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Mechanisms of immune evasion by tumors.

In the past decade, basic studies in animal models have begun to elucidate the physiological barriers which impede a successful antitumor immune response. These barriers operate at a number of levels, and involve the tumor, the tumor microenvironment and various components of the innate and adaptive immune systems. In this review, we discuss the multiple mechanisms by which tumors evade an immune response, with an emphasis on clinically relevant strategies to overcome these inhibitory checkpoints.

Animals↗

FLIP protein and TRAIL-induced apoptosis.

Death ligands (such as Fas/CD95 ligand and TRAIL?Apo2L) and death receptors (such as Fas/CD95, TRAIL-R1?DR4, and TRAIL-R2/DR5) are involved in immune-mediated neutralization of activated or autoreactive lymphocytes, virus-infected cells, and tumor cells. Consequently, dysregulation of death receptor-dependent apoptotic signaling pathways has been implicated in the development of autoimmune diseases, immunodeficiency, and cancer. Moreover, the death ligand TRAIL has gained considerable interest as a potential anticancer agent, given its ability to induce apoptosis of tumor cells without affecting most types of untransformed cells. The FLICE-inhibitory protein (FLIP) potently blocks TRAIL-mediated cell death by interfering with caspase-8 activation. Pharmacologic down-regulation of FLIP might serve as a therapeutic means to sensitize tumor cells to apoptosis induction by TRAIL.

Animals↗

Gastroesophageal reflux and cow's milk allergy in infants: a prospective study.

BACKGROUND: Recent reports have suggested that gastroesophageal reflux in pediatric patients may be caused by food allergy. OBJECTIVE: The aim of our study was to determine the frequency of the association of gastroesophageal reflux with cow's milk protein allergy in patients win the first year of life. METHODS: We studied 204 consecutive patients (median age, 6.3 months) who had been diagnosed as having gastroesophageal reflux on the basis of 24-hour continuous pH monitoring and histologic examination of the esophageal mucosa. RESULTS: Clinical history suggested diagnosis of cow's milk allergy in 19 infants, and 93 others had positive test results (serum IgE anti-lactoglobulin, prick tests, circulating or fecal or nasal mucus eosinophils) but did not have symptoms indicating cow's milk allergy. The cow's milk-free diet and two successive blind challenges confirmed the diagnosis of cow's milk allergy in 85 of the 204 patients with gastroesophageal reflux. The clinical presentations of the infants with gastroesophageal reflux alone were different, in view of the greater frequency of diarrhea (p less than 0.0001) and atopic dermatitis (p less than 0.0002). In all, gastroesophageal reflux was associated with, and probably caused by cow's milk allergy, in 85 of 204 cases (41.8%). CONCLUSIONS: Considering the frequency of this association, patients younger than 12 months old with symptoms of gastroesophageal reflux should be carefully examined to determine whether this disorder is primary or caused by cow's milk allergy.

Diagnosis, Differential↗

Quantitating cellular immune responses to cancer vaccines.

While the future of immunotherapy in the treatment of cancer is promising, it is difficult to compare the various approaches because monitoring assays have not been standardized in approach or technique. Common assays for measuring the immune response need to be established so that these assays can one day serve as surrogate markers for clinical response. Assays that accurately detect and quantitate T-cell-mediated, antigen-specific immune responses are particularly desired. However, to date, increases in the number of cytotoxic T cells through immunization have not been correlated with clinical tumor regression. Ideally, then, a T-cell assay not only needs to be sensitive, specific, reliable, reproducible, simple, and quick to perform, it must also demonstrate close correlation with clinical outcome. Assays currently used to measure T-cell response are delayed-type hypersensitivity testing, flow cytometry using peptide major histocompatibility complex tetramers, lymphoproliferation assay, enzyme-linked immunosorbant assay, enzyme-linked immunospot assay, cytokine flow cytometry, direct cytotoxicity assay, measurement of cytokine mRNA by quantitative reverse transcriptase polymerase chain reaction, and limiting dilution analysis. The purpose of this review is to describe the attributes of each test and compare their advantages and disadvantages.

Cancer Vaccines↗

Detection of Mycobacterium bovis infection in cattle using an immunoassay for bovine soluble interleukin-2 receptor-alpha (sIL-2R-alpha) produced by peripheral blood T-lymphocytes following incubation with tuberculin PPD.

