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HIV-specific cellular immune response is inversely correlated with disease progression as defined by decline of CD4+ T cells in relation to HIV RNA load.

The average time between infection with human immunodeficiency virus (HIV) and development of acquired immune deficiency syndrome is approximately 8 years. However, progression rates vary widely, depending on several determinants, including HIV-specific immunity, host genetic factors, and virulence of the infecting strain. In untreated HIV-infected patients with different progression rates, we examined HIV-specific T cell responses in combination with host genetic markers, such as chemokine/chemokine-receptor (CCR) polymorphisms and human leukocyte antigen (HLA) genotypes. HIV-specific CD4(+) T cell responses and, to a lesser extent, HIV-specific CD8(+) T cell responses were inversely correlated with progression rate. Slower progression was not related to polymorphisms in CCR genes, HLA genotype, or GB virus C coinfection. These data suggest that HIV-specific T cell responses are involved in protecting the host from disease progression.

Adult↗

Sequential ultrastructural podocytic lesions and development of proteinuria in serum sickness nephritis in the rat.

Serum sickness nephritis was induced in Fisher rats by immunization with egg albumin (EA) and correlations between immune complex deposition, alterations of podocytes and development of proteinuria were analysed. Immunoelectron microscopy showed that EA, rat IgG and C3 were confined to the electron-dense deposits (Ds). From 3 weeks, when significant proteinuria had developed, the subepithelial region was filled with large numbers of Ds on the peripheral capillary wall as well as in the paramesangium. The loss of slit diaphragms and detachment of foot processes overlying Ds were observed and the escape of Ds into urinary space was frequently detected. Morphometric evaluation showed that the volume of subepithelial Ds and the number of the sites of podocytic detachment correlate significantly with the amount of proteinuria. In addition, the native ferritin injected via the abdominal aorta was seen in large amounts in the urinary space near the areas devoid of epithelial covering. The development of podocytic detachment was clearly coincident with the appearance of proteins with a larger molecular weight in urine. From these results, it is suggested that the loss of slit diaphragms and the detachment of podocytes resulting from the progressive accumulation of Ds will allow the leakage of proteins of larger molecular weight across the capillary wall. These podocytic lesions may be one of the main aetiologies for the development of heavy proteinuria in this model.

Animals↗

[Cryoglobulins and circulating immune complexes in rheumatoid arthritis. Clinical and biological correlations].

We studied circulating immune complexes using a test involving the precipitation of these complexes with polyethylene glycol 6000 at 2.5 percent, and characterization of the Clq bound in vivo to immunoglobulins in the serum of 126 healthy subjects, 95 hospitalized controls and 181 patients suffering from rheumatoid arthritis (RP). Likewise, the RP benefited from a study of cryoglobulins (CG). The PEG-Clq proved positive (PEG +) in 7 per cent of the healthy controls, 25 per cent in the seronegative RP. ThePEG & RP have a level of proteins, gammaglobulins, IgM and IgG that is higher than in patients in whom the test is negative. On the other hand, they have a lower level of C4. One CG was detected in 43 patients who were all PEG +. The level of CG is proportionate to the intensity of the articular inflammation, the sedimentation rate, the level of seric iron and that of hemoglobin. The composition of the precipitins obtained by activity of the PEG is very close to that of the CG.

Adolescent↗

Circulating immune complexes in old people and in diabetics: correlation with autoantibodies.

