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Difficulties in establishing a serological correlate of protection after immunization with Haemophilus influenzae conjugate vaccines.

In several studies the protective concentration of anti-Haemophilus influenzae type b (Hib) capsular polysaccharide (PS) antibodies has been concluded to be around 0.04 to 0.20 microgram/ml. After the Finnish Hib polysaccharide vaccine trial it was estimated that 1 microgram/ml has to be achieved to predict long term protection after vaccination. These estimates of protective anti-Hib PS antibody concentrations were based on the assumption that protection from invasive Hib disease is mediated by antibodies and the role of cell-mediated immunity is negligible. This assumption was justified since the Hib PS is a T cell-independent antigen. The matter becomes quite different when the character of the PS vaccine is altered by conjugating it to a protein carrier, so that it acquires the ability to stimulate T cells, and the immunological memory plays a role in the protection. The immunized infants are thought to be able to respond with a rapid and high antibody response after exposure to the organism. After immunization with conjugate vaccines, protection can be seen at a lower serum antibody concentration than after polysaccharide vaccine. In addition, higher avidity of anti-Hib PS antibodies is associated with the response to conjugate than PS vaccine, and there are differences between the conjugates. This might have an influence on the functional activity of the antibodies. Hib conjugate vaccines are also able to reduce the carriage rate of Hib. This should be kept in mind when estimating what is needed from protective immune response after immunization with Hib conjugate vaccines.

Adult↗

Abnormal cytokine serum levels correlate with impaired cellular immune responses after surgery.

Serum levels of the interleukins (IL)-2, -1 beta, and -6, tumor-necrosis factor alpha (TNF-alpha), and prostaglandin E2 (PGE2) were measured serially before and after operation in patients undergoing various surgical procedures. Peripheral blood mononuclear cells (PBMC) from the same patients were analyzed before and after surgery for proliferative responses in the autologous mixed lymphocyte reaction (AMLR) and for cytolytic activity against the natural killer (NK)-sensitive K562 cell line. In patients who had major surgery, a decrease in IL-2 levels and increases in IL-1 beta, TNF-alpha, IL-6, and PGE2 levels were observed up to 9 days after the operation compared to those of the preoperative values. Decreased AMLR responses and NK activity were also observed in PBMC collected 5 days after surgery. All these changes were more intense in patients who had undergone major surgical procedures of increasing severity (i.e., cancer patients). Similar, although weaker, changes in cytokine serum levels, AMLR responses, and NK activity were also observed in patients undergoing minor surgery. Our data suggest that changes in cytokine serum levels may cause cellular immune dysfunctions, particularly in patients undergoing major surgery, and provide the basis for immune intervention in order to avoid infections occurring after major surgery.

Cytokines↗

Corticotropin-releasing hormone modulates cytokines release in cultured human peripheral blood mononuclear cells.

Immune and neuroendocrine systems interact at various levels. In particular, either cytokines activate the hypothalamus-pituitary-adrenal axis (HPA) or corticotropin-releasing hormone (CRH) induces the release of beta-endorphin from peripheral human mononuclear cells. The aim of the present study was to investigate whether CRH may affect cytokine production and activity in human peripheral blood mononuclear cells (PBMC). Primary cultures of human PBMC and monocytes were used. They were incubated in presence of different doses of synthetic human CRH. Media were collected and interleukin-1 beta (IL-1 beta) and interleukin-6 (IL-6) levels were measured by ELISA, while interferon-gamma (IFN-gamma) levels were measured by bioassay. In addition, phytohemoagglutinin-induced lymphocyte proliferation was evaluated by testing [3H]thymidine incorporation in the presence of various doses of CRH. CRH significantly increased IL-6 release from PBMC (p < 0.01). The addition of CRH to PBMC significantly decreased IFN-gamma levels, in a dose dependent manner (p < 0.01). No significant effect of CRH was observed on lymphocyte proliferation or IL-1 beta production. The present results suggest a role for CRH as a paracrine mediator for human immune cells, increasing the evidence of a clear correlation between immune and neuroendocrine system.

Adult↗

Antibodies against tick-borne encephalitis virus (TBEV) non-structural and structural proteins in human sera and spinal fluid.

Western immunoblotting of the serum and spinal fluid of patients with tick-borne encephalitis (TBE) revealed the presence of antibodies against non-structural and internal virion proteins. Antibodies against different viral proteins have been shown to appear 8 days postinfection and to circulate for more than 2 months in case of acute TBE. Antibodies against structural glycoprotein E and non-structural glycoprotein NS1 do not prevail over antibodies against other kinds of viral proteins. The large viral non-structural proteins NS5 and NS3 and small hydrophobic proteins NS2A and NS4B can cause an effective immune response as well. There is no strong correlation between immune response spectrum and fever or meningitis forms of disease. However, sera of patients with chronic TBE contained IgM antibodies to virus-specific proteins more than 1 year later and IgG antibodies with very low titers (if any).