After activation of T-lymphocytes with antigen there is an increase in the expression of interleukin-2 receptor-alpha (IL-2R-alpha) followed by the release of a soluble form of the molecule (sIL-2R-alpha) from the membrane of the stimulated cells. The present study investigates the novel use of the release of sIL-2R-alpha from activated T-lymphocytes as a marker of cell-mediated immunity (CMI) in cattle infected with Mycobacterium bovis. An enzyme immunoassay was used to detect sIL-2R-alpha produced following incubation of bovine peripheral blood mononuclear cells with mycobacterial antigens. Using this assay, 63/67 cattle naturally infected with M. bovis were identified whereas only 1/51 uninfected animals were considered to give a positive result. This assay is more convenient to use than lymphocyte proliferation assays which involve the use of radionucleosides. It should prove useful for monitoring the immunological activation of bovine T-lymphocytes in a variety of situations including the development of CMI responses in cattle to novel mycobacterial antigens or potential vaccines.

Animals↗

Immune and pathophysiological processes in baboons experimentally infected with Ebola virus adapted to guinea pigs.

The dynamics of pathophysiological and immunological parameters monitored in monkeys Papio hamadryas infected with the guinea pig-adapted Ebola virus strain demonstrated that this viral strain preserved its virulence for monkeys and caused the disease with characteristic features similar to those caused by non-adapted Ebola virus. However, certain previously unknown patterns have been observed: (1) prolongation of the febrile period by two days; (2) extended period was characterized by stability of serum biochemical parameters; (3) marked vacuolization of the neutrophil cytoplasm; (4) appearance of juvenile lymphocytes on day 3 and by the end of the disease; and (5) a considerable increase in the spontaneous mononuclear proliferation (along with a decrease in the mitogen-induced proliferation) during the terminal stage of infection. The severity of pathological coagulation was found to correlate with the activity of serum cytokines IFN-alpha and TNF-alpha: their activities increased about 250- and 100-fold, respectively. There was significant alteration in the activity of natural killer cells, that dropped by the time of animal death.

Adaptation, Physiological↗

T cell vaccination in secondary progressive multiple sclerosis.

Four secondary progressive MS patients were vaccinated with bovine myelin-reactive irradiated T cell lines from their peripheral blood. Patients were followed for 30-39 months, and monitored for immunological responses toward the vaccine, and for their clinical characteristics. Two patients showed stable EDSS score over time, one patient showed improvement by one EDSS step, and in the remaining patient her EDSS advanced over time. After the second inoculation there was a progressive decline of circulating whole myelin-reactive T cells, MBP143-168, PLP104-117, and MOG43-55-peptide-reactive T cells. In contrast the frequency of tetanus toxoid-reactive T cells remained unchanged. T cell vaccination (TCV) was also associated with a decline of myelin-specific IL-2- and IFN-gamma-secreting T cells. Twelve T cell lines (TCL) that recognize the inoculates were isolated from the peripheral blood of two patients. Ten of these TCL were CD8(+) and lysed the inoculates in a MHC Class I restricted manner. The remaining two TCL were CD4(+), and lysed the inoculates by MHC Class II restricted cytolytic activity. All T cell lines lysed not only myelin-reactive T cells, but also TCL specific for MBP143-168, PLP104-117 and MOG43-55 peptides. Control TCL specific for tetanus toxoid were not lysed. Neutralizing anti-Fas mAb did not influence the killing. Moreover, culture supernatants from two TCL which produce IL-10, were able to block the proliferation of myelin protein-specific TCL. This effect was abrogated using mAbs specific for IL-10. The data obtained indicated that TCV using autologous irradiated bovine myelin-reactive T cells promotes an effective depletion of T cells reactive against different myelin antigens.

Animals↗

Immune monitoring: it's prudent to adopt current quality regulations.

The United States Food and Drug Administration and its international governmental counterparts provide strict guidelines for product manufacture, quality control and clinical practice, but no regulations exist for immune monitoring. This is not surprising because it is a relatively new field that is increasingly applied in clinical trials of immunotherapy. Immune monitoring is experimental in nature, usually performed in an R&D laboratory, and is typically not integrated into an organization's quality assessment system. With the proliferation of immunotherapy studies and immunogenicity testing, regulatory agencies will progressively increasingly demand that quality regulations be applied to immune monitoring in the future. Here, I highlight the relevance of existing regulations, which, I believe, should be prospectively tied into the development and performance of immune monitoring methods.

