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Thursday, July 3, 2014

Progress in HIV-1 Vaccine Development

Advances in HIV vaccine development have been hampered by roadblocks associated with failure to prevent infection. In recent years, a number of basic and translational science advances have shown promise in the development for an effective vaccine. In their review, Haynes and colleagues summarize these advances along with the roadblocks that still remain, as well as the most promising approaches to successful vaccine design (J Allergy Clin Immunol 2014, 134(1): 3-10). 

This year, the field of HIV-vaccine research had a major disappointment in the announcement of the lack of a vaccine efficacy seen in a DNA prime, recombinant adenovirus type 5 (rAd5) boost HIV-1 vaccine trial developed by the NIH Vaccine Research Center. The vaccine was designed to test the hypothesis that high levels of CD8+ cytotoxic T cells (CTLs) could either protect against transmission or lead to control of plasma HIV-1 viral load. The second failed trial, the Merck recombinant adenovirus type 5 trail, not only lacked vaccine efficacy, but also appeared to enhance infection in those vaccines seropositive for Ad5. Although these 2 trials were of great disappointment, they provided valuable information on the types of immune responses that are unlikely to be protective.

New advances have demonstrated a variety of promising results such as the discovery of new envelope (Env) targets of potentially protective antibodies. A recent study shows promise with the finding that CD8+ T cells are associated with control and eradication of early retrovirus infections in rhesus macaques. Another recent study shows that the development of immunogens to overcome HIV-1 T cell epitope diversity while another study identifies correlates of transmission risk in an HIV-1 efficacy trail. And finally, a recent advancement has mapped the co-evolution of HIV-1 founder Env mutants in infected individuals who develop broad neutralizing antibodies (bnAbs), thereby defining bnAb developmental pathways.

Despite these advances, the field is still years away from deployment of an effective vaccine. Moving forward in HIV-1 vaccine research requires the conversion of subdominant immune responses into dominant ones, which has yet to be accomplished by an infectious disease vaccine. HIV-1 vaccine research is breaking promising new ground in vaccinology, and success in its development will herald success for other difficult vaccines such as influenza and hepatitis C. 

Prenatal exposure to diesel exhaust induces asthma susceptibility through NK cell priming

Asthma often begins early in life and is attributed to more than just genetic factors, because the prevalence continues to rise. Epidemiological studies have indicated roles for prenatal and early childhood exposures, including exposure to diesel exhaust, however, little is known about the mechanisms involved. To elucidate this, Manners et al developed a mouse model of asthma susceptibility through prenatal exposure to diesel exhaust (J Allergy Clin Immunol 2014; 134(1): 63-72).

In this model, pregnant mice were repeatedly exposed to diesel exhaust particles (DEPs). Offspring were immunized and challenged with ovalbumin (OVA) or exposed to PBS (control) then examined for features of asthma. Compared to controls, offspring that were exposed to DEP were hypersensitive to OVA, indicated by airway hyperresponsiveness, elevated serum levels of OVA-specific IgE, and elevated levels of pulmonary and systemic T-helper type 2 (Th2) and Th17 cytokines. The authors determined that natural killer (NK) cells were the primary source of cytokine production and airway inflammation was diminished by antibody-mediated depletion of NK cells. Furthermore, asthma susceptibility was associated with increased transcription of genes known to be specifically regulated by the aryl hydrocarbon receptor (AhR) and oxidative stress.

These results coincide with previous data that suggests NK cells initiate allergic inflammation. AhR is expressed in NK cells which may provide a link between maternal exposure to diesel exhaust and asthma in offspring. Taken together, this data provides mechanistic insight into the process of prenatally-induced asthma susceptibility. 

Monday, June 2, 2014

The effects of calcitriol treatment in glucocorticoid resistant asthma

The current and most effective treatment for asthma therapy is the use of glucocorticoids by improving the clinical features and airway inflammation associated with asthma. However, a cohort of well-defined asthma patients exists in whom high-dose glucocorticoid treatment is not only clinically ineffective, but potentially detrimental.  Several mechanisms have been proposed to contribute to glucocorticoid resistance, including vitamin D insufficiency. Nanzer et al recently published data that glucocorticoid resistant patients fail to synthesize the anti-inflammatory cytokine interleukin-10 (IL-10) in response to glucocorticoid in vitro compared to glucocorticoid sensitive patients (J Allergy Clin Immunol 2014; 133(6): 1755-1757). When resistant patients ingested a form of vitamin D called calcitriol (1,25-dihydroxyvitamin D3) in combination with glucocorticoid, levels of IL-10 were restored in vivo and ex-vivo. Taken together, these data along with epidemiological evidence linking vitamin D insufficiency/deficiency with poor clinical response to asthma treatment provided the rationale for the authors to perform a proof-of-concept clinical trial.

