The Editors’
`
`Choice
`
`Donald Y. M. Leung, MD, PhD
`Stanley J. Szefler, MD
`and the Associate Editors of the JACI
`
`MP29-02: A major advancement in the
`treatment of allergic rhinitis
`
`Intranasal corticosteroids (INSs) are the most effective
`therapy for the treatment of allergic rhinitis (AR). Little evi-
`dence exists to support the benefit of one INS over another.
`Furthermore, there is a paucity of head-to-head data involving
`INS therapy, with most studies focusing on patient preference
`and not on efficacy and safety. In the current issue of the
`Journal, Carr et al (p 1282) compare, for the first time, the
`efficacy of MP29-02 (a novel azelastine/fluticasone propionate
`formulation) with fluticasone propionate, azelastine, and pla-
`cebo using the same formulation in 3398 patients with
`moderate-to-severe seasonal AR in 3 multicenter, randomized,
`double-blind, placebo-controlled, 14-day, parallel-group trials.
`In these 3 head-to-head comparisons, they reproducibly
`demonstrate that MP29-02 is significantly more effective than
`intranasal fluticasone or azelastine (see Figure). The im-
`provement of MP29-02 over standard therapy was substantial,
`occurred faster (up to 5 days faster than fluticasone and up to
`7 days faster than azelastine), and was more complete, with
`1 of 8 MP29-02–treated patients exhibiting complete/near-
`complete symptom resolution. With this improved efficacy,
`there were no new safety concerns beyond those of currently
`marketed fluticasone and azelastine. Given these findings,
`MP29-02 can be considered the drug of choice for the treat-
`ment of AR.
`
`This material may be protected by Copyright law (Title 17 U.S. Code)
`
`THE JOURNAL OF
`AllergyA N DClinical
`Immunology
`
`VOLUME 129
`
`NUMBER 5
`
`MP4004 (n=776)
`
`I
`
`FLU
`
`AZE
`
`MP29-02
`
`MP29-02
`
`FLU
`
`AZE
`
`MP4006 (n=1791)
`
`Meta-analysis (n=3398)
`
`MP29-02
`
`FLU
`
`AZE
`
`MP29-02
`
`FLU
`
`AZE
`
`N=3398, ' p<0.001 VS FP; t p<0.001 VS AZE.
`
`Effect of MP29-02, fluticasone propionate (FP), and azelastine (AZE) on the
`overall reflective total nasal symptom score (rTNSS; AM + PM) in patients
`with moderate-to-severe seasonal AR.
`
`Allergen-specific immunotherapy reduced
`to 3 injections
`
`Allergen-specific immunotherapy is the only disease-
`modifying treatment of allergies, but it requires numerous
`allergen administrations over 3 to 5 years, so that less than 5%
`of patients with allergies choose immunotherapy. Senti et al
`(p 1290) could reduce the number of allergen injections to 3
`by enhancing antigen presentation. First, allergen was in-
`jected directly into lymph nodes. Second, the allergen, re-
`combinant cat dander allergen Fel d 1, was fused with an
`intracellular translocation sequence and with an invariant
`chain to enhance presentation through MHC class II to CD4 T
`
`cells. Such rapid intracellular translocation of the allergen has
`the additional advantage of reducing IgE cross-linking on mast
`cells, reducing skin test reactivity approximately 100-fold. In
`this double blind, placebo-controlled trial, patients with cat
`dander allergy received 3 intralymphatic injections within 2
`months, either with modified Fel d 1 or placebo. Injections
`were practically painless and safe. Induction of regulatory T
`cells correlating to IgG4 responses was observed, and nasal
`tolerance increased 74-fold (P < .001, vs placebo). In summary,
`intralymphatic immunotherapy with modified recombinant Fel
`d 1 elicited no adverse events, and 3 injections were sufficient
`to render patients with cat allergy tolerant. Reduced treatment
`duration might make immunotherapy more attractive for to-
`day’s busy patient.
`
`Innate antiviral responses at birth can
`predict the future
`
`Viral respiratory tract infections are perhaps the most
`common cause of acute illness and a major factor in chronic
`sinusitis and asthma in childhood and later life, but why one
`patient might be more or less susceptible to infection is uncer-
`tain in almost all cases. In this issue Sumino et al (p 1267)
`studied cord blood monocytes obtained from a high-risk cohort
`of children with at least 1 parent with allergy or asthma and
`found that a decrease in the usual induction of IFNG mRNA in
`response to a common virus (respiratory syncytial virus) was
`
`predictive of an increase in upper respiratory tract infections
`(nose, ear, and sinus), pneumonias, and respiratory hospitaliza-
`tions during the first year of life. Because the investigators stud-
`ied the innate immune system, the findings challenge the
`previous dogma that the adaptive immune system (particularly a
`skewed T-cell response) is the primary determinant for suscep-
`tibility to viral and perhaps postviral illness. The findings also
`revise the conventional view that the IFNG gene is only active in
`lymphoid cells. Moreover, because the investigators studied the
`response present at birth, the observations also challenge the
`proposal that microbial hygiene in the childhood environment is
`the primary influence on viral sequelae.
`
`Page 1216 May 2012
`
`J ALLERGY CLIN IMMUNOL
`
`

`

`IFN-c–induced apoptosis of keratinocytes
`in patients with atopic dermatitis
`
`Atopic dermatitis is a common chronically relapsing skin dis-
`ease. TH2 bias with increased IgE levels are widely recognized
`hallmarks of extrinsic atopic dermatitis. However, it is less well
`known that in the chronic phase of skin inflammation, IFN-c as a
`characteristic cytokine for TH1 cells plays a role as a dominant
`factor and causes enhanced apoptosis of keratinocytes in the ec-
`zematous lesions of patients with atopic dermatitis. In this issue
`Rebane et al (p 1297) demonstrate that keratinocytes from patients
`with atopic dermatitis exhibit increased IFN-c–induced apoptosis
`compared with keratinocytes from healthy subjects. Further ex-
`pression analysis demonstrated differences in apoptosis-related
`genes (ADM, NOD2, PCSK9, ANXA5, and INNP5D) and upregula-
`tion of IFN-c–inducible genes in keratinocytes and skin from
`patients with atopic dermatitis. In silico analysