
Background
We evaluated the profiles of allergic rhino-conjunctivitis and asthma patients annually in Antalya, a Mediterranean coastal city in Turkey.
Material/Methods
We evaluated patients’ allergic clinical status, and recorded the climate and pollens in the city center air, investigating any correlation between pollination, climatic conditions and allergic disorders. The meteorological conditions and the pollen count/cm2 during every month of the year and the concordance of this with the patient’s clinical status were evaluated.
Results
SPT positivity for plantago lanceolata, aspergillus fumigatus and d. pteronyssinus was significant in patients younger than 40 years old. Pollination levels are consistent from March 2010 to February 2011. In Antalya, high levels occur mostly from April to June, thus we performed skin prick tests mostly in May/June (~30%). During these months meteorological conditions of the city were windy with low humidity, without rain, and lukewarm temperatures, all of which contribute to high-risk conditions for seasonal allergies.
Conclusions
The major allergen between April and June was derived from Graminea; between February and March was Cupressus spp; and between March and June was Pinus spp. These results suggest that the pollination is correlated with allergic conditions and thus SPT might be best performed according to the pollen count.
doi:10.12659/MSM.883762
PMCID: PMC3629014  PMID: 23396359
aero allergens; climate; allergic rhinoconjunctivitis; allergic asthma; Mediterranean coast
5.  IL-8, IL-10, TGF-β, and GCSF Levels Were Increased in Severe Persistent Allergic Asthma Patients with the Anti-IgE Treatment 
Mediators of Inflammation  2012;2012:720976.
Background. Allergic asthma is showed an increase in Th2-cytokine and IgE levels and an accumulation activation of Th2 cells, eosinophils and mast cells. However, recent studies focused on cell-based mechanisms for the pathogenesis of allergic asthma. Objectives. In this study, we compare the anti-IgE treatment modality in the dynamics of immune system cytokine levels in severe persistent asthma (SPA) patients who had no other any allergic disease, newly diagnosed allergic asthma patients and healthy volunteers. Study Design. The study population consisted of 14 SPA patients, 14 newly diagnosed allergic asthma patients and 14 healthy volunteers included as controls. Cytokine levels were measured. Total and specific IgE levels of anti-IgE monoclonal antibody treated patients, serum high-sensitivity C-reactive protein (hsCRP) levels, FEV1/FVC rates and asthma control test (ACT) were measured for the clinical follow-up. Results. We observed that SPA patients presented increasing levels of IL-8, IL-10, TGF-β and GCSF during the anti-IgE treatment in period of sampling times at 4 months and 18 months. However this increase was not correlated neither with serum hsCRP levels nor FEV1/FVC rates. Conclusions. Our study gives a different perspective for the SPA and anti-IgE immunotherapy efficacy at the cell cytokine-linked step.
doi:10.1155/2012/720976
PMCID: PMC3536437  PMID: 23316107
6.  Serum-soluble TRAIL levels in patients with severe persistent allergic asthma: Its relation to omalizumab treatment 
Summary
Background
In this study we compare the Omalizumab treatment modality in the dynamics of cell apoptosis regulating molecules in both severe persistent asthma patients who had no other any allergic disease, newly diagnosed patients with allergic asthma, and healthy volunteers.
Material/Methods
Severe persistent allergic asthma patients were subjected to measurement of serum soluble TRAIL (TNF-related apoptosis-inducing ligand) levels during the active disease phase and the stable phase which occurred 4 months after Omalizumab treatment. Serum sTRAIL concentrations were measured by a solid phase sandwich enzyme-linked immunosorbent assay. Concentration levels were compared with those of age- and sex-matched newly diagnosed patients with allergic asthma, and healthy controls. All assays were carried out in duplicate. Total serum IgE levels, antinuclear antibody (ANA), rheumatoid factor (RF), hepatitis markers, C3, C4 and eosinophil levels were evaluated in all patients.
Results
ANA, RF, hepatitis markers were negative in all patients. Complement 3 and 4 levels were normal in all patients. Prick tests in all patients were detected in mite and grass allergy. These results correlated with specific IgE. There were no differences between the healthy controls, newly diagnosed allergic asthma patients, and non-treated severe persistent allergic asthma patients during the active phase. Interestingly, the levels in variances of the patients who had the effective omalizumab treatment were significantly lower than the healthy controls, while the mean values were not statistically significant.