Circulating immune complexes (CIC) were detected by a solid-phase radioassay in 34% of fifty-three insulin-dependent diabetics (IDD) as compared to 18% of forty-five non-insulin-dependent diabetics (NIDD) and 14% of 173 control subjects. In control subjects, the prevalence of CIC increased with age and was higher in males than in females. In IDD, immune complexes were found with the highest frequency before the age of 30 and after 50. There was no significant difference between the incidence of CIC in old IDD and their age-matched controls. The same sera were also tested for the presence of the following autoantibodies; nuclear , thyroid, gastric, smooth and striated muscle; mitochondria, sub-maxillary and adrenal gland and liver-kidney microsome. Sera containing at least one antibody were found in 16.4% of controls, 55.3% of IDD and 40% of NIDD. The prevalence of autoantibodies increased with age in controls but not in IDD. Islet cell antibodies were present in 28.5% of IDD and 2.9% of control subjects; they were more frequent in young patients. CIC and autoantibodies were statistically associated both in controls and IDD; in the patients, CIC were associated not only with islet cell antibodies but also with other autoantibodies. The possible relation between autoimmunity, degenerative vascular diseases and CIC is discussed.

Adult↗

Vitamin D metabolism by alveolar immune cells in tuberculosis: correlation with calcium metabolism and clinical manifestations.

The aim of this study was to investigate the relationship between the pulmonary vitamin D metabolism in tuberculosis and the calcium metabolism abnormalities and other clinical characteristics of the disease. The metabolism of 25-hydroxyvitamin D3 (25(OH)D3) by alveolar immune cells recovered by bronchoalveolar lavage (BAL) was evaluated in parallel to the results of calcium metabolism, 25(OH) D and 1,25 dihydroxyvitamin D (1,25(OH)2D) plasma levels and other clinical parameters obtained in 14 tuberculosis patients. Whilst predominant metabolites produced by lavage cells in patients and controls were 5(E)--and 5(Z) -19-nor-10-oxo-25(OH)D3, 1,25(OH)2D3 was produced by cells from all tuberculosis patients but not by cells from controls. Calcium metabolism abnormalities were observed in only some patients, but the production of 1,25 (OH)2D3 by lavage cells was found to correlate both with 1,25(OH)2D levels (r = 0.67) and post-load urinary calcium excretion (r = 0.59). 1,25(OH)2D3 production by lavage cells was increased in patients of black origin, and those presenting with hilar adenopathy without pulmonary infiltrates, and was correlated with the number of lymphocytes recovered by lavage (r = 0.87). We conclude that 1,25(OH)2D3 production by alveolar immune cells makes a major contribution to the abnormalities in calcium metabolism seen in tuberculosis patients, and may be partly dependent on the clinical characteristics evaluated here.

Adult↗

Nuclear receptors in human immune cells: expression and correlations.

Nuclear receptors (NR) are key modulators of gene transcription. Their activity is ligand induced and modulates a large variety of tissue-specific cellular functions. However, for many NR little is known about their role in cells of the immune system. In this study, expression patterns and distribution of 24 NR were investigated in human peripheral blood mononuclear cells. We provide the first evidence of the expression of the 12 receptors CAR, CoupTFalpha, CoupTFbeta, FXR, GCNF, HNF4alpha, PPARbeta/delta, PXR, RevErbbeta, TR2, TR4 and TLX in highly purified CD4, CD8, CD19, CD14 cells. The expression profile of RevErbalpha and LXRalpha previously observed in B cell and macrophages, respectively, has been extended to CD4, CD8 and CD14 cells. Except for RARbeta, which was absence in any of the cells tested, our results suggest an almost ubiquitous expression of the NR in the different cell lineages of the immune system. The expression of CAR, CoupTFalpha, FXR was also confirmed at a protein level and despite conspicuous mRNA levels of HNF4alpha, only low levels of this receptor were detectable in the nuclear fraction of PBMCs. Expression of the latter receptors was mostly only a fraction (4-20%) of their expression in the thyroid gland, the adrenal gland, the lung or subcutaneous adipose tissue. The Spearman rank order correlation test was performed to examine the correlation in expression between individual nuclear receptor pairs in the four cell types for several donors. Distinct correlation patterns were observed between receptor pairs in the individual cell types. In CD4 T cells four NR, GCNF, PPARgamma, PPARalpha7 and RevErbbeta are perfectly correlated with each other (P> or =0.0167). In the other cell types correlations between NR pairs were more diverse, but also statistically highly significant. Interestingly, the relative expression level of a number of receptor pairs ranked identical or similar in at least three (CoupTFalpha and PPARbeta/delta, CoupTFbeta and HNF4alpha as well as RORbeta and PXR) or four cell types (CoupTFalpha and CoupTFbeta, PPARgamma and RevErbbeta). Despite the variability of NR expression in immune cells, these results suggest that some of the NR may be co-regulated in human immune cells.

