The impact of disease activity and tumour necrosis factor-α inhibitor therapy on cytokine levels in juvenile idiopathic arthritis.

The aim of this study was to evaluate prospectively cytokine levels and disease activity in juvenile idiopathic arthritis (JIA) patients treated with and without tumour necrosis factor (TNF)-α inhibitors. TNF-α inhibitor-naive JIA subjects were followed prospectively for 6 months. Cytokine levels of TNF-α, interleukin (IL)-1ß, IL-6, IL-8, IL-10 and IL-17 were measured at baseline for JIA subjects and healthy controls (HCs). Cytokine levels were then measured at four time-points after initiation of TNF-α inhibition for anti-TNF-α-treated (anti-TNF) JIA subjects, and at two subsequent time-points for other JIA (non-TNF) subjects. JIA disease activity by Childhood Health Assessment Questionnaire (CHAQ) disability index/pain score and physician joint count/global assessment was recorded. Sixteen anti-TNF, 31 non-TNF and 16 HCs were analysed. Among JIA subjects, those with higher baseline disease activity (subsequent anti-TNFs) had higher baseline TNF-α, IL-6 and IL-8 than those with lower disease activity (non-TNFs) (P < 0·05). TNF-α and IL-10 increased, and IL-6 and IL-8 no longer remained significantly higher after TNF-α inhibitor initiation in anti-TNF subjects. Subgroup analysis of etanercept versus adalimumab-treated subjects showed that TNF-α and IL-17 increased significantly in etanercept but not adalimumab-treated subjects, despite clinical improvement in both groups of subjects. JIA subjects with increased disease activity at baseline had higher serum proinflammatory cytokines. TNF-α inhibition resulted in suppression of IL-6 and IL-8 in parallel with clinical improvement in all anti-TNF-treated subjects, but was also associated with elevated TNF-α and IL-17 in etanercept-treated subjects.

CD56(+dim) and CD56(+bright) cell activation and apoptosis in hepatitis C virus infection.

CD3- CD56(+dim) natural killer (NK) cells, which are cytotoxic against virally infected cells, may be important in hepatitis C virus (HCV)-infected patients who are successfully treated with pegylated interferon (PEG-IFN)-alpha. We used flow cytometry to enumerate activated (CD69+) and apoptotic (annexin-V+) dim (CD3- CD56(+dim)) and bright (CD3- CD56(+bright)) NK cells obtained from HCV-infected patients before treatment (n=16) and healthy controls (n=15) in the absence and presence of pegylated interferon (PEG-IFN)-alpha-2b. A subset of HCV-infected patients, subsequently treated with PEG-IFN-alpha-2b in vivo, was determined to have a sustained virological response (SVR, n=6) or to not respond (NR) to treatment (n=5). In the absence of IFN, activated dim (CD3- CD56(+dim) CD69+) NK cells were significantly decreased (P=0.04) while activated apoptotic dim (CD3- CD56(+dim)CD69+ annexin-V+) NK cells tended to be increased (P=0.07) in SVR patients compared with NR patients. Activated bright (CD3-CD56(+bright)CD69+) and activated apoptotic bright (CD3- CD56(+bright)CD69+ annexin-V+) NK cells were significantly correlated (P=0.02 and P=0.01, respectively) with increasing hepatic inflammation. These findings suggest that in the absence of PEG-IFN, activated dim (CD3- CD56(+dim)CD69+) NK cell turnover may be enhanced in SVR compared with NR patients and that activated bright (CD3- CD56(+bright)CD69+) NK cells may play a role in liver inflammation.

Neutrophil and monocyte adhesion molecules in bronchopulmonary dysplasia, and effects of corticosteroids.