Conclusions
Our study gives a different perspective on severe persistent allergic asthma and omalizumab treatment efficacy at the cell apoptosis-linked step by the serum sTRAIL levels.
doi:10.12659/MSM.882504
PMCID: PMC3560751  PMID: 22367138
severe persistent allergic asthma; allergic asthma; soluble TRAIL; omalizumab
7.  481 Differences in Humoral and Cellular Immunity in Young and Old Individuals 
Background
The immune system changes with the age. In this study we characterized immune changes by performing immunologic screening profiles on aging individuals (graduation thesis).
Methods
This study was performed at Akdeniz University, in the Faculty of Medicine, Dept. of Immunology. Healthy volunteers consisted of a young group (22 donors) and an older group (45 individuals). Using flow cytometry analysis, CD3, CD4, CD8, CD16, CD19, CD28, CD40, CD45, CD56, CD80, CD86, CTLA-4 and with ELISA IL-1 β, IL-2, IL-6, IL-10, IFN-γ, TNF-α expression were evaluated, along with and NK activity and induced cytokine expression (by bioassay/ELISA respectively).
Results
No statistical differences were observed between the 2 groups in expression of CD3, CD8, CD19, CD80, CD86, CD16, CD 56 or CD28. A higher frequency of expression of CD4, CTLA-4, CD40 and CD45 was seen in older subjects by comparison with young subjects. Cytokine profiles expressed by stimulated monocytes from the 2 groups showed no difference in IL-1 β, IL-2, IL-6, IL-10, TNF-α and IFN-γ production levels. Cytokine profiles expressed by stimulated lymphocytes from the 2 groups showed no difference in IL-1 β, IL-2, IL-6, IL-10, TNF-α and IFN-γ production levels.
Conclusions
We found increased expression levels of CD40 and CD45 levels in healthy older (>55 years old) versus young individuals (media age 28 years). CTLA-4 expression levels were also higher in elderly subjects, with no difference in CD28 expression levels between young/elderly individuals.
doi:10.1097/01.WOX.0000411596.10529.68
PMCID: PMC3512630
8.  233 The Evaluation of Allergen Sensitivity in Allergic Rhinoconjunctivitis and Allergic Asthma Patients in Antalya, Turkey 
The World Allergy Organization Journal  2012;5(Suppl 2):S93-S94.
Background
Allergic rhinitis is a common health problem which has 2 forms; seasonal and perennial. The prevalence and etiology of allergic rhinitis varies from region to region and affect 10 to 20% of the population approximately. The prevalences of asthma, allergic rhinitis and allergic eye disease were detected as 8.2%, 10.8% and 7.5% respectively in Antalya, the south coast of Turkey.
Methods
The study was conducted in Antalya between 10th of November 2009 and 20th of September 2010. 866 of 2862 patients who had allergic rhinoconjunctivitis and asthma were enrolled in the study due to having high total IgE levels in blood conducted at the Allergy-Immunology Division of Antalya Research and Training Hospital. Allergen-spesific subcutaneous immunotherapy was given 626 of 866 patients.
Results
Of the 866 patients studied, 66.1 % were females. Most of the cases had declaired that the rhinitis symptomes were due to pollens and house dust the second most common irritant. Also the cases have said that their symptoms got worse with exposure to dust, smoke, heavy odors, perfumes, and detergents. Most of the patients have said that air pollution was the most important factor that exacerbated the symptoms of rhinitis and asthma. While there is a comparison between the age and SPT positivity, Aspergillus fumigatus and Dpteronyssinus sensitivity was statistically different in the mites and fungal mixture dermal test groups. As a result, in the study group of 866 allergic rhinitis patients, only the Plantagolanceolata, Corylusavellana, Aspergillus fumigatus, Dpteronyssinus and cockroach sensitivity was significantly varies with the age.
Conclusions
In allergic diseases; we all know that allergens may have regional variations. That's why; the allergen profiles of the regions must be determined and the dermal Prick tests must be prepared accordingly. Mostly grass and cereal mixtures and mites are responsible from the allergic rhinitis cases due to our observations in our clinic. The other important allergens that are linked to the flora and climate of the region are olive and the cockroaches. High asthma prevalence in people living in shanties and in housewives may be due to exposure to house dust mites.
doi:10.1097/01.WOX.0000411990.41169.0a
PMCID: PMC3512677
9.  277 Serum Soluble Trail Levels in Patients With Severe Persistent Allergic Asthma: Its Relation to Omalizumab Treatment 
Background
The pathogenesis of allergic asthma and other allergic conditions are believed to be closely interrelated because of the similar dynamics of allergy-inducing cells and molecules, and the independent evidence for their clinical overlap. In this study we compare the diseases and the effect of Omalizumab treatment on the dynamics of cell apoptosis regulating molecules.