Female↗

Protection of neonatal macaques against experimental SHIV infection by human neutralizing monoclonal antibodies.

Neonatal macaques were completely protected against oral challenge with SHIV-vpu+, a simian-human immunodeficiency virus that encodes the envelope gene of a laboratory-adapted HIV strain, by pre- and post-natal treatment with a triple combination of human neutralizing monoclonal antibodies (mAbs). The mAbs were directed either against the CD4 binding site, a glycosylation-dependent gp120 epitope, or against a linear epitope on gp41. This triple combination was highly synergistic in vitro and neutralized primary HIV completely. Subsequently, oral challenge was performed with pathogenic SHIV89.6P, an animal-passaged variant of a chimeric virus that encodes the envelope gene of the primary, dual-tropic HIV89.6. Only post-natal treatment with a similar triple mAb combination was used. One out of 4 mAb-treated infants was completely protected from infection. In the other 3 treated animals, there was a tendency towards lower peak viral RNA loads compared with untreated controls. Two out of 4 mAb-treated infants maintained normal CD4+ T-cell numbers, in contrast to all controls that had steep declines at 2 weeks post-challenge. We conclude that the triple mAb combination significantly protected the neonates, even against mucosal challenge with pathogenic SHIV89.6P. Passively administered synergistic human mAbs may play a role in preventing mother-infant transmission of HIV, both against intrapartum transmission as well as against infection through breast milk. As passive immunization is a tool to assess correlates of immune protection, we conclude that the epitopes recognized by the mAbs in our combinations are important for AIDS vaccine development. Future passive immunization studies may reveal other important conserved epitopes.

AIDS Vaccines↗

Enhanced T cell-mediated protection against malaria in human challenges by using the recombinant poxviruses FP9 and modified vaccinia virus Ankara.

Malaria is a major global health problem for which an effective vaccine is required urgently. Prime-boost vaccination regimes involving plasmid DNA and recombinant modified vaccinia virus Ankara-encoding liver-stage malaria antigens have been shown to be powerfully immunogenic for T cells and capable of inducing partial protection against experimental malaria challenge in humans, manifested as a delay in time to patent parasitemia. Here, we report that substitution of plasmid DNA as the priming vector with a specific attenuated recombinant fowlpox virus, FP9, vaccine in such prime-boost regimes can elicit complete sterile protection that can last for 20 months. Protection at 20 months was associated with persisting memory but not effector T cell responses. The protective efficacy of various immunization regimes correlated with the magnitude of induced immune responses, supporting the strategy of maximizing durable T cell immunogenicity to develop more effective liver-stage vaccines against Plasmodium falciparum malaria.

Adult↗

Activation of the alternative pathway of complement by skin immune deposits.

Skin immune deposits at the basement membrane zone have been demonstrated by functional assays to activate complement. This important biologic function has not yet been explored for immune deposits present in other locations mainly because many cytoplasmic structures in the skin have the capacity to activate the complement cascade by the classical pathway. In this study the capacity of immune deposits to activate directly the alternative pathway was examined using a functional guinea pig C3 binding test. This test was devised so as to avoid complement activation by normal cutaneous structures, thus it did not examine the capacity of immune reactants to activate the classical pathway. The main findings were that alternative pathway activation could be demonstrated only when human C3 deposits were seen by direct immunofluorescence, but not all C3 deposits were found to activate the alternative pathway; such activation was restricted to vascular deposits; the phlogistic potential of the immune deposits correlated with serologic evidence of ongoing immune reactions, i.e., hypocomplementemia and circulating immune complexes. It is suggested that this test provides data on one aspect of the phlogistic potential of skin immune deposits not detectable by direct immunofluorescence.