AIMS: To study a longitudinal change in the expression of adhesion molecules CD11b, CD18, and CD62L on neutrophils and monocytes in very low birth weight babies who develop respiratory distress syndrome, to compare these levels between bronchopulmonary dysplasia (BPD) and non-BPD infants, and to assess the effect of corticosteroid treatment on these adhesion molecules. METHODS: Of 40 eligible neonates, 11 neonates were oxygen dependent at 36 weeks (BPD 36 weeks), 16 infants were oxygen dependent at 28 days, but not at 36 weeks (BPD d28), and 13 infants did not develop BPD. Seventeen neonates received a six day course of steroid treatment. Expression of CD11b, CD18, and CD62L was measured on neutrophils and monocytes in arterial blood on days 1, 3, 7, 14, 21, and 28, and before and 2-3 days after initiation of dexamethasone treatment by flow cytometry. RESULTS: CD18 expression on neutrophils and monocytes and CD62L on neutrophils, measured as mean fluorescent intensity, was significantly decreased in BPD neonates compared to non-BPD neonates on days 1-28. Dexamethasone treatment significantly decreased CD11b, CD18, and CD62L expression on neutrophils, and CD11b and CD18L expression on monocytes. CONCLUSIONS: Decreased CD18 expression on neutrophils and monocytes, and decreased CD62L expression on neutrophils, measured as mean fluorescent intensity during the first four weeks of life in micropremies may be risk factors and early predictors of BPD. Dexamethasone use was associated with decreased expression of CD11b, CD18, and CD62L.

The effect of aging on mucosal host defense.

Mucosal immune response is primed at birth and responses generated at this time support specific immunity in later life. Conversely development of mucosal immune response to new antigens is diminished in aging. Availability of key nutrients that are conditionally essential especially in the context of sub-acute infections may limit immune response. A critical hypothesis is that conditionally essential nutrient requirements are associated with aging and form the fundamental basis of observed immune senescence. Since mucosal immunity is modulated by the interaction of microflora with the gut immune system, it is likely that changes in the gut during aging affect this microenvironment. Probiotic lactic acid bacteria offer one approach to stimulating the gastrointestinal immune system thereby enhancing systemic as well as mucosal immune response in aging. The mechanisms of action appear to include specific stimulation of natural killer cells (NK) and the innate immune system.

Respiratory burst activity in bronchopulmonary dysplasia and changes with dexamethasone.

The first objective of this study was to evaluate longitudinal changes in respiratory burst activity in circulating neutrophils and monocytes in infants of less than 30 weeks of gestation with respiratory distress syndrome (RDS), and to examine differences in neonates who subsequently developed bronchopulmonary dysplasia (BPD) compared with those neonates who did not. The second objective was to investigate the effects of dexamethasone on respiratory burst activity in neutrophils and monocytes. We measured burst activity on neutrophils and monocytes in fresh heparinized blood in response to E. coli, N-formyl-met-leu-phe (fMLP), and phorbol 12-myristate 13-acetate stimulation on days 3, 7, 14, and 21 of life, before and 2-3 days after initiating a 6-day course of dexamethasone treatment. Infants with RDS participating in the study were followed until discharge, and were classified as non-BPD and either 1) BPD d28, reflecting their oxygen requirement at day of life 28, or 2) BPD 36 weeks, reflecting oxygen dependence at 36 weeks' corrected gestational age. The diagnosis of BPD was supported by radiological changes of BPD. The percentage of activated neutrophils producing a respiratory burst increased in all premature infants with increasing postnatal days during the first 28 days of life, when the physiological stimulus E. coli was used as an activator (P < 0.02). There was no significant difference in respiratory burst activity measured either as percent activation or as mean fluorescence intensity between non-BPD and BPD infants after adjusting for the difference in weight and gestational age between the two groups. The treatment of premature infants with dexamethasone was associated with decreased activation of neutrophils (P < 0.005) when E. coli was used as a stimulus. In conclusion, a significant increase in neutrophil respiratory burst activity occurs during the first month of life in very low birth weight infants. Greater pulmonary damage in BPD cannot be attributed to reduced burst activity in either neutrophils or monocytes. Dexamethasone treatment was associated with decreased neutrophil respiratory burst activity.

Resistance to multiple steroids in two sisters.

A 14-year-old Native American girl from the Iroquois Nation was referred as a potential patient with the syndrome of Apparent Mineralocorticoid Excess. Instead, her evaluation revealed resistance to glucocorticoids, mineralocorticoids, and androgens. She lacked Cushingoid features in spite of significantly high cortisol levels. Menstruation was regular and there was no clinical evidence of masculinization despite high serum androgen levels in the male range. The patient's sister had similar clinical features. Partial resistance to exogenous glucocorticoid and mineralocorticoid administration was well demonstrated in both patients. It is proposed that these patients represent the first cases of partial resistance to multiple steroids, possibly owing to a coactivator defect.

