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PubMed2006

Cytomegalovirus-specific immunity and protection against viremia and disease in HIV-infected patients in the era of highly active antiretroviral therapy.

To define the immune correlates of protection against cytomegalovirus (CMV) end-organ disease, CMV-specific interferon (IFN)- gamma enzyme-linked immunospot (ELISPOT) and CD8(+) and CD4(+) intracellular IFN- gamma synthesis assays were performed for subjects with CD4(+) cell counts of < or =50 cells/ microL who were enrolled in a prospective observational study of CMV infection in the era of highly active antiretroviral therapy. Of 87 subjects, 46 developed viremia, 14 developed end-organ disease, and 20 died. Positive ELISPOT assay results, but not positive results for CD4(+) or CD8(+) intracellular IFN- gamma synthesis, were associated with delayed development of viremia and CMV end-organ disease or death. CMV viremia did not appear to boost CMV-specific immunity. ELISPOT assays may be used to identify HIV-infected patients who might benefit from anti-CMV prophylactic interventions.

AIDS-Related Opportunistic Infections↗

PubMed2006

The potential role of fowlpox virus in rational vaccine design.

The design of optimal vaccines requires detailed knowledge of how protective immune responses are generated in vivo under normal circumstances. This approach to vaccine development, where the immune correlates of protection are defined and vaccines are designed to elicit the same response, is called rational vaccine design. Poxviruses are attractive candidates for inclusion in such design strategies owing to their large genome, which allows for the inclusion of multiple heterologous genes, including those encoding antigens, co-stimulatory molecules and cytokines. Fowlpox virus, the prototypical member of the Avipoxvirus genus, is particularly suitable, as it is also incapable of replicating in mammalian cells. The potential of recombinant fowlpox virus as a safe vaccine vector is being evaluated currently in a number of clinical trials for diseases, including HIV, malaria and various types of cancer. Despite their promise, intricate details regarding how fowlpox virus interacts with the host immune system have not been resolved. In this review, the issues surrounding the use of fowlpox virus as a vaccine vector and possible strategies for enhancing its efficacy are discussed.

AIDS Vaccines↗

PubMed2003

Defining the protective antibody response for HIV-1.

The development of an effective HIV-1 vaccine would be greatly facilitated by knowledge regarding the type and quantity of antibodies that are protective. Since definitive immune correlates are established only after a vaccine has been shown to be effective in humans, animal models are often used to guide vaccine development. Experimental lentivirus infection of non-human primates has shown that neutralizing antibodies can protect against infection. Most specifically, studies of passive antibody transfer in the chimeric SIV/HIV-1 immunodeficiency virus (SHIV) model have provided quantitative data on the level of protective antibody required. While direct extrapolation to humans is difficult, these data likely provide important insights into the protection afforded by antibodies against HIV-1. When used alone, high levels of neutralizing antibodies are required to completely block infection. However, even modest levels of antibody can provide partial protection and affect disease course. Understanding the exact level of protective antibody becomes even more complex in the setting of active immunization and coexisting cellular immunity. Despite this uncertainty, recent findings from lentiviral animal models strongly suggest that neutralizing antibodies will contribute to protection against HIV-1. Based on these data, a major goal of HIV-1 vaccine strategies is the induction of neutralizing antibodies against circulating primary HIV-1 strains.

AIDS Vaccines↗

PubMed2005

Advances in pneumococcal vaccines: advantages for infants and children.