Animals↗

Induction of cellular immune responses to simian immunodeficiency virus gag by two recombinant negative-strand RNA virus vectors.

A recombinant Newcastle disease virus (rNDV) expressing simian immunodeficiency virus (SIV) Gag protein (rNDV/SIVgag) was generated. The rNDV/SIVgag virus induced Gag-specific cellular immune responses in mice, leading to a specific anti-Gag antiviral immunity. This was evidenced by the inhibition of growth of recombinant vaccinia virus expressing an identical Gag antigen (rVac/SIVgag) but not of wild-type vaccinia virus in rNDV/SIVgag-immunized mice. Among intravenous, intraperitoneal, or intranasal immunization routes, intranasal administration induced the strongest protective response against challenge with rVac/SIVgag. We further demonstrated that these immune responses were greatly enhanced after booster immunization with recombinant influenza viruses expressing immunogenic portions of SIV Gag. The magnitude of the protective immune response correlated with the levels of cellular immune responses to Gag, which were still evident 9 weeks after immunization. These results suggest that rNDV and influenza virus vectors are suitable candidate vaccines against AIDS as well as against other infectious diseases.

Amino Acid Sequence↗

[Correlation between HLA antigens and immune status in dust-induced lung diseases in workers of machine-building industry].

Simultaneous study of immune state and HLA-testing was conducted for 73 patients with pneumoconiosis and 52 sufferers from dust bronchitis. The HLA antigens appeared to correlate with immune disorders in those diseases. The study revealed differences in the HLA antigens causing immune changes in pneumoconiosis and dust bronchitis. Those differences corresponded to differences between the markers of propensity to those diseases. Thus, the authors assume that formation of pneumoconiosis or dust bronchitis could depend on genetically determined variants of immune disorders.

B-Lymphocytes↗

[Immune status and micro-hemodynamic function of patients with chronic alcoholism and liver pathology].

126 patients with chronic alcoholism combined with hepatic pathology (of alcoholic genesis) were examined. Laboratory immunological observations with the using of monoclonal antibodies demonstrated the expressed alterations of immune homeostasis exactly the decrease of total T-lymphocytes population (CD11+) as well as the number of T-helpers/inductors (CD40, immunoregulatory index and the increase of the level of circulating immune complexes. The correlation between the immune alterations and the microhemodynamic disturbances was also observed. In connection with the results mentioned above the question arose about application worth of both immunological correctors and angioprotectors in therapy of alcoholism espessially combined with hepatic pathology.

Adult↗

Immune deviation in relation to ocular immune privilege.

Immune privilege in the eye is a dynamic state in which the immune response to ocular Ags is molded and modified by the eye itself. Immune privilege correlates with systemic alterations in the immune response such that deviant forms of immunity emerge. The eye itself contributes to immune deviation, in part by displaying unique immunoregulatory factors in aqueous humor and expressed on ocular cells. When T cells encounter Ag in the eye, they can become anergic, undergo apoptosis, secrete TGF-beta, and/or release soluble regulatory factors containing the TCR alpha-chain. Ags taken up by indigenous APC escape the eye and reach the spleen where they activate a unique spectrum of Ag-specific T and B cells. The absence of systemic delayed hypersensitivity and complement-fixing Abs in this deviant response probably relates to the fact that inflammation is deleterious to vision and leads to blindness. Immune privilege is the eye's way of protecting its vital function from the ravages of immunopathogenic injury.

Animals↗

Cell-mediated immunity in patients with carcinoma: correlation between clinical stage and immunocompetence.