Effect of transfusional iron overload on immune response.

Increased susceptibility to infectious disease is observed in persons with transfusion-dependent thalassemia and iron overload who experience increased exposure to pathogens and chronic immune stimulation. An abnormal low CD8(+) T (LT8) immune phenotype defines a subgroup of patients. The CD8(+) T cell immunophenotype is stable despite continued blood transfusion and is independent of age. CD8(+) T cells, but not CD4(+) T cells, were modulated during intravenous chelation with deferoxamine. Return to characteristic pretreatment levels of CD8 was observed in both the low and the normal groups, suggesting the possibility of a set point. Proliferative response to mitogens and antigens was increased by chelation. Because CD8(+) T cells are important in immune response to infectious disease, these studies suggest that intrinsic CD8(+) T cell subset differences may be a critical factor in determining susceptibility to infection independent of transfusional iron overload or alloantigen exposure.

Probiotics and immune response.

Current evidence supports the concept that oral administration of probiotic lactobacilli may be therapeutic in preventing antibiotic-associated diarrhea in children and in reestablishing normal flora in the gastrointestinal tract. Children with human immunodeficiency virus (HIV) infections may have episodes of diarrhea and frequently experience malabsorption associated with possible bacterial overgrowth; together these may interact to produce the growth abnormalities characteristic of this group. The overall objective of this investigation has been to determine whether oral administration of the probiotic Lactobacillus plantarum 299v could improve nutrient status and promote growth in children congenitally exposed to HIV. In addition, the possible beneficial effect of Lactobacillus plantarum 299v in modulating immune response was evaluated. In preliminary results described here, we report on the ability of Lactobacillus plantarum 299v to colonize children with HIV and to elicit specific systemic immune response after oral supplementation.

Cytokines and neonates.

This review is a short synopsis of the roles cytokines play during fetal life, initiation of labor, and in neonatal immunity and diseases. Hematopoietic growth factors regulate the maturation of progenitors in fetal and neonatal hematopoietic organs. Cytokines act as extra-hematopoietic growth factors, modulators of feto-maternal tolerance and are involved in selective apoptosis during tissue remodeling. Inter-regulation of cytokine networks is critical for normal function and maturation of neonatal host defenses. Antigen specific immunity develops later in life and neonates initially depend on natural (innate) immunity. Cytokines regulate innate immunity and connect it with antigen specific adaptive immunity. Some cytokines have already found a place in routine NICU therapy (EPO and G-CSF), while diagnostic and therapeutic uses of others are under investigation (TPO, TNF-alpha, etc.).

Resistance to several steroids in two sisters.

A 14-yr-old native American girl from the Iroquois Nation was referred as a potential patient with the syndrome of apparent mineralocorticoid excess. Instead, her evaluation revealed resistance to glucocorticoids, mineralocorticoids, and androgens, but no resistance to vitamin D or thyroid hormones. She lacked Cushingoid features despite significantly high cortisol levels. Menstruation was regular, and there was no clinical evidence of masculinization despite high serum androgen levels in the male range. The patient's sister had similar clinical features. Partial resistance to exogenous glucocorticoid and mineralocorticoid administration was well demonstrated in both patients. It is proposed that these patients represent the first cases of partial resistance to multiple steroids, possibly due to a coactivator defect.

Nutrition and the immune system of the gut.

