Additive immunosuppressive effects of 1,25-dihydroxyvitamin D3 and corticosteroids on TH1, but not TH2, responses

BACKGROUND: The biologic role of the vitamin D analogue 1, 25-dihydroxyvitamin D(3), such as antiinflammatory functions, reduction of cytokine production by T cells, and immunoglobulin production by B cells, has been reported. Such immunomodulatory effects may be potentially useful in dealing with autoimmunity and transplantation. However, whether this hormone has an additive immunosuppressive effect when it is used with corticosteroids has not been investigated, although these agents are commonly used together. OBJECTIVE: Our purpose was to investigate the additive immunomodulatory effects of 1,25-dihydroxyvitamin D(3) on lymphocyte proliferation and cytokine production when used with corticosteroids. METHODS: To investigate the additive effects of 1, 25-dihydroxyvitamin D(3) and dexamethasone on suppression of lymphocyte proliferation, normal PBMCs were cultured in anti-CD3 with or without different concentrations of dexamethasone (0-10(-7) mol/L) plus or minus different concentrations of 1, 25-dihydroxyvitamin D(3) (0-10(-6) mol/L). After 3 days, lymphocyte proliferation was assessed by [(3)H]-thymidine incorporation. To investigate the additive effects of 1,25-dihydroxyvitamin D(3) and dexamethasone on cytokine production, PBMCs were cultured for 3 days in the presence of anti-CD3 with or without 10(-6) mol/L dexamethasone plus or minus 10(-6) mol/L 1,25-dihydroxyvitamin D(3). IFN-gamma, IL-5, and IL-13 production in supernatants were measured by ELISA. RESULTS: Our study demonstrated that, at concentrations of 10(-8), 10(-7), and 10(-6) mol/L, 1,25-dihydroxyvitamin D(3) significantly decreased lymphocyte proliferation compared with an ethanol control (P <.05). The IC(50) for dexamethasone was 4 x 10(-9) mol/L in culture without 1,25-dihydroxyvitamin D(3.) When 10(-9) mol/L of 1,25-dihydroxyvitamin D(3) was added to cultures with dexamethasone, IC(50) became 2 x 10(-9) mol/L. Moreover, when 10(-6), 10(-7), and 10(-8) mol/L of 1,25-dihydroxyvitamin D(3) were added in culture with dexamethasone, IC(50) became less than 1 x 10(-9) mol/L. IFN-gamma production in culture with either dexamethasone or 1,25-dihydroxyvitamin D(3) was significantly decreased compared with media or ethanol control (P <.0001). Moreover, when both agents were added in the same culture, IFN-gamma production was further decreased compared with either agent alone (P <.05). In contrast, 1,25-dihydroxyvitamin D(3) significantly (P <. 0001) increased IL-5 and IL-13, whereas dexamethasone significantly decreased these 2 cytokines (P <.0005). When 1,25-dihydroxyvitamin D(3) was combined with dexamethasone, IL-5 and IL-13 production was increased compared with dexamethasone alone (P <.001). CONCLUSIONS: Our results demonstrate that 1,25-dihydroxyvitamin D(3) has significant additive effects on dexamethasone-mediated inhibition of lymphocyte proliferation. This hormone also has additive effects on inhibition of T(H)1 cytokine production when combined with dexamethasone. However, this hormone upregulates T(H)2 cytokines and inhibits steroid-mediated suppression of cytokines. These findings demonstrate the potential use of 1,25-dihydroxyvitamin D(3) as an immunosuppressive agent when combined with corticosteroids in T(H)1, but not T(H)2, immune responses.     

Association between atrial fibrillation and central sleep apnea

BACKGROUND: We previously described an association between atrial fibrillation and central sleep apnea in a group of patients with congestive heart failure. We hypothesized that the prevalence of atrial fibrillation might also be increased in patients with central sleep apnea in the absence of other cardiac disease. METHODS AND RESULTS: We compared the prevalence of atrial fibrillation in a series of 60 consecutive patients with idiopathic central sleep apnea (apnea-hypopnea index > 10 events per hour, > 50% central events) with that in 60 patients with obstructive sleep apnea (apnea-hypopnea index > 10, > 50% obstructive events) and 60 patients without sleep apnea (apnea-hypopnea index < 10), matched for age, sex, and body mass index. Subjects with a history of congestive heart failure, coronary artery disease, or stroke were excluded from the study. The prevalence of atrial fibrillation among patients with idiopathic central sleep apnea was found to be significantly higher than the prevalence among patients with obstructive sleep apnea or no sleep apnea (27%, 1.7%, and 3.3%, respectively, P < .001). However, hypertension was most common and oxygen desaturation most extreme among patients with obstructive sleep apnea. CONCLUSIONS: We conclude that there is a markedly increased prevalence of atrial fibrillation among patients with idiopathic central sleep apnea in the absence of congestive heart failure. Moreover, the high prevalence of atrial fibrillation among patients with idiopathic central sleep apnea is not explainable by the presence of hypertension or nocturnal oxygen desaturation, since both of these were more strongly associated with obstructive sleep apnea.     