Cell-mediated immunity (CMI) was evaluated in 82 patients with non-lymphoid tumors by in vivo and in vitro methods. These included skin test with ubiquitous antigens, 2,4 dinitrochlorobenzene (DNCB) sensitization, determination of T and B peripheral blood lymphocytes, and lymphocyte response to phytohemagglutinin (PHA). The patients were divided into two groups: those with localized and those with disseminated disease (LD and DD). The patients with LD showed no significant differences in CMI when compared with normal controls. The patients with DD showed various defects in CMI when compared with controls and patients with LD. There were significant differences in the response to DNCB, and streptokinase-streptodornase (SK-SD) was the most discriminative of the skin-test antigens. The response to PHA was greatly depressed in patients with DD, whether in the presence of autologous or homologous plasma; in some patients a factor inhibiting to blastogenesis was detected in the serum. In patients with DD, a T-cell lymphopenia was observed. These data showed a correlation between immunocompetence and clinical stage.

Adult↗

Evolutionary rate and genetic drift of hepatitis C virus are not correlated with the host immune response: studies of infected donor-recipient clusters.

Six donor-recipient clusters of hepatitis C virus (HCV)-infected individuals were studied. For five clusters the period of infection of the donor could be estimated, and for all six clusters the time of infection of the recipients from the donor via blood transfusion was also precisely known. Detailed phylogenetic analyses were carried out to investigate the genomic evolution of the viral quasispecies within infected individuals in each cluster. The molecular clock analysis showed that HCV quasispecies within a patient are evolving at the same rate and that donors that have been infected for longer time tend to have a lower evolutionary rate. Phylogenetic analysis based on the split decomposition method revealed different evolutionary patterns in different donor-recipient clusters. Reactivity of antibody against the first hypervariable region (HVR1) of HCV in donor and recipient sera was evaluated and correlated to the calculated evolutionary rate. Results indicate that anti-HVR1 reactivity was related more to the overall level of humoral immune response of the host than to the HVR1 sequence itself, suggesting that the particular sequence of the HVR1 peptides is not the determinant of reactivity. Moreover, no correlation was found between the evolutionary rate or the heterogeneity of the viral quasispecies in the patients and the strength of the immune response to HVR1 epitopes. Rather, the results seem to imply that genetic drift is less dependent on immune pressure than on the rate of evolution and that the genetic drift of HCV is independent of the host immune pressure.

Blood Donors↗

Circulating immune complexes in Hashimoto's thyroiditis. Correlation to HLA and autoantibodies.

Circulating immune complexes (IC) were determined in sera from 41 patients with Hashimoto's thyroiditis by a polyclonal rheumatoid factor (pRF) assay based on the inhibition of the agglutination of IgG-coated latex particles. Elevated levels of IC were found in 63% (26/41) of the sera. There was a significant correlation (Rho = 0.91, P less than 0.001) between results obtained before and after treatment of sera with dithiothreitol (DTT). By precipitation with 2.5% polyethylene glycol (PEG) before pRF inhibition assay, the activity of IC was found in only 7% (3/41) of the sera. Size chromatography studies of the sera showed the inhibitory activity predominantly in the intermediary region. When found in the IgM-region the activity was not reduced by DTT. By use of a polyethylene glycol complement consumption test (PEG-CC) the occurrence of IC was 10% (4/41). It was not possible to find any correlation between the detectable IC and the presence of microsomal, thyroglobulin, or thyroid-stimulating antibodies. Based on our studies the sizes of IC seemed to be heterogeneously distributed and the majority were not precipitated by PEG (2.5%), final concentration). The antibodies involved in the formation of complexes seemed to be of IgG or IgA classes. HLA-D typing of the patients showed a non-significant association between HLA-Dw5 and low levels of IC while the presence of HLA-Dw4 was significantly associated with a high level of IC (P less than 0.05).

Antigen-Antibody Complex↗

Immune response gene function correlates with the expression of an Ia antigen. II. A quantitative deficiency in Ae:E alpha complex expression causes a corresponding defect in antigen-presenting cell function.