Studies suggest that the development and expression of the regional immune system in the gastrointestinal (GI) tract is relatively independent of systemic immunity. This is reflected in significant differences in functional response of T cells and B cells and affects cytokine patterns and activation pathways when regional immunity is compared to systemic immunity. Nutrients have fundamental and regulatory influences on the immune response of the GI tract and, therefore, on host defense. In addition to the effect of nutrition during development, the local impact of different dietary and antigenic elements on the regional immune system contributes to potential diversion of the two systems throughout life. The route of exposure during antigenic contact is known to affect host immune response, whether it be a normal process, happening in the context of normal environmental encounter with nonpathogenic microbes or planned immunization, or occurring as a result of resolution of a potentially pathologic process i.e., an infectious encounter. Interactions at the local level profoundly influence systemic immune response, in part because of intrinsic differences in these systems, and also because of different requirements for optimal function. Although inflammatory processes are central to host defense in the periphery, the protective blocking action of the secretory immunoglobulin A immune response is crucial to local host defense, and, therefore, to the integrity of GI tract immune function. For these reasons, interaction with normal bacteria of the GI tract may be seen as the model of how the system has evolved and provide clues to the restoration of balance in the immunocompromised host. Reduction of normal commensal bacteria in the context of infection or after antibiotic treatment may interfere with nutrient availability and impair beneficial stimulation of GI immune response. This impairment may be associated with continued colonization with opportunistic microbes and inflammatory immune response that could lead to malabsorption and malnutrition. Study of the impact of nutrient imbalance on the function of the GI tract has profound implications for clinical medicine and may in the future lead to the rational design of preventive approaches to support immune response and host defense.

Intravenous anti-D treatment of immune thrombocytopenic purpura: experience in 272 patients.

We report the results of intravenous anti-D (WinRho, WinRho SD) therapy in 261 non-splenectomized patients treated at the New York Hospital-Cornell Medical Center over the period from 1987 to 1994. Children (n = 124) and adult patients (n = 137) with classic immune thrombocytopenic purpura (ITP; n = 156) or human immunodeficiency virus (HIV) related thrombocytopenia (n = 105) and acute (n = 75) or chronic (n = 186) disease at the time of the initial anti-D treatment were studied. In addition, 11 previously splenectomized patients were treated as a separate group. Our objectives were to evaluate the following. (1) Efficacy of anti-D: The response after the initial infusion was analyzed according to clinical parameters, such as patient's age, HIV status, gender, disease duration, pretreatment platelet count, and hemoglobin value, as well as treatment-related factors, including the dose of anti-D, the solvent detergent treatment of the preparation, and the type of administration. (2) Use of anti-D as maintenance therapy: The duration of response after the initial infusion and the results of subsequent treatments were evaluated. (3) Safety/toxicity of anti-D: Postinfusion reactions and hemoglobin decrease after treatment were studied. Anti-D is a safe treatment providing a hemostatic platelet increase in greater than 70% of the Rh+ non-splenectomized patients. The group with the best results is HIV- children, but all patient groups respond and the effect lasts more than 21 days in 50% of the responders. Duration of response is not influenced by HIV status; furthermore, HIV+ patients show no adverse effects on hemoglobin decrease or HIV disease progression. Patients with chronic ITP after splenectomy have minimal or no response to intravenous anti-D.

Soluble factor of transformed B lymphocytes in patients with HIV infection stimulates monocytes to produce PGE2.

Prostaglandins of the E series (PGE) were measured in the culture supernatants of peripheral blood mono-nuclear cells (PBMC) obtained from patients with human immunodeficiency virus (HIV) infection. Cell culture supernatants from 6 patients with acquired immunodeficiency disease (AIDS) and 11 patients with AIDS-related complex contained significantly higher concentrations of PGE than those from a group of 6 healthy HIV-negative male homosexual control subjects. The PGE producer cells were among the population of plastic-adherent PBMC. Transformed B lymphocyte cell lines spontaneously derived from the blood of patients with AIDS secrete a factor that stimulates normal donor adherent PBMC to produce PGE. The HIV permissive H9 cell line stimulated a significantly lower level of PGE production, which was not associated with HIV infection.

Micronutrient and cytokine interaction in congenital pediatric HIV infection.