No association between VNTR polymorphisms of dopamine transporter gene and attention deficit hyperactivity disorder in Chinese children.

Dopamine transporter (DAT) gene is implicated in the pathogenesis of attention deficit hyperactivity disorder (ADHD). Previously a meta-analysis concluded no association between the variable-number-of-tandem-repeats (VNTR) polymorphisms of the DAT gene and ADHD. However, significant heterogeneity was present among studies and no conclusion can be drawn about the association in any single ethnicity given the small number of studies. There were also conflicting results in Chinese populations. We therefore perform the present study to investigate the association in Chinese children in Hong Kong. In this prospective family-based and case-control study during January to June 2004, we recruited consecutive Chinese children diagnosed with ADHD by DSM-IV criteria, their family members, and sex-matched controls admitted for acute upper respiratory infection, excluding those with perinatal brain insults, mental retardation, or neurological deficits. VNTR polymorphisms of the DAT gene were determined by standard PCR followed by agarose gel electrophoresis. Sixty-four ADHD cases (52 boys, 12 girls), their family members and 64 normal controls were recruited. The 10-repeat allele (92.6%) and the 10/10 repeat genotype (85.2%) were the most prevalent. Both family-based and case-control analyses showed no association between the DAT gene polymorphisms and ADHD (transmission dysequilibrium test: P = 0.99; odds ratio of 10-repeat allele = 0.89 (95%CI 0.35-2.28), P = 0.81; odds ratio of 10/10 repeat genotype = 0.69 (95%CI 0.26-1.84), P = 0.46). We concluded that VNTR polymorphism of the DAT gene is not associated with ADHD in Chinese children, and further studies are needed to clarify the polygenic and environmental influences for pathogenesis of ADHD.     

The kinetics of specific immune responses in rhesus monkeys inoculated with live recombinant BCG expressing SIV Gag, Pol, Env, and Nef proteins

Development of an effective preventive or therapeutic vaccine against HIV-1 is an important goal in the fight against AIDS. Effective virus clearance and inhibition of spread to target organs depends principally on the cellular immune response. Therefore, a vaccine against HIV-1 should elicit virus-specific cytotoxic lymphocyte (CTL) responses to eliminate the virus during the cell-associated stages of its life cycle. The vaccine should also be capable of inducing immunity at the mucosal surfaces, the primary route of transmission. Recombinant Bacille Calmette-Guérin (BCG) expressing viral proteins offers an excellent candidate vaccine in view of its safety and ability to persist intracellularly, resulting in the induction of long-lasting immunity and stimulation of the cellular immune response. BCG can be administered orally to induce HIV-specific immunity at the mucosal surfaces. The immunogenicity of four recombinant BCG constructs expressing simian immunodeficiency virus (SIV) Gag, Pol, Env, and Nef proteins was tested in rhesus macaques. A single simultaneous inoculation of all four recombinants elicited SIV-specific IgA and IgG antibody, and cellular immune responses, including CTL and helper T cell proliferation. Our results demonstrate that BCG recombinant vectors can induce concomitant humoral and cellular immune responses to the major proteins of SIV.     