A small group of glucocorticoid resistant severe asthmatics were chosen and placed on a 2-week course of oral prednisolone and then randomly assigned placebo or 0.25ug calcitriol twice daily for 4 weeks. During the last 2 weeks patients repeated a course of oral prednisolone. The authors hypothesized that the concomitant calcitriol therapy would improve clinical glucocorticoid responsiveness in these patients. They did not expect the short course of calcitriol to restore Vitamin D sufficiency, but to address the short-term effects of calcitriol itself.

A within group comparison showing the change in lung function during the initial screening in response to 2-weeks oral prednisolone versus the response to an identical course of prednisolone plus either placebo or calcitriol, revealed a modest but significant improvement in absolute and predicted FEV₁ within the calcitriol but not the placebo arm. Furthermore, a trend for a positive correlation between baseline serum Vitamin D concentrations and change in predicted lung function following prednisolone was observed in placebo patients. This data suggests that treatment with a short course of calcitriol may improve the clinical glucocorticoid responsiveness in asthma, including patients classified as clinically glucocorticoid resistant. While larger studies with clinically well-defined cohorts are warranted, these results are very encouraging for the treatment of glucocorticoid resistant asthma. 

Mechanisms underlying the neuronal based symptoms of allergy

People with allergies often present with symptoms that are the result of alterations in the nervous system in the organ in which the reaction occurs. Common neuronal symptoms include itchy eyes, sneezing, nasal congestion, rhinorrhea, cough, bronchoconstriction, airway mucus secretion, dysphagia, altered gastrointestinal motility, and itchy swollen skin. Mediators released during an allergic reaction interact with sensory nerves, altering the transmission of signals in the sympathetic and parasympathetic autonomic nerves. Undem and Taylor-Clark describe how the nervous system itself is altered in allergic disease either due to events occurring during critical periods of neuronal development or to persistent nerve stimulation (J Allergy Clin Immunol 2014; 133(6): 1521-1534).

Those that suffer from allergic rhinitis for example, more often react strongly by sneezing when stimulants are applied to the nasal mucosa compared to healthy controls. Considering sneezing is a parasympathetic reflex, it is not surprising that these allergic individuals are often more likely to have nasal allergic symptoms when exposed to smoke, irritants, and cold air.  Similarly, in response to food allergy, immunological activation of mast cells in the gut is associated with alterations in neurotransmission. The authors detail the basic mechanisms of allergen-induced neuromodulation, highlighting the molecular interactions and phenotypic changes that occur. 

The authors emphasize that not only those with allergy produce neuroactive mediators at sites of allergic inflammation, but that the nervous system itself is altered in allergic diseases. Whether this is due to events occurring during critical periods of neuronal development or to persistent nerve activation, the nervous system is rendered hyperactive. As the understanding of basic mechanisms continue to evolve, new therapeutic strategies that target the nervous system will continue to emerge that work synergistically with anti-inflammatory treatments that allow for new, more powerful therapeutic options for allergy sufferers.

Potential food allergens in medications

Excipients are all of the substances found in pharmaceuticals that are added to the active ingredient to provide a benefit in manufacturing, stability, bioavailability, or patient acceptability.  Some excipients are foods or substances derived from foods.  Food allergic patients may rarely have reactions to these products. In his review, John M. Kelso, MD details which food-derived substances are used as pharmaceutical excipients and in which medications. Furthermore, the safety of administration of these medications in food allergic patients is also discussed (J Allergy Clin Immunol 2014; 133(6): 1509-1518). 

Food allergens are proteins that can generate IgE-mediated responses in food-allergic individuals. Since some food-derived excipients in medications are proteins, there is potential for an allergic response.  However, in most cases there is not enough of the food protein present to cause a reaction even in an allergic individual.  For example, most influenza vaccines are grown in eggs,  however there are only trace amounts of the protein in the vaccines and they are considered safe in egg-allergic recipients.  Other vaccines, however, contain substantial quantities of gelatin and do pose a risk of an allergic reaction in those with gelatin allergy.  Other excipients are derived from foods but do not contain protein, thus fish-allergic patients need not avoid fish oil for example.  In some cases, a food-derived excipient such as lactose may be contaminated with milk protein accidentally.