Methods
In the first group, 6 males and 8 females (a total of 14 patients) were selected with severe persistent asthma with a mean age of 42.4 years (Table I). All patients received omalizumab therapy for 4 months, with treatment administered every 2 weeks. Symptoms and severity of allergic reactions were recorded before and after treatment with omalizumab. Clinical changes and adverse effects were assessed and recorded at each patient visit. The second group consisted of 14 newly diagnosed allergic asthma patients with mean age was 43.8 years. All of these patients were followed up in the Immunology Allergy Clinic of the Antalya Education and Training Hospital, and were evaluated by clinical status. The third group consisted of 14 healthy volunteers, with no difference in age and sex (mean age was 43,3 years. Serum sTRAIL levels in all individuals (patients and healthy controls) were measured by a sandwich enzyme-linked immunosorbent assay (Diaclone, France).
Results
There were no differences between the healthy controls, newly diagnosed allergic asthma patients and non-treated severe persistent allergic asthma patients during the active phase (P < 0.05). Interestingly, the variance levels in patients who received omalizumab treatment were significantly lower than the healthy controls.
Conclusions
In summary, we speculate that the physiological functions of sTRAIL in allergic conditions, and the elucidation of the molecular mechanisms by which sTRAIL: TRAIL receptor signals cells, will be of significant interest to the scientific allergy community in the coming years. Our study provides a novel perspective on severe persistent allergic asthma and the effect of omalizumab treatment on cell apoptosis, using serum sTRAIL measurements.
doi:10.1097/01.WOX.0000412034.85125.4f
PMCID: PMC3512706
10.  384 Jessner-kanoff Lymphocytic Infiltrate as a Side Effect of Immunotherapy 
The World Allergy Organization Journal  2012;5(Suppl 2):S139-S140.
Background
Allergen immunotherapy has been used in the management of allergic diseases for nearly 100 years. It is the only specific treatment for hymenoptera venom anaphylaxis. Various venom immunotherapy schedules have been designed to treat anaphylaxis. Although the effect of venom immunotherapy is well documented, there is also an increased risk of side-effects in bee-venom-treated patients and in those with rapid dose increase.
Methods
This report describes the first case of a patient in the literature with Jessner's Lymphocytic infiltration as a side effect of venom immunotherapy. This is a chronic, benign, T cell pseudolymphoma characterized by the occurrence of recurrent, asymptomatic, smooth, erythematous, non-scaling papules or plaques. However, the exact cause of Jessner's Lymphocytic Infiltration is unknown.
Results
The case here reported was a 61 year-old male pediatrician, who has been followed by at our Immunology Service because of an immediate allergy to a bee sting managed with venom immunotherapy. His chief complaint was an anaphylactic reaction after 5 minutes of a bee sting. The onset of his symptoms was gradual and began just 25 minutes after the sting. The venom immunotherapy regimen was planned and the protocol immediately began without premedication. But during the initial phases of treatment, on the third dose of immunotherapy, he reported severe itching. After complaining of itching, many erythematous papules and plaques on his chest were developed. The lesions flared up for 3 days period just after injection and decreased afterwards. The type of lesions and their location supported the diagnosis of Jessner disease, which had also a histopathological confirmation.
Conclusions
We herein report this case to call attention to this side effect of VIT that there may be more similar cases never reported.
doi:10.1097/01.WOX.0000412147.11920.7f
PMCID: PMC3512780
11.  270 Clinical Experience in Allergic Asthma Patients: Omalizumab with Immunotherapy 
Background
To evaluate the therapeutic efficacy of omalizumab and specific subcutaneous immunotherapy (SCIT) as a treatment modality in patients with more than one allergic-type condition.
Methods
In the first group (Group A), 2 males and 7 females with severe persistent asthma and a mean age of 34.2 years received omalizumab and SCIT. In the second group (Group B), 4 males and 2 females with severe persistent asthma and a mean age of 52.7 years received omalizumab only. In the third group (Group C), 1 male and 3 females with severe persistent asthma and a mean age of 28.8 years received omalizumab followed by SCIT. All patients were followed for 2 years and comparisons were made using pulmonary function tests and asthma control tests.