Drug Approval↗

Tailoring of immunosuppression in renal and liver allograft recipients displaying donor specific T-suppressor cells.

Although transplantation tolerance cannot be yet reliably achieved in humans, there is evidence that active immunosuppression contributes to the maintenance of quiescence. However, the mechanism that underlies quiescence and the precise identity of regulatory cells are not completely understood. We have demonstrated that allograft recipients who remain rejection-free display allospecific T-suppressor cells (Ts). Ts express the CD8(+) CD28(-) phenotype, recognize major histocompatibility complex (MHC) class I antigens, and suppress the up-regulation of costimulatory molecules induced by CD40 ligation of donor antigen presenting cells. The presence of Ts is inversely correlated with T cell alloreactivity to donor MHC peptides, alloantibody production, and rejection. Monitoring of Ts has been successfully used in our studies for tailoring immunosuppression in kidney and liver allograft recipients.

Antigen-Presenting Cells↗

Using capture-recapture methods to assess varicella incidence in a community under active surveillance.

The Varicella (chickenpox) Active Surveillance Project (VASP) has been conducting active surveillance since 1 January 1995 in the high desert community known as Antelope Valley, CA (population 300,000) among 300 public and private schools, daycares, and healthcare providers. Capture-recapture methods were applied to estimate reporting completeness for 1995 varicella incidence data and these were compared with the national average incidence rates by age reported by the National Health Interview Survey (NHIS). Varicella cases reported among individuals aged <20 years reflect under-reporting in excess of 50%. Despite limitations on accuracy, capture-recapture estimates are a reasonably accurate, quick, and inexpensive approach in epidemiologic studies.

Adolescent↗

Incidence of herpes zoster among children and adolescents in a community with moderate varicella vaccination coverage.

Active surveillance for herpes zoster (HZ) was conducted for 2 years (2000-2001) in the Antelope Valley community of 312,000 residents among 290 public and private schools, daycares, and healthcare providers. The true ascertainment-adjusted HZ incidence rate is 307 per 100,000 person-years and 138 per 100,000 person-years among children <10 and individuals aged 10-19, respectively. The unadjusted rate among vaccinated children is 9.5 per 100,000 person-years and an estimated 22 per 100,000 vaccine doses. Unvaccinated children with a previous history of varicella may have greater sensitivity to exogenous exposures (boosting) and a poorer cell-mediated response following primary infection relative to older age groups.

Adolescent↗

Varicella susceptibility and incidence of herpes zoster among children and adolescents in a community under active surveillance.

Licensure of varicella vaccine by the US Food and Drug Administration in March 1995 has given rise to concerns that include a potential shift in varicella incidence to susceptible adults and increase in herpes zoster (HZ) incidence. Baseline values prior to widespread vaccination were obtained through distribution of an adolescent survey to all 13 public middle (seventh and eighth grade) schools in the Antelope Valley, CA health district. Based on 4216 respondents aged 10-14 years, varicella susceptibility is 7.7% (95% CI, 6.9-8.5%) and true cumulative (1987-2000) HZ incidence rate is 133 per 100,000 person-years (95% CI, 95-182 per 100,000 person-years).

Adolescent↗

Comparison of measles virus-specific antibody titres as measured by enzyme-linked immunosorbent assay and virus neutralisation assay.

We assessed whether measles virus-specific antibody levels in the Dutch population as estimated by an enzyme-linked immunosorbent assay (ELISA) were comparable with estimates by virus neutralisation assay (NT), prompted by a relatively low ELISA seroprevalence in the 10-21-year-old group. We tested 791 sera from individuals aged 2-49 years both in ELISA and NT. Seroprevalence in the 10-21-year-old group was 93.4% (95% confidence interval (CI) 89.5-97.2%) in ELISA versus 97.2% (CI 94.7-99.6%) in NT. There was good agreement between NT and ELISA seroprevalences in the vaccinated 2-9-year-olds and the unvaccinated 22-49-year-olds.

Adolescent↗