The introduction of Haemophilus influenzae type b (Hib) vaccine into the universal immunisation schedules of many industrialised countries and the subsequent remarkable decline in the incidence of invasive Hib disease has further highlighted the impact of invasive pneumococcal diseases. Streptococcus pneumoniae is now the leading cause of bacterial meningitis in children in many settings and a leading cause of vaccine-preventable bacterial disease in children worldwide. The currently marketed 23-valent pneumococcal polysaccharide vaccine provides large serotype coverage at a relatively low cost. However, it is not efficacious in young children. Pneumococcal conjugate vaccines (PCVs) are highly effective in preventing invasive disease in infants and young children, with favourable safety and immunogenicity profiles. These vaccines have also shown efficacy in reducing cases of non-invasive disease (i.e. otitis media), nasopharyngeal acquisition of vaccine-specific serotypes of S. pneumoniae, and protection against pneumococcal disease caused by resistant strains. However, PCV contains a limited number of pneumococcal serotypes and, given adequate ecological pressure, replacement disease by non-vaccine serotypes remains a threat, particularly in areas with very high disease burden. Furthermore, although capsular-specific antibodies have been shown to be highly protective, it remains unclear what concentration of these serotype-specific antibodies protect against disease and, more recently, it has become clear that opsonic activity and avidity of these antibodies are more critical determinants of protection than concentration. Therefore, monitoring disease burden and defining immune correlates of protection after widespread use of conjugate vaccines are crucial for the evaluation of these new generation vaccines. Furthermore, a need exists to develop pneumococcal vaccines with lower cost and larger serotype coverage. Development of one or more protein vaccines that might be easier and, thus, less expensive to manufacture, and which might provide protection against multiple serotypes, is in progress. This article reviews the current state of pneumococcal disease and pneumococcal vaccines in clinical use.

Child↗

PubMed1976

Experimental allergic uveitis: induction by retinal rod outer segments and pigment epithelium.

EAU was produced in strain 13 guinea pigs after immunization with purified guinea pig retinal rod outer segments and with retinal pigment epithelium in mycobacterial adjuvant emulsion. The lesions of EAU appear as inflammatory infiltrates of the iris and ciliary body followed by choroidal inflammation, often with retinal photoreceptor degeneration. Specific antibodies are detected in the serum of a majority of the animals with clinical disease. Immunohistochemical staining of normal and inflamed eyes with serum from the immunized animals with uveitis demonstrates specific antigens localized in the outer segments. All immunized animals demonstrate delayed-type hypersensitivity characterized by skin reactions of mononuclear cells, by the in vitro inhibition of migration of peritoneal macrophages from the sensitized animals in the presence of specific antigen, and by antigen-specific lymphocyte stimulation. More pronounced delayed-type hypersensitivity reactions occurred during uveitis and indicated that cellular immunity correlates with clinical EAU, whereas no correlation was found with serum antibody. Successful experiments at transferring clinical disease passively with sensitized lymphocytes from animals with uveitis to normal recipients were conducted via the intravenous as well as intravitreal routes. No inflammatory reactions occurred after similar transfer of nonsensitized lymphocytes. The recipients of the passively transferred cells demonstrated both humoral and delayed type hypersensitivity to the retinal antigens. These findings suggest that the retinal rod outer segments and pigment epithelium are the sourve of significant antigens in autoimmune uveitis and retinitis.

Animals↗

PubMed2004

Beyond help: direct effector functions of human immunodeficiency virus type 1-specific CD4(+) T cells.

The immune correlates of protection in human immunodeficiency virus type 1 (HIV-1) infection remain poorly defined, particularly the contribution of CD4(+) T cells. Here we explore the effector functions of HIV-1-specific CD4(+) T cells. We demonstrate HIV-1 p24-specific CD4(+)-T-cell cytolytic activity in peripheral blood mononuclear cells directly ex vivo and after enrichment by antigen-specific stimulation. We further show that in a rare long-term nonprogressor, both an HIV-1-specific CD4(+)-T-cell clone and CD4(+) T cells directly ex vivo exert potent suppression of HIV-1 replication. Suppression of viral replication was dependent on cell-cell contact between the effector CD4(+) T cells and the target cells. While the antiviral effector activity of CD8(+) T cells has been well documented, these results strongly suggest that HIV-1-specific CD4(+) T cells are capable of directly contributing to antiviral immunity.

CD4-Positive T-Lymphocytes↗

PubMed1999

Immune determinants of organism and outcome in febrile hospitalized Thai patients with bloodstream infections.