A series of experiments were performed to explore the role of complementing major histocompatability complex (MHC)-linked immune response Ir genes in the murine T cell proliferative response to the globular protein antigen pigeon cytochrome c. The functional equivalence of I-E-subregion-encoded, structurally homologous E(a) chains from different haplotypes bearing the serologic specificity Ia.7 was demonstrated by the complementation for high responsiveness to pigeon cytochrome c of F(1) hybrids between low responder B 10.A(4R) (I-A (k)) or B 10.S (I-A(8)) mice and four low responder E(a)- bearing haplotypes. Moreover, this Ir gene function correlated directly with both the ability of antigen-pulsed spleen cells from these same F(1) strains to stimulate pigeon cytochrome c-primed T cells from B10.A or B10.S(9R) mice, and with the cell surface expression of the two-chain Ia antigenic complex, A(e):E(a), bearing the conformational or combinatorial determinant recognized by the monoclonal anti-Ia antibody, Y-17. The B 10.PL strain (H-2(u)), which expresses an Ia.7-positive I-E- subregion-encoded E(a) chain, failed to complement with B10.A(4R) or B10.S mice in the response to pigeon cytochrome c. However, (B10.A(4R) x B10.PL)F(1) and (B10.S x B10.PL)F(1) mice do express A(k)(e):E(u)(a) and A(8)(e):E(u)(a) on their cell surface, although in reduced amounts relative to A(k,s)(e):E(k,d,p,r)(a) complexes found in corresponding F(1) strains. This quantitative difference in Ia antigen expression correlated with a difference in the ability to present pigeon cytochrome c to B 10.A and B 10.S(9R) long-term T cell lines. Thus, (B10.A(4R) x B10.PL)F(1) spleen cells required a 10-fold higher antigen dose to induce the same stimulation as (B10.A(4R) x B10.D2)F(1) spleen cells. In addition, the monoclonal antibody, Y-17, which reacts with A(e):E(a) molecules of several strains, had a greater inhibitory effect on the proliferative response to pigeon cytochrome c of B10.A T cells in the presence of (B10.A(4R) X B10.PL)F(1) spleen cells than in the presence of (B10.A(4R) X B10.D2)F(1) spleen cells. These functional data, in concert with the biochemical and serological data in the accompanying report, are consistent with the molecular model for Ir gene complementation in which appropriate two-chain Ia molecules function at the antigen-presenting cell (APC) surface as restriction elements. Moreover, they clearly demonstrate that the magnitude of the T cell proliferative response is a function of both the concentration of nominal antigen and of the amount of Ia antigen expressed on the APC. Finally, the direct correlation of a quantitative deficiency in cell surface expression of an Ia antigen with a corresponding relative defect in antigen-presenting function provides strong independent evidence that the I-region-encoded Ia antigens are the products of the MHC-linked Ir genes.

Animals↗

Active hexose correlated compound enhances the immune function of mice in the hindlimb-unloading model of spaceflight conditions.

Hindlimb unloading is a ground-based model that simulates some of the aspects of spaceflight conditions, including lack of load bearing on hindlimbs and a fluid shift to the head. It has been shown that treatment with active hexose correlated compound (AHCC) restores resistance to infection in mice maintained under hindlimb-unloading conditions. The present study was designed to clarify the mechanisms by which AHCC enhances resistance to infection in this model. We hypothesized that oral administration of AHCC will enhance the function of the immune system, which could lead to the increased resistance to infection observed in this model. AHCC or the excipient was orally administered to mice, and the function of the immune system was assessed in spleen and peritoneal cells isolated from those groups. The results of the present study showed that administration of AHCC for 1 wk before and throughout the second day of the hindlimb-unloading period enhanced the function of the immune system assessed by spleen cell proliferation and cytokine production in spleens and nitric oxide and cytokine production in peritoneal cells. These findings suggest that AHCC can be used as a potent immunoenhancer, especially in cases in which the immune system is suppressed by any condition, including diseases such as human immunodeficiency virus infection and cancer.

Administration, Oral↗