Effect of HLA class I or class II incompatibility in pediatric marrow transplantation from unrelated and related donors

The degree of histoincompatibility that can be tolerated, and the relative importance of matching at individual HLA class I and class II locus in bone marrow transplantation (BMT) has not been established. We hypothesized that matching for HLA-DR may not be more important than matching for HLA-A or HLA-B in selection of a donor for successful BMT. We retrospectively analyzed the outcomes of 248 consecutive pediatric patients who received allogeneic BMT from related donors (RD, n = 119) or unrelated donors (URD, n = 129). HLA-A and HLA-B were serologically matched, and HLA-DRB1 were identical by DNA typing in 69% of donor-recipient pairs. Most patients (89%) had hematologic malignancies; the rest had aplastic anemia or a congenital disorder. One HLA-A antigen mismatch was associated with a decrease in survival (p = 0.003) and a delay in granulocyte engraftment (p = 0.02) in recipients of RD marrow; as well as a decrease in survival (p = 0.02) and the development of severe acute graft-versus-host disease (GVHD) (p = 0.03) in recipients of URD marrow. One HLA-B antigen mismatch was associated with a decrease in the survival (p = 0.05) and the development of severe GVHD (p = 0.0007) in recipients of RD marrow. One HLA-DRB1 allele mismatch was associated only with a decrease in the survival (p = 0.0003) of recipients of RD marrow. Results of this study suggest that disparity in HLA-A and HLA-B antigens may not be better tolerated than disparity in HLA-DR allele in allogeneic BMT. Further studies are warranted to confirm our results.     

Norepinephrine and amino acids in prepyriform cortex of rats fed imbalanced amino acid diets

Monoamines and amino acids were measured in anterior prepyriform cortex (PPC) and anterior cingulate cortex (CC) of male Sprague-Dawley rats after they were offered basal, imbalanced (IMB) or corrected amino acid diets, limited in threonine (THR) or isoleucine (ILE). In the THR study, brains were taken after 2.5 hr of feeding, when intake of THR-IMB was just depressed. In the ILE study the brains were taken after 3.5 hr on ILE-IMB, a less severely imbalanced ration, before the onset of food intake depression. The PPC has been shown to be involved in the acute response of animals to imbalanced amino acid diets. In the PPC from the IMB diet groups, NE was reduced by 30%, but the other monoamines were unchanged. In CC, an area involved in the adaptive, but not the acute feeding response to imbalanced diets, the monoamines were unchanged in the IMB diet groups. In both studies, in both tissues, the limiting amino acids were decreased in the IMB groups, although the decrease of ILE in the CC failed to reach significance. The remaining indispensable amino acids, added to create the imbalance, were slightly reduced in the THR-IMB group, but not in the ILE-IMB group in both tissues. Thus, the amino acid patterns were altered in the PPC and CC, as they are in whole brains from animals fed imbalanced amino acid diets. These results also suggest that the concentration of NE in the PPC may be associated with the initial food intake response of animals to imbalanced amino acid diets.     

Dominantly inherited syndrome of microcephaly and congenital lymphedema

A Chinese family is reported in which microcephaly and congenital lymphedema have been observed in at least 4 generations. This combination of symptoms can be presumed to represent a rare but well defined hereditary syndrome transmitted by an autosomal dominant gene.     

Immunobiological properties of a recombinant simian retrovirus-1 envelope protein and a neutralizing monoclonal antibody directed against it.

We previously reported that an area encompassing amino acids 147-162 of the envelope region of the simian (type D) retrovirus serotype 1 (SRV-1) constitutes an antigenic site for the binding of murine and rhesus neutralizing antibodies. Neutralizing antibodies to SRV-2 are directed to a different area, encompassing residues 96-102 of SRV-2. This paper presents data on the activity of an SRV-1 recombinant envelope protein (rEP) and of monoclonal hybridoma cell line, C11B8, produced from murine spleen cells immunized with SRV-1 rEP. Purified monoclonal antibodies from C11B8 bind to the SRV-1 rEP and to both SRV-1 and SRV-2. However, the monoclonal antibody exhibits strain specificity in the capacity to neutralize SRV-1 infection in vitro. Thus, C11B8 neutralizes SRV-1 infection but fails to neutralize four other known serotypes of the virus. C11B8 also binds to an SRV-1 synthetic peptide representing residues 142-167, which encompasses the previously defined antigenic site of recognition for neutralizing antibodies to SRV-1. This paper also contains evidence that the SRV-1 rEP construct binds the site for SRV-1 attachment to the cell receptor. This is indicated by the ability of SRV-1 rEP to compete with SRV-1 (but not with SRV-2) and inhibit its infectivity in vitro. In addition, SRV-1 rEP inhibits the neutralizing activity of C11B8 against SRV-1 infection in vitro. SRV-1 rEP has no inhibitory effect on rhesus neutralizing antibodies to SRV-2. Taken together, the above findings indicate that immunity conferred at the level of neutralizing antibodies during SRV infection is strain-specific and involves the recognition of envelope sequences unique to each strain.