Opportunistic infections (OI) and the human immunodeficiency virus (HIV) cause significant morbidity and mortality in developing countries. Immune cell and cytokine profiles may be related to the type and course of OI and to the OI-HIV interaction. Examining cell-specific cytokine production ex vivo has only recently become feasible. In Thailand, 53 febrile, hospitalized adults were enrolled in a study of the immune correlates of bloodstream infections (BSI). On site, blood cells were stimulated ex vivo. Cell-surface antigens and eight intracellular cytokines were subsequently analyzed using flow cytometry to determine associations with mortality and the organism causing the BSI. By logistic regression analysis, the percentage of CD3(+) CD16/56(+) cells making tumor necrosis factor alpha (TNF-alpha) (P = 0.033) and the percentage of CD3(-) CD16/56(+) cells (NK) (P = 0.032) were related to HIV positivity. Lymph node enlargement with HIV infection and the percentage of CD3(+) CD16/56(+) making TNF-alpha were predictive of death. A lower percentage of CD3(+) CD8(+) lymphocytes making interleukin-8 (IL-8) (P = 0.005), fewer monocytes expressing CD14 (P = 0.009), and the percentage of CD3(+) CD8(+) cells producing gamma interferon (P = 0. 011) were associated with blood culture positivity and the causative organism. For every one point decrease in the percentage of CD3(+) CD8(+) cells making IL-8, the likelihood of a positive culture increased 23%; for every one point decrease in the percentage of monocytes expressing CD14, the likelihood of a positive culture increased by 5%. Only a few immune cell types and three of their related cytokines were significantly associated with HIV disease outcome or the BSI organism. These cell types did not include CD3(+) CD8(-) cells (a surrogate for CD4(+) cells), nor did they involve cytokines associated with a type I to type II cytokine shift, which might occur with advancing HIV infection. These associations support the premise that CD8(+) and CD16/56(+) lymphocytes play significant roles in HIV and type I infections.

AIDS-Related Opportunistic Infections↗

PubMed1999

Changes in immune function following surgery for esophageal carcinoma.

Changes in immune function due to surgical injury have been well-documented. Immunosuppression is one of the causes of infectious complications leading to organ dysfunction in critical illness. It is not known what kind of surgery in the daily clinical practice causes immunosuppression. Stress response and immune function following surgery for esophageal carcinoma, assuming a highly-stressed operation, were studied and then compared with the stress response and immune function following gastric surgery, a moderately-stressed procedure. Forty patients who underwent esophagectomy and 39 patients receiving gastric operation were studied. The concentrations of serum interleukin-6 (IL-6) were measured preoperatively, at 1, 2, and 6 h, and at 1, 3, and 10 d after operation. Total protein, serum albumin, rapid turnover protein, serum CRP, and cortisol were measured before operation and at 1, 3, 7, and 21 d after operation. ConA- and PHA-stimulated lymphocyte proliferation, IgA, IgG, and IgM were also measured preoperatively, and on 7 and 21 d following surgery. The patients were fed exclusively by total parenteral nutrition (TPN). A striking rise of IL-6 was observed, with a peak in both groups at 1 to 6 h following operation. The peak values were 419+/-30 pg/mL, which was approximately twice as high in the esophagectomy patients as in the gastrectomy patients (195+/-40 pg/mL). CRP and cortisol also increased after operation, and these increases were also significantly greater in the esophagectomy patients. ConA- and PHA-stimulated lymphocyte proliferation decreased significantly 7 d after esophagectomy (P<0.05), but was unchanged in the patients receiving gastrectomy. Suppression of cellular immunity correlated significantly with serum cortisol, and was preceded by a rise in serum IL-6. The IgA, IgG, and IgM levels, however, remained unchanged from their preoperative values throughout the study in both groups. Nutritional status in terms of serum protein, albumin, and rapid turnover protein, decreased postoperatively, but there was no difference between the two groups. It is, therefore, concluded that cell-mediated immunosuppression, preceded by a hyperinflammatory response, is an observable reaction in patients following esophageal surgery, but not in patients undergoing gastric surgery.

Aged↗

PubMed2006

A review of vaccine research and development: the human immunodeficiency virus (HIV).

