Jennifer J. McIntire

Asthma: an epidemic of dysregulated immunity

The remarkable increase in asthma prevalence that has occurred over the last two decades is thought to be caused by changes in the environment due to improved hygiene and fewer childhood infections. However, the specific infections that limit T helper type 2 (TH2)-biased inflammation and asthma are not fully known. Infectious organisms, including commensal bacteria in the gastrointestinal tract and hepatitis A virus, may normally induce the development of regulatory T (TR) cells and protective immunity that limit airway inflammation and promote tolerance to respiratory allergens. In the absence of such infections, TH2 cells—which are developmentally related to TR cells—develop instead and coordinate the development of asthmatic inflammation.

Identification of Tapr (an airway hyperreactivity regulatory locus) and the linked Tim gene family

To simplify the analysis of asthma susceptibility genes located at human chromosome 5q23-35, we examined congenic mice that differed at the homologous chromosomal segment. We identified a Mendelian trait encoded by T cell and Airway Phenotype Regulator (Tapr). Tapr is genetically distinct from known cytokine genes and controls the development of airway hyperreactivity and T cell production of interleukin 4 (IL-4) and IL-13. Positional cloning identified a gene family that encodes T cell membrane proteins (TIMs); major sequence variants of this gene family (Tim) completely cosegregated with Tapr. The human homolog of TIM-1 is the hepatitis A virus (HAV) receptor, which may explain the inverse relationship between HAV infection and the development of atopy.

Critical Role for IL-13 in the Development of Allergen-Induced Airway Hyperreactivity

Airway hyperresponsiveness to a variety of specific and nonspecific stimuli is a cardinal feature of asthma, which affects nearly 10% of the population in industrialized countries. Eosinophilic pulmonary inflammation, eosinophil-derived products, as well as Th2 cytokines IL-13, IL-4, and IL-5, have been associated with the development of airway hyperreactivity (AHR), but the specific immunological basis underlying the development of AHR remains controversial. Herein we show that mice with targeted deletion of IL-13 failed to develop allergen-induced AHR, despite the presence of vigorous Th2-biased, eosinophilic pulmonary inflammation. However, AHR was restored in IL-13−/− mice by the administration of recombinant IL-13. Moreover, adoptive transfer of OVA-specific Th2 cells generated from TCR-transgenic IL-13−/− mice failed to induce AHR in recipient SCID mice, although such IL-13−/− Th2 cells produced high levels of IL-4 and IL-5 and induced significant airway inflammation. These studies definitively demonstrate that IL-13 is necessary and sufficient for the induction of AHR and that eosinophilic airway inflammation in the absence of IL-13 is inadequate for the induction of AHR. Therefore, treatment of human asthma with antagonists of IL-13 may be very effective.

CD4+ T helper cells engineered to produce latent TGF-β1 reverse allergen-induced airway hyperreactivity and inflammation

T helper 2 (Th2) cells play a critical role in the pathogenesis of asthma, but the precise immunological mechanisms that inhibit Th2 cell function in vivo are not well understood. Using gene therapy, we demonstrated that ovalbumin-specific (OVA-specific) Th cells engineered to express latent TGF-beta abolished airway hyperreactivity and airway inflammation induced by OVA-specific Th2 effector cells in SCID and BALB/c mice. These effects correlated with increased concentrations of active TGF-beta in the bronchoalveolar lavage (BAL) fluid, demonstrating that latent TGF-beta was activated in the inflammatory environment. In contrast, OVA-specific Th1 cells failed to inhibit airway hyperreactivity and inflammation in this system. The inhibitory effect of TGF-beta-secreting Th cells was antigen-specific and was reversed by neutralization of TGF-beta. Our results demonstrate that T cells secreting TGF-beta in the respiratory mucosa can indeed regulate Th2-induced airway hyperreactivity and inflammation and suggest that TGF-beta-producing T cells play an important regulatory role in asthma.