Results
The patients studied had severe persistent asthma for periods ranging from 2 to 10 years, and in addition had been diagnosed as allergic asthmatics for 5 to 40 years. The mean IgE levels were as follows: Group A: 553.9 IU/mL; Group B: 422.3 IU/Ml; and Group C: 383.5 IU/mL. In all 3 groups results in the asthma control test increased by 2.5 fold over the period of study.
Conclusions
After the addition of SCIT to omalizumab therapy at 48 week of our study, no change was detected in urticarial attack rates. In another 17 year old male patient with moderate allergic rhinoconjunctivitis, asthma and atopic dermatitis, omalizumab administration with SCIT at the same time, increased the severity of atopic dermatitis. We stopped the immunotherapy than the skin lesions lost.omalizumab therapy is continued.
doi:10.1097/01.WOX.0000412027.16513.76
PMCID: PMC3512926
12.  278 Total Antioxidant Capacity, Hydrogen Peroxide, Malondialdehyde and Total Nitric Oxide Concentrations in Patients With Severe Persistent Allergic Asthma: Its Relation to Omalizumab Treatment 
The World Allergy Organization Journal  2012;5(Suppl 2):S107-S108.
Background
There is no data available to adequately explain the alterations in total antioxidant capacity, hydrogen peroxide, malondialdehyde and total nitric oxide concentrations in severe persistent asthma and newly diagnosed allergic asthma patients. In the study below we have examined changes in total antioxidant capacity, hydrogen peroxide, malondialdehyde and total nitric oxide levels in severe persistent asthma and newly diagnosed allergic asthma patients and the association(s) between these variables.
Methods
The first group of patients included 6 male and 8 female subjects with severe persistent asthma, having a mean age of 42.4 years. A second group of subjects consisted of 14 newly diagnosed allergic asthma patients with a mean age of 43.8 years. All patients were followed in our clinic, and were evaluated by clinical status. A third group of 14 age-sex matched healthy controls were also included. Serum samples were collected and stored at –70 until use for the determination of total antioxidant capacity, hydrogen peroxide, malondialdehyde and total nitric oxide concentrations. Serum IgE levels, ANA, RF, hepatitis markers, C3, C4 and eosinophil levels were evaluated in all patients. All assays were carried out in duplicate.
Results
Total antioxidant capacity levels of Group IB, group II and group III were lower than the IA group. Total antioxidant capacity levels of groups II and III were higher than in group IB. Hydrogen peroxide concentrations in group IB were lower than in group IA, while concentrations in group II were higher than in group IB. The malondialdehyde concentration of group IB was lower than in all other groups. The malondialdehyde concentration of group III was higher than all other groups. The malondialdehyde concentration of group II was lower than in group III. The total nitric oxide level of group IB was lower than all other groups. The total nitric oxide level of group III was higher than all other groups, while that of group II was higher than for both groups IA/IB.
Conclusions
To monitor the omalizumab treatment efficacy in the severe allergic asthma patients; total antioxidant capacity, hydrogen peroxide, malondialdehyde and total nitric oxide concentrations might be new markers.
doi:10.1097/01.WOX.0000412035.92748.e6
PMCID: PMC3512995
13.  426 The Evaluation of Allergen Sensitivity in Food Allergy Patients in Antalya, Turkey 
Background
In this study, the socio-demographic characteristics, skin prick test were evaluated in treated patients diagnosed with Food allergies.
Methods
The study was conducted in Antalya between 10 November 2009 and 20 September 2010. A questionnaire made by the investigators taking the latest literature data into consideration were used during the study. The total and specific IgE levels were made by fluoroenzyme immunoassay method via use of ImmunoCAP kit. For dermal prick tests Alyostal ST-IR standard allergen extracts were used. The statistical data derived were evaluated by using 14.00 SPSS software. Ki-Square test and percent ratios were used for data analysis. A P value less than 0.05 was assumed for statistical significance.
Results
During the study 173 patients: 116 female (67%), 57 male (32.9%) were included. Among patients 42% belonged to the 20 to 29 years of age group and 39% were University degree graduates. The total duration of the food allergy was 3.12 ± 0.39 years. The total Ig E level was 103.6 ± 11.5 Ku/L. The most common allergen was orange and kakao.