Since the discovery of AIDS in 1981, the global spread of HIV has reached pandemic proportions, representing a global developmental and public health threat. The development of a safe, globally effective and affordable HIV vaccine offers the best hope for the future control of the pandemic. Significant progress has been made over the past years in the areas of basic virology, immunology, pathogenesis of HIV/AIDS and the development of antiretroviral drugs. However, the development of an HIV vaccine faces formidable scientific challenges related to the high genetic variability of the virus, the lack of immune correlates of protection, limitations with the existing animal models and logistical problems associated with the conduct of multiple clinical trials. More than 35 vaccine candidates have been tested in Phase I/II clinical trials, involving more than 10,000 volunteers, and two Phase III trials have been completed, themselves involving more than 7500 volunteers. Multiple vaccine concepts and vaccination strategies have been tested, including DNA vaccines, subunit vaccines, live vectored recombinant vaccines and various prime-boost vaccine combinations. This article reviews the state of the art in HIV vaccine development, summarizes the results obtained so far and discusses the challenges to be met in the development of the various vaccine candidates.

AIDS Vaccines↗

PubMedDate not supplied

Active and passive immunisation against respiratory syncytial virus.

RSV is a major cause of respiratory illness in infants under 2 years of age. Evidence is accumulating that it is also underestimated as a cause of respiratory infection in adults, the elderly and immunocompromised individuals. Active interventions to control the impact of RSV infection have been hampered by a lack of understanding of the immune response to RSV in different age groups. A number of different strategies for developing RSV vaccines have been pursued, including live attenuated vaccines, genetically engineered live and subunit vaccines and peptide vaccines with varying degrees of success. The target populations for RSV vaccines include infants, the elderly and women of childbearing age, but the efficacy of different vaccines may differ according to age. Desirable immune responses and immune correlates of protection to RSV in humans remain uncertain and determining these is critical for introduction of any vaccines. Prophylaxis and treatment of RSV in infants using human immunoglobulin containing high titres of RSV specific neutralising antibody (RSV-Ig) has shown limited success in different infant populations. Prophylaxis of premature infants with RSV-Ig, particularly those with bronchopulmonary dysplasia, has demonstrated limited clinical efficacy against RSV. In contrast, there are significant safety concerns for use of this preparation for prophylaxis in infants with congenital heart disease and no demonstrable efficacy in treatment of RSV disease in healthy infants. The cost of the preparation will limit use to highly selected infant groups. Production of humanized monoclonal antibodies to RSV offers another potential passive immunotherapy intervention for RSV, with increased specific activity and reduced side effects, although its use remains experimental.

Humans↗

PubMed2003

HIV vaccines: a global perspective.

Twenty years after its recognition, HIV/AIDS has become the most important infectious disease globally and the leading cause of death in Africa. A preventive vaccine represents the best long-term hope for its control. The development of such a vaccine, however, has encountered a number of scientific challenges, including the lack of information on immune correlates of protection, the limitations in our understanding of the relevance of primate protection experiments in relation to vaccine-induced protection in humans, and the significance of genetic and immunologic variability of HIV strains for potential vaccine efficacy. Despite these uncertainties, the first phase I trial of an HIV vaccine was conducted in the United States in 1987. Since then more than 30 candidate vaccines have been tested in over 70 phase I/II clinical trials in both industrialized and developing countries. The first HIV vaccine trial in a developing country was conducted in 1993, six years after the first trial in the United States. Since then eighteen phase I/II trials and one phase III trial have been or are being conducted in developing countries, and additional phase II and III trials are planned to start in 2003. Most of these initial trials have been conducted in Thailand, but more recently trials have been initiated in Africa, Latin America and the Caribbean. Over the past years, the HIV vaccine development effort has followed three major overlapping paradigms. The first "wave" of candidate vaccines aimed at inducing neutralizing antibodies. The second wave focused on stimulation of CD8+ T-cell responses. The current "wave" of HIV vaccine research is aimed at optimizing both humoral and cell-mediated immune responses. The first generation of candidate vaccines (based on the HIV envelope protein) entered phase III efficacy evaluation in 1998, and definitive results from these trials will become available in 2003. Plans to ensure wide access to future HIV vaccines must be developed well in advance.

AIDS Vaccines↗

PubMed2026

Immortal genome assumption significantly underestimates replication and death rates of Mycobacterium tuberculosis in mice and monkeys.