Immunology : hepatitis A virus link to atopic disease

Atopic diseases, including asthma, allergic rhinitis and atopic dermatitis, are caused by both environmental and genetic factors. Here we show that infection by hepatitis A virus (HAV) may protect individuals from atopy if they carry a particular variant of the gene that encodes TIM-1 (also known as HAVcr-1) — the cell-surface receptor used by HAV to infect human cells. Exposure to HAV is associated with poor hygiene, large family size and attendance at day-care centres, all factors that are also inversely associated with atopy. Our discovery indicates that interaction between HAV and TIM-1 genotype may contribute to the aetiology of atopic diseases, and provides a mechanism to account for the hygiene hypothesis.

Clinical efficacy of microencapsulated timothy grass pollen extract in grass-allergic individuals

BACKGROUND Conventional allergen immunotherapy is clinically effective in reducing the symptoms of allergic rhinitis and asthma. It differs from other pharmacotherapies in that it can induce long-term clinical remission of these diseases. However, it requires years of treatment and is associated with serious allergic reactions. OBJECTIVE To evaluate the safety, clinical efficacy, and immunologic mechanisms of immunotherapy with an oral, microencapsulated form of timothy grass allergen. METHODS In this double-blind, placebo-controlled study, 24 patients aged 19 to 55 years with grass pollen allergy were randomized to receive either microencapsulated timothy grass pollen extract or placebo once a day for 10 weeks. The dose of study drug was doubled weekly. Safety was evaluated through weekly visits, daily symptom diaries, and routine laboratory tests. Efficacy was evaluated by comparing medication use and symptoms scores during peak grass pollen season before and after treatment. Allergen-specific T-cell responses, cytokine production, and IgG, IgE, and skin reactivity were measured to evaluate immunologic mechanisms. RESULTS Eleven of 12 patients in the active treatment group had a decrease in the combined medication and symptom score, but only 4 of 10 patients in the placebo group had a decrease in scores. The proliferative response to timothy grass was reduced by at least 30% in 9 of the 12 grass-treated patients, but only 3 of 11 placebo patients had a proliferative response reduction. Timothy grass-induced interleukin-5 messenger RNA was reduced in the active group, but not in the placebo group. There were no significant changes in either group in IgG, IgE, and skin reactivity. CONCLUSIONS Oral immunotherapy with microencapsulated allergen induces a form of immunologic tolerance to the allergen and is a safe, efficient, and effective method of allergen immunotherapy.

TIM-1, hepatitis A virus and the hygiene theory of atopy: association of TIM-1 with atopy.

Atopic diseases, including asthma, allergic rhinitis and atopic dermatitis, are caused by environmental and genetic factors (1). We examined the association in humans between atopy and TIM-1, a gene that we discovered using a congenic positional cloning strategy and a mouse model of asthma, and that regulates Th cell differentiation (2). By sequencing human lymphocyte cDNA for TIM-1, we identified a 6-amino-acid insertion at residue 157, termed 157insMTTTVP, as well as two single amino-acid changes, 195delT and A206T. To determine the effect of 157insMTTTVP on the occurrence of atopy, we performed a cross-sectional study of 375 individuals who were evaluated by history and tested serologically for atopy. Because TIM-1 is the receptor for hepatitis A virus (HAV), we also examined subjects for serologic evidence of past infection with HAV. To correct for potentially confounding effects of population admixture, we used stratified Mantel–Haenszel tests to quantify the association between atopy and 157insMTTTVP in the total sample. We found that individuals with the 157insMTTTVP variant of TIM-1 were protected against the development of atopy but only when there was prior infection with HAV (P 0.0005) (3). In other words, we identified a significant interaction between HAV, TIM-1 and atopy, such that HAV protects individuals from atopy, according to their TIM-1 genotype. HAV exposure is associated with poor hygiene, large family size and attendance at daycare, and each of these factors is inversely associated with atopy. Because the incidence of infection with HAV before 1975 approached 100% in the population at large, but has declined significantly over the past two decades, our discovery demonstrates at a genetic level that interactions between HAV and TIM-1 may contribute to the etiology of atopic diseases and may help explain the hygiene hypothesis of atopy.