Adolescent↗

Deficiency of decidual IL-10 in first trimester missed abortion: a lack of correlation with the decidual immune cell profile.

PROBLEM: To determine if first trimester missed abortion decidua is characterized by an altered immune cell profile and/or a modified interleukin (IL)-10 and interferon (IFN)-gamma production pattern compared with decidua from elective termination. METHOD OF STUDY: Flow cytometry and immunohistochemistry techniques were used to determine the decidual immune cell phenotypic profile and production pattern of IL-10 and IFN-gamma in cases of elective termination (n = 14) and missed abortion (n = 12). RESULTS: Both groups had a similar proportion of CD56+ CD16-, CD56+ CD16+, CD19+, CD3+, CD4+, CD8+, alphabeta T cells and gammadelta T cells. The majority of alphabeta and gammadelta positive T cells in both groups coexpressed the natural killer (NK) cell marker CD56, but lacked cell surface expression of CD3. Diminished decidual IL-10 staining was noted in 7/10 missed abortion cases compared with none of the elective termination cases (n = 12) (P = 0.007). A uniform decidual IFN-gamma staining pattern was observed in both groups. CONCLUSION: Decreased IL-10 production coupled with a sustained IFN-gamma presence noted in missed abortion compared with elective termination cases suggest that these cytokines may be important determinants in pregnancy outcome. In contrast, differences in the proportion of immune cells between both groups may not be a critical factor in early pregnancy loss. In normal pregnancy, decidual alphabeta and gammadelta positive T cells with reduced CD3 on their cell surface may be intrinsically restricted in T-cell receptor (TCR)-mediated activation.

Abortion, Induced↗

Immune response gene function correlates with the expression of an Ia antigen. I. Preferential association of certain Ae and E alpha chains results in a quantitative deficiency in expression of an Ae:E alpha complex.

These studies were stimulated by the observation, reported in the accompanying paper (19), that IEu failed to interact with I-Ak or I-As in F1 mice to allow a response to the antigen, pigeon cytochrome c, unlike I-E subregions derived from other Ia.7+ haplotypes. Serological and biochemical analyses were performed to determine whether or not cells from these F1 mice express the Ak,se:E alpha complexes that should function as restriction elements for T cell recognition of pigeon cytochrome c on antigen-presenting cells. Using the Y-17 monoclonal antibody, which recognizes the combinatorial or conformational determinant Ia.m44 on certain Ae:E alpha complexes, we were able to distinguish between Aue:Eu alpha and Ab,k,se:Eu alpha complexes on cell surfaces. Although complement-dependent microcytotoxicity with Y-17 failed to detect Ab,k,se:Eu alpha complexes on cells from appropriate F1 mice, these molecules were detected by both quantitative absorption and quantitative immunofluorescence studies. However, Ab,k,se:Eu alpha complexes were found to be present at levels only one-seventh to one-eighth the levels expressed by homozygous I-Ab, I-Ek; I-Ak, I-Ek; and I-As, I-Ek cells. The results of two-dimensional polyacrylamide gel electrophoresis analyses suggest that the low levels of expression of Ab,k,se:Eu alpha complexes are a consequence of the preferential association of Aue and Eu alpha chains with each other in the F1 cells. As will be shown in the following paper (19), the quantitative deficiency in the expression of Ake:Eu alpha and Ase:Eu alpha complexes results in a corresponding defect in antigen-presenting cell function, thus providing strong evidence that Ia antigens represent products of Ir genes.

Animals↗

Primary Mycobacterium avium complex infections correlate with lowered cellular immune reactivity in Matschie's tree kangaroos (Dendrolagus matschiei).

The National Zoological Park has maintained a breeding colony of Matschie's tree kangaroos (Dendrolagus matschiei) since 1975 with a documented history and continued prevalence of Mycobacterium avium complex (MAC) infections. No evidence of immunosuppressive retrovirus infections or loss of heterozygosity that may have led to an immune dysfunction in these animals was found. Isolates of MAC organisms from affected tree kangaroos and from their environment had no common restriction fragment DNA types. Cellular immune reactivity in apparently healthy tree kangaroos was 3- to 6-fold lower than in humans and other marsupial and eutherian mammals, as determined by lymphocyte proliferative assays. Thus, while MAC infections are typically opportunistic in humans and other mammals, tree kangaroos commonly develop primary progressive disease with MAC from random sources. Comparative information derived from this study should benefit both the endangered tree kangaroo and humans with immunosuppressive disorders that lead to mycobacterial infections.

Animals↗

Increasing CD4+ T cells specific for tuberculosis correlate with improved clinical immunity after highly active antiretroviral therapy.