Immune correlates of protection against infection with Mycobacterium tuberculosis (Mtb) or against tuberculosis (TB) remain poorly defined. The ratio of colony forming units (CFUs) to chromosomal equivalents (CEQs), Z = CFUs/CEQs, recovered either from the whole lung (mice) or individual lesions (monkeys or rabbits) of Mtb-infected animals has been used as a metric for how effectively Mtb is killed in vivo. However, the contribution of bacterial killing to changes in the CFU/CEQ ratio during an infection has not been rigorously investigated. We developed alternative mathematical models to study the dynamics of CFUs, CEQs, and their ratio during an Mtb infection. We find that the ratioalone cannot be used to infer the death rate of bacteria, unless the dynamics of CEQs and CFUs are entirely uncoupled, which is biologically unreasonable and inconsistent with the view that CEQs reflect an accumulated burden of both viable and non-viable bacteria. Importantly, we estimate a decay rate of 3.6%/day (a half life of about 20 days) of Mtb H37Rv CEQs in B6 mice that is similar to 4%/day, previously found for Mtb Erdman in cynomolgus macaques. While the estimated Mtb DNA decay rate seems small, we found that estimated rates of Mtb replication and death/killing are still extremely sensitive even to slow decay of Mtb DNA, in part, because Mtb replication and death rates are also small especially during chronic phases of infection. By applying our models to data on Mtb dynamics during the first 3 weeks of infection in macaques, we provide evidence of substantial killing of Mtb bacteria, prior to arrival of adaptive immunity to the site of infection, challenging the previously established notion of non-dying bacteria in the absence of T cell immunity and granuloma formation. We also propose experiments that will allow more accurately to measure the rate of Mtb DNA loss, helping more rigorously quantify impact of immunity on within-host Mtb dynamics.

Mycobacterium tuberculosis↗

PubMed2005

Boophilus microplus: the pattern of bovine immunoglobulin isotype responses to high and low tick infestations.

Cattle present variable levels of resistance to ticks and the immune correlates of these heritable phenotypes must be known in order to develop effective vaccines. The antibody responses to tick salivary antigens were examined in cattle of tick-susceptible (Holstein) and tick-resistant (Nelore) breeds. After heavy infestations, levels of IgG1 and IgG2 antibodies decreased in Holsteins and remained the same in Nelores. Conversely, levels of IgE antibodies increased in Holsteins. Different sizes of tick burdens modulated the IgG1 antibody response in a susceptible breed (Aberdeen): levels were higher than in controls in heavily infested animals, but not in those undergoing intermediary or minimal infestations. The three experimental groups presented similar levels of IgG2 antibodies. Levels of IgE antibodies were higher only in animals undergoing intermediate infestations. These results indicate that tick infestations suppress the IgG antibody response in susceptible breeds, that IgE antibodies are not protective, and that the dose of tick saliva modulates the isotype of host antibody responses.

Animals↗

PubMed1984

Chronic immune stimulation by sperm alloantigens. Support for the hypothesis that spermatozoa induce immune dysregulation in homosexual males.

Putative, sperm-induced allogeneic immunization was correlated with immune dysregulation in a study of 30 asymptomatic, monogamously paired homosexual males. Evidence for allogeneic immunization existed among 19 of 26 homosexual males who were anal sperm recipients. No evidence for any form of alloimmunization was found in four exclusive sperm donors. Immune dysregulation in the form of a reduced effector/suppressor T-cell ratio (Te/Ts less than 1.0) was exclusively documented in eight anal-sperm-recipient homosexual males, five of whom also manifested evidence for allogeneic immunization. In three of those, immune dysregulation was further manifested by functional T-cell deficiency in the form of a subnormal (less than 50 cu mm) local graft-v-host reaction. Similar evidence for alloimmunization was associated with a reduced Te/Ts ratio (0.85) in the female of a heterosexual couple who routinely practiced anal intercourse. Based on these findings, we suggest that chronic, repeated exposure to sperm during anal intercourse results in a high frequency of allogeneic immunization and may play an important role in the development of acquired immune dysregulation among homosexual males.

Acquired Immunodeficiency Syndrome↗

PubMed2001

Identification, molecular cloning and functional characterization of NKp46 and NKp30 natural cytotoxicity receptors in Macaca fascicularis NK cells.