Malnutrition is a frequent manifestation of HIV infection that has received comparatively little attention despite growing clinical importance with improved treatment and lengthened survival times. Fundamental relationships and mechanisms of HIV viral interaction in nutrient metabolism remain to be established. In an attempt to begin to fill the void of information relative to pediatric HIV infection, we have summarized the extant knowledge with regard to micronutrients and present some of the data from studies performed in our laboratory. Previous studies have shown both that vitamin A deficiency is associated with increased mortality in HIV+ intravenous drug users and that maternal vitamin A deficiency is a risk factor for transmission in congenital exposure. Our most significant finding is that 70% of children congenitally exposed to HIV are vitamin A-deficient in the first months of life compared to age-matched controls whether they are HIV-infected or not. About 25% of our patient population was found to have growth or developmental delay, frequently without other signs of progression and in the presence of an intact T-cell compartment. In addition, we found evidence of cytokine imbalance, specifically elevated plasma levels of TNF which has been implicated in loss of lean body mass. Inflammatory reactions in the mucosa and increased TNF production in association with regional HIV infection may compromise gastrointestinal absorption. Based on the review of the literature and our research findings, it is clear that understanding the interaction between nutrients and both the regional and systemic immune system is vital for intervention and effective nutrient repletion in congenital HIV infection.

New perspectives on use of thymic factors in immune deficiency.

Current knowledge on the role of thymic factors in the immune response is inadequate and remains relatively primitive when compared with present technical possibilities for assessing lymphocyte subsets or cytokine interaction. New studies support the potential importance of thymic factors as regulators of immune interactions. Indirect evidence supports the concept that thymic factors may work at the level of IL-2. The functional identity of cells responsive to thymic factors and the relation of observed effects to cytokine network interactions need to be established. The use of thymic factors in the future will depend on the development of criteria to identify appropriate settings in which to use such factors and the implementation of appropriate measures of immune functional response.

Antineurofilament and antiretinal antibodies in AIDS patients with cytomegalovirus retinitis.

Sera obtained from AIDS patients with cytomegalovirus (CMV) retinitis before and after treatment with foscarnet, AIDS patients with human immunodeficiency virus (HIV) retinopathy, AIDS patients without retinal disease, and normal healthy controls with and without positive CMV serologies were assayed for the presence of antibodies against the 200-kDa outer, 160-kDa middle, and 68-kDa core subunits of the neurofilament triplet. Additional studies were performed to determine the presence of antibodies reactive with proteins extracted from crude human retinal antigen preparations. Antibodies against the 200-, 260-, and 68-kDa proteins of the neurofilament triplet were detected in 15 of 15 AIDS patients with CMV retinitis. The expression of these antibodies was unaffected, qualitatively, by successful treatment with foscarnet. In contrast, only 30% of patients with HIV retinopathy unrelated to CMV, fewer than 35% of AIDS patients with positive CMV titers but without evident retinitis, and fewer than 25% of healthy controls with positive or negative CMV titers possessed antibodies against any of the triplet proteins (P < 0.001). Antibodies against several clusters of retinal antigens were also identified in the sera of patients with CMV retinitis. In summary, the data indicate that retinal elements damaged by CMV infection induce an antibody response against the 200-, 160-, and 68kDa components of the neurofilament triplet as well as other, as yet undefined retinal antigens.

Immunomodulation in choroidal melanoma: reversal of inverted CD4/CD8 ratios following treatment with ultrasonic hyperthermia.

It has long been suggested that malignant melanomas, cutaneous as well as uveal, are responsive to human immune-mediated host defenses. We report here 5 consecutive cases of posterior choroidal melanomas which were treated with hyperthermia generated by high-intensity focused ultrasound. Patient immune function was monitored by determination of T-cell helper/suppressor (CD4/CD8) ratios immediately before and approximately 1 week following hyperthermia treatment. All 5 patients had normal total T-cell counts as measured by the pan-T-cell marker CD3. Two patients were noted to have inverted CD4/CD8 ratios (< 1:1) before hyperthermia. In both these cases, the ratio reverted to normal (> 1:1) 1 week following treatment. One patient whose CD4/CD8 ratio was not inverted was noted to have a further increase in his CD4 T cells relative to his CD8 (37% increase). Two patients with initially normal CD4/CD8 demonstrated no significant change following hyperthermia. It appears that ultrasonic hyperthermia may induce a systemic immunomodulatory effect in patients with posterior choroidal melanoma and inverted T-cell helper/suppressor resulting in a normalization of T-cell subset ratios.