Although food-derived excipients may contain food proteins, reactions are generally quite rare likely because protein amounts are too low to elicit a reaction. If there is a reaction to a medication, it may be from a specific lot that was accidentally contaminated with food protein. However, if a reaction occurs, allergy to the food component should be investigated as a possible cause.

Wednesday, May 7, 2014

Effects of antioxidants on asthma

While the prevalence of asthma and allergic diseases continues to rise, the consumption of dietary antioxidants is decreasing around the world.  The western diet is becoming more popular around the world even though it is characterized by a reduction of fresh fruits and vegetables with an increase of processed foods and antioxidant enriched foods. As pulmonary and systemic oxidative stress increase allergic inflammation, dietary or supplemental antioxidants have been proposed to counteract the incidence and morbidity of allergic disease.  Moreno-Macias and Romieu summarize various studies associated with the effects of antioxidants on asthma and allergic diseases (J Allergy Clin Immunol 2014; 133(5): 1237-44).

Meta-analyses of epidemiologic studies of variable quality suggest associations of low dietary intake of antioxidants and increased asthma and allergy. Compared to asthma, few trials have looked at associations between diet and atopic dermatitis, allergic rhinitis, or IgE levels.  Large trials of antioxidant supplementation to prevent cancer suggest an increased mortality with supplementation at least in populations with sufficient dietary intake of antioxidants.  High levels of antioxidants are found in the Mediterranean diet which is associated with a decrease in asthma and allergic disease suggesting high levels of antioxidants in the diet are beneficial. However, antioxidant supplementation may be protective under certain conditions where vulnerable populations have a deficiency in dietary antioxidants and/or are exposed to environmental oxidants. 

The authors explain that while appropriate levels of antioxidants are necessary to eliminate oxidants, the source of the antioxidant intake may be crucial when counteracting oxidative stress. Taken together, these data highlight the importance of antioxidant effects in asthma and allergic diseases and that future studies should focus on the source of antioxidant intake.

Question for the authors:  The source of antioxidants is likely relevant in other inflammatory conditions similar to the cancer study. Being that this sheds more light on the quality of the Western diet, what types of future research do you foresee coming from such important information?

We think that dietary interventions based on food exchange may be useful.  In addition, although following people over time implies big efforts in terms of money and human resources,  it is necessary to understand the disease dynamic taking into account variables that may change over time such as antioxidant intake and life styles. The use of biomarkers instead of surrounding variables would be more informative. Since the source of the antioxidant diet is relevant, this variable should be included as well.  Moreover, since we are in the genomic era, epigenetic,  nutrigenomic and toxicogenomic analyses  will be incorporating relevant information.

Tuesday, May 6, 2014

Peanut, milk and wheat intake during pregnancy is associated with reduced allergy and asthma in children

The relationship between maternal diet and childhood allergy and asthma is controversial.  Not long ago, the American Academy of Pediatrics advised that maternal dietary restrictions are not necessary with the possible exception of excluding peanuts.  Subsequent systematic reviews concluded that the evidence was inadequate to support any dietary restrictions during pregnancy. In fact, recent research suggests that fetal exposure to common food allergens may be beneficial. Bunyavanich et al examined the associations between maternal intake of common childhood food allergens during pregnancy and childhood asthma and allergies (J Allergy Clin Immunol 2014; 133(5): 1373-1382).
The authors studied a healthy pre-birth cohort of 1277 mother-child pairs from the United States and used food frequency questionnaires administered during pregnancy. Children were assessed for food allergy, asthma, allergic rhinitis, and atopic dermatitis by questionnaire and serum specific IgE levels at a mean age of 7.9 years. They discovered that higher maternal peanut intake during the first trimester was associated with 47% reduced odds of peanut allergic reaction. Higher milk intake during the first trimester was associated with reduced asthma and allergic rhinitis, while higher maternal wheat intake during the second trimester was associated with reduced atopic dermatitis. The authors discuss that the first trimester is a formative period of fetal immune development and the mother’s diet may influence helper T cell differentiation as well as fetal airway differentiation. 

The results of this study do not support avoidance of specific foods during pregnancy to prevent allergy and asthma in children.  The authors conclude that the inclusion of peanut, milk, and wheat during pregnancy could be beneficial for the prevention of allergic diseases.