Conclusions
Food allergies are the most common cause of anaphylaxis and no pharmacologic treatments are available to prevent a reaction. The emergency use of epinephrine, antihistamines, and steroids are usually successful in treating a systemic reaction that is already underway. That's why; the allergen profiles of the regions must be determined and the dermal Prick tests must be prepared accordingly.
doi:10.1097/01.WOX.0000412189.71123.cb
PMCID: PMC3513023
14.  TRAIL Death Receptor-4, Decoy Receptor-1 and Decoy Receptor-2 Expression on CD8+ T Cells Correlate with the Disease Severity in Patients with Rheumatoid Arthritis 
Background
Rheumatoid Arthritis (RA) is a chronic autoimmune inflammatory disorder. Although the pathogenesis of disease is unclear, it is well known that T cells play a major role in both development and perpetuation of RA through activating macrophages and B cells. Since the lack of TNF-Related Apoptosis Inducing Ligand (TRAIL) expression resulted in defective thymocyte apoptosis leading to an autoimmune disease, we explored evidence for alterations in TRAIL/TRAIL receptor expression on peripheral T lymphocytes in the molecular mechanism of RA development.
Methods
The expression of TRAIL/TRAIL receptors on T cells in 20 RA patients and 12 control individuals were analyzed using flow cytometry. The correlation of TRAIL and its receptor expression profile was compared with clinical RA parameters (RA activity scored as per DAS28) using Spearman Rho Analysis.
Results
While no change was detected in the ratio of CD4+ to CD8+ T cells between controls and RA patient groups, upregulation of TRAIL and its receptors (both death and decoy) was detected on both CD4+ and CD8+ T cells in RA patients compared to control individuals. Death Receptor-4 (DR4) and the decoy receptors DcR1 and DcR2 on CD8+ T cells, but not on CD4+ T cells, were positively correlated with patients' DAS scores.
Conclusions
Our data suggest that TRAIL/TRAIL receptor expression profiles on T cells might be important in revelation of RA pathogenesis.
doi:10.1186/1471-2474-11-192
PMCID: PMC2936350  PMID: 20799941
15.  Alternative splicing of CD200 is regulated by an exonic splicing enhancer and SF2/ASF 
Nucleic Acids Research  2010;38(19):6684-6696.
CD200, a type I membrane glycoprotein, plays an important role in prevention of inflammatory disorders, graft rejection, autoimmune diseases and spontaneous fetal loss. It also regulates tumor immunity. A truncated CD200 (CD200tr) resulting from alternative splicing has been identified and characterized as a functional antagonist to full-length CD200. Thus, it is important to explore the mechanism(s) controlling alternative splicing of CD200. In this study, we identified an exonic splicing enhancer (ESE) located in exon 2, which is a putative binding site for a splicing regulatory protein SF2/ASF. Deletion or mutation of the ESE site decreased expression of the full-length CD200. Direct binding of SF2/ASF to the ESE site was confirmed by RNA electrophoretic mobility shift assay (EMSA). Knockdown of expression of SF2/ASF resulted in the same splicing pattern as seen after deletion or mutation of the ESE, whereas overexpression of SF2/ASF increased expression of the full-length CD200. In vivo studies showed that viral infection reversed the alternative splicing pattern of CD200 with increased expression of SF2/ASF and the full-length CD200. Taken together, our data suggest for the first time that SF2/ASF regulates the function of CD200 by controlling CD200 alternative splicing, through direct binding to an ESE located in exon 2 of CD200.
doi:10.1093/nar/gkq554
PMCID: PMC2965252  PMID: 20558599
16.  CD200-dependent and nonCD200-dependant pathways of NK cell suppression by human IVIG 
Problem
Intravenous immunoglobulin (IVIG) has been used to suppress autoimmune and inflammatory disorders by a variety of mechanisms. Recently, the CD200 tolerance-promoting signal has been found to play a role in IVIG suppression of blood natural killer (NK) cells. Further, different types of IVIG have been reported to differ in this activity, and that has been related to efficacy (and inefficacy) of treatment of women with pregnancy failure. CD200 acts by binding to CD200 receptors (C200R). The objective of this study was to determine if CD200-dependent NK suppression by IVIG involved direct binding of IVIG-associated CD200 molecules to CD200R on NK cells.
Method of study
Peripheral Blood Lymphocytes isolated from human blood were used as a source of NK cells to lyse Cr51-labelled K562 target cells in vitro in 18 and 4 h assays, and three different types of IVIG were tested for suppressive activity in the presence or absence of specific monoclonal anti-huCD200. In some experiments, CD56+ NK cells were purified using anti-CD56 magnetic beads. Western blotting of IVIG using a specific anti-huCD200 antibody was done. Enzyme-Linked ImmunoSorbent Assays were used to measure cytokine production in NK assays.