Natural killer (NK) cell recognition and function in humans is regulated by multiple cell surface receptors. The "on" signal leading to NK cell triggering is primarily mediated by natural cytotoxicity receptors (NCR). Analysis of NK cells in primate animal models is of particular relevance because NK cells may play an essential role in host defenses against infections. We analyzed Macaca fascicularis PBMC and in vitro-derived NK cell populations and clones by cytofluorometry, using a wide panel of mAb, and by cytolytic activity assays. In addition, RT-PCR strategy and transient transfections were used to isolate M. fascicularis NCR. NCR-specific mAb reactivity (anti-NKp46 and anti-NKp30) was present on M. fascicularis PBMC and on NK cell cultures. Macaque NCR were functional in both redirected killing and in mAb-mediated masking assays. Cloning of macNKp46 and macNKp30 NCR homologous genes showed a high sequence similarity (86 % and 88 %, respectively) with their human counterparts. Attempts at identifying NKp44 surface reactivity and at cloning the macaque homologue were unsuccessful. NKp46 and NKp30 NCRs, but not NKp44, are highly conserved in M. fascicularis NK cells. This suggests the possibility of a staged appearance of the NCR during phylogenesis and provides a useful tool for the study of natural immunity correlates of protection in primate SIV/SHIV infection models.

Amino Acid Sequence↗

PubMed2004

Suppressive oligonucleotides protect against collagen-induced arthritis in mice.

OBJECTIVE: To examine whether systemic administration of oligonucleotides (ODNs), known to inhibit the production of proinflammatory cytokines, alters host susceptibility to collagen-induced arthritis (CIA), a murine model of rheumatoid arthritis (RA). METHODS: CIA was induced by injecting DBA/1 mice with type II collagen (CII) in Freund's complete adjuvant, followed 3 weeks later by CII in Freund's incomplete adjuvant. The effect of suppressive ODNs on the incidence and severity of disease was monitored, as were immune correlates of CIA. RESULTS: Suppressive ODNs administered during the inductive phase of CIA significantly reduced the incidence and severity of arthritis. Treatment with suppressive ODNs significantly decreased serum titers of pathogenic IgG anti-CII autoantibodies and interferon-gamma production by collagen-reactive T cells. CONCLUSION: Suppressive ODNs may be of therapeutic value in the treatment of RA, and potentially other autoimmune diseases.

Animals↗

PubMed2006

Antibodies with amylase activity from the sera of autoimmune-prone MRL/MpJ-lpr mice.

Animals spontaneously developing lupus-like autoimmune pathology (SLE) are very promising models to study the mechanisms of natural abzymes (Abzs) generation and their role in etiology and pathogenesis of autoimmune diseases, but Abzs from the sera of animals remain virtually unstudied. In this work, electrophoretically homogeneous IgGs were isolated from the sera of MRL/MpJ-lpr mice. It was shown for the first time that amylase activity is an intrinsic property of antibodies (Abs) and their isolated heavy and light chains. Various markers of SLE pathology (proteinuria, enhanced concentration of anti-DNA Abs) increased with spontaneous development of SLE and especially after animal immunization, correlating with the increase in Abz relative amylase activity. The highest amylase activity was found in the sera Abs of healthy mice after delivery and at the beginning of lactation; this was not correlated with markers of mouse SLE but supports the idea that pregnancy could "activate" or "trigger" autoimmune-like manifestations and Abzs production in healthy mammals. The possible differences in mechanisms of Abzs production in lactating mice and animals developing SLE are discussed.

Amylases↗

PubMed2005

TGF-beta prevents eosinophilic lung disease but impairs pathogen clearance.

Respiratory infections are the third leading cause of death worldwide. Complications arise directly as a consequence of pathogen replication or indirectly due to aberrant or excessive immune responses. In the following report, we evaluate the efficacy, in a murine model, of nasally delivered DNA encoding TGF-beta1 to suppress immunopathology in response to a variety of infectious agents. A single nasal administration suppressed lymphocyte responses to Cryptococcus neoformans, influenza virus and respiratory syncytial virus. The suppression did not depend on the phenotype of the responding T cell, since both Th1 and Th2 responses were affected. During Th2-inducing infection, pulmonary eosinophilic responses were significantly suppressed. In all cases, however, suppressed immunity correlated with increased susceptibility to infection. We conclude that nasal TGF-beta treatment could be used to prevent pulmonary, pathogen-driven eosinophilic disease, although anti-pathogen strategies will need to be administered concordantly.

Animals↗