Treatment advances have led to dramatic clinical improvements for patients with HIV-1 infection. These clinical improvements reflect treatment-related improvements in immune function, which are most striking in individuals who develop exaggerated immune inflammatory responses to occult opportunistic infections. The mechanisms accounting for these exaggerated immune responses are unknown. To gain insight into these mechanisms, we intensively studied a subject untreated for disseminated tuberculosis and HIV-1 coinfection who then began treatment for both diseases. We examined the changing frequencies of Mycobacterium tuberculosis (MTB)-specific CD4(+) T cells that produced interferon gamma (IFN-gamma) after short-term stimulation with MTB antigen, and we compared these frequencies with those in HIV-1-seronegative subjects with and without prior exposure to MTB antigens. For the HIV-1/MTB-coinfected subject, the proportion of peripheral blood CD4(+) T cells expressing MTB-specific IFN-gamma was 8.6% at 11 days, 11% at 33 days, and 33% at 95 days after starting treatment for HIV-1. CD4(+) IFN-gamma(+) T cells had a CD45RA(-)CD62L(-) (effector memory) phenotype and most coexpressed interleukin 2. Median frequencies of CD4(+) IFN-gamma(+) T cells from six subjects without and nine subjects with prior exposure to MTB antigens were 0.06 and 0.46%, respectively. We conclude that individuals starting treatment for disseminated tuberculosis and HIV-1 coinfection can accumulate remarkably large numbers of MTB-specific CD4(+) T cells in the peripheral blood. The rapid expansion of antigen-specific effector CD4(+) T cells is one mechanism to explain immediate improvements in clinical immunity after HIV-1 treatment. This mechanism provides a theoretical framework to understand the unusual inflammatory responses recently reported to occur after starting HIV-1 treatment.

AIDS-Related Opportunistic Infections↗

Bacterial infections in the acquired immune deficiency syndrome. Clinicopathologic correlations in a series of autopsy cases.

In a group of 46 adult patients with acquired immunodeficiency syndrome (AIDS) who came to autopsy in 1983-1987, the authors found that 38 (83%) had bacterial (nonmycobacterial) infections some time during the course of their illness, compared with 34 (74%) who had parasitic infections, 31 (67%) who had viral infections, 28 (61%) who had fungal infections, and 12 (26%) who had mycobacterial infections. Twenty-five of these patients (54%) had Staphylococcus aureus infections, compared with 7 (15%) who had Pseudomonas aeruginosa infections and 6 (13%) who had enterococcal infections. Overall, undiagnosed infections or malignancies were found in 48%, 22 of the 46 autopsies, including 12 cases of undiagnosed bacterial infections, 8 of these due to S. aureus. These results suggest that bacterial infections in general, and S. aureus infections in particular, are important causes of morbidity and mortality in patients with AIDS.

Acquired Immunodeficiency Syndrome↗

School-based measles outbreaks: correlation of age at immunization with risk of disease.

During the Spring of 1978, students with a history of previous measles vaccination accounted for over three-forths of 203 cases of measles in a metropolitan county. Seventy cases occurred in two schools where 99% of the students were vaccinated. We analyzed countywide data to determine past patterns of measles vaccination, including outbreak control and vaccination update clinics. We also examined records of children from the two schools to assess the relationship between disease incidence and age at vaccination. When susceptibility was determined by trained health workers rather than by parents, fewer doses of measles vaccine were estimated to be needed. The majority of cases occurred among children 5 to 9 years old. Attack rates were higher for children vaccinated at 12 months of age or younger than for those vaccinated at 13 months of age or older. There were no significant differences in attack rates among children vaccinated at 13 months of age or older. These findings support recommendations for delaying routine measles vaccination until after 12 months of age and suggest that, during outbreaks, all children vaccinated prior to 13 months of age be revaccinated.

Adolescent↗

Patients with Hereditary Hemorrhagic Telangectasia (HHT) exhibit a deficit of polymorphonuclear cell and monocyte oxidative burst and phagocytosis: a possible correlation with altered adaptive immune responsiveness in HHT.

Hereditary Hemorrhagic Telangiectasia (HHT) is a rare genetic disease characterized by mutations occurring in the endoglin and ALK-1, two receptors of transforming growth factor-beta1. From a pathogenic point of view, a possible involvement of the immune system in HHT has been suggested since a mononuclear cell infiltrate was found around the area of telangiectases. Up until now, no information has been available about the role played by leukocytes in HHT and the mechanisms elicited by secretion of their mediators. However, the fact that a deficit of adaptive immunity in HHT has been reported in a companion paper in this issue will represent a great contribution to the understanding of HHT pathogenesis. The purpose of this study was to evaluate whether patients with HHT manifest also alterations in the innate immune response. Therefore, the phenotype of T, B and natural killer lymphocytes, serum immunoglobulin levels, phagocytosis and oxidative burst activity exerted by polymorphonuclear cells (PMN) and monocytes (MO) were analyzed in 22 patients. Twenty individuals demonstrated single or multiple deficits of PMN and MO functions, while the immunophenotype of lymphocytes and serum concentrations of immunoglobulins were normal. To the best of our knowledge, this is the first demonstration of a reduction in PMN and MO functions in HHT, thus suggesting a higher susceptibility to infectious complications in these patients. The relationship between innate immune deficits and T helper 1 and monocyte-derived cytokine dysfunction in HHT, as previously reported, is discussed.

Adult↗