Results
Different IVIGs showed significant differences in potency in suppressing NK cytolytic activity in vitro (mg/ml for 60% suppression, Gammagard 4.1, Gamunex 14.1, Gamimmune 20.2). For CD200-dependent suppression, Gammagard was twice as potent as Gamimmune, but equivalent to Gamunex. The presence of suppression in 4 hour assays indicated stimulation of cytokine synthesis was unlikely to explain CD200-dependent suppression. Purification of NK cells led to loss of the CD200-dependent component. Western blotting confirmed that material reactive with anti-CD200 antibody was present in Immunoglobulin G (IgG) preparations, and at a lower level in human serum that contains IgG.
Conclusions
IVIGs are not all equipotent in suppressing NK cell cytolytic activity. CD200 associated with IVIG is an important component of suppression. CD200-dependent suppression appears to be mediated by a non-NK population that then acts on NK cells by direct contact rather than indirectly through release of immunosuppressive cytokines.
doi:10.1007/s10815-008-9202-9
PMCID: PMC2582113  PMID: 18256920
IVIG; CD200; NK cells; Pregnancy immunology
17.  The Fgl2/fibroleukin prothrombinase contributes to immunologically mediated thrombosis in experimental and human viral hepatitis 
Fibrin deposition and thrombosis within the microvasculature is now appreciated to play a pivotal role in the hepatocellular injury observed in experimental and human viral hepatitis. Importantly, the pathways by which fibrin generation is elicited in viral hepatitis may be mechanistically distinct from the classical pathways of coagulation induced by mechanical trauma or bacterial lipopolysaccharide (LPS). In the setting of murine hepatitis virus strain-3 (MHV-3) infection, a member of the Coronaviridae, activated endothelial cells and macrophages express distinct cell-surface procoagulants, including a novel prothrombinase, Fgl2/fibroleukin, which are important for both the initiation and localization of fibrin deposition. To assess the role of Fgl2/fibroleukin in murine viral hepatitis we generated a Fgl2/fibroleukin–deficient mouse. Peritoneal macrophages isolated from Fgl2/fibroleukin–/– mice did not generate a procoagulant response when infected with MHV-3. Fibrin deposition and liver necrosis were markedly reduced, and survival was increased in mice infected with MHV-3. To address the relevance of Fgl2/fibroleukin in human chronic viral hepatitis we studied patients with minimal and marked chronic hepatitis B. We detected robust expression of Fgl2/fibroleukin mRNA transcripts and protein in liver tissue isolated from patients with marked chronic hepatitis B. Fibrin deposition was strongly associated with Fgl2/fibroleukin expression. Collectively, these data indicate a critical role for Fgl2/fibroleukin in the pathophysiology of experimental and human viral hepatitis.
doi:10.1172/JCI200318114
PMCID: PMC162293  PMID: 12840059
18.  Functional human T-cell immunity and osteoprotegerin ligand control alveolar bone destruction in periodontal infection  
Periodontitis, a prime cause of tooth loss in humans, is implicated in the increased risk of systemic diseases such as heart failure, stroke, and bacterial pneumonia. The mechanisms by which periodontitis and antibacterial immunity lead to alveolar bone and tooth loss are poorly understood. To study the human immune response to specific periodontal infections, we transplanted human peripheral blood lymphocytes (HuPBLs) from periodontitis patients into NOD/SCID mice. Oral challenge of HuPBL-NOD/SCID mice with Actinobacillus actinomycetemcomitans, a well-known Gram-negative anaerobic microorganism that causes human periodontitis, activates human CD4+ T cells in the periodontium and triggers local alveolar bone destruction. Human CD4+ T cells, but not CD8+ T cells or B cells, are identified as essential mediators of alveolar bone destruction. Stimulation of CD4+ T cells by A. actinomycetemcomitans induces production of osteoprotegerin ligand (OPG-L), a key modulator of osteoclastogenesis and osteoclast activation. In vivo inhibition of OPG-L function with the decoy receptor OPG diminishes alveolar bone destruction and reduces the number of periodontal osteoclasts after microbial challenge. These data imply that the molecular explanation for alveolar bone destruction observed in periodontal infections is mediated by microorganism-triggered induction of OPG-L expression on CD4+ T cells and the consequent activation of osteoclasts. Inhibition of OPG-L may thus have therapeutic value to prevent alveolar bone and/or tooth loss in human periodontitis.
This article may have been published online in advance of the print edition. The date of publication is available from the JCI website, http://www.jci.org. J. Clin. Invest. 106:R59–R67 (2000).
PMCID: PMC3102542  PMID: 10995794

Results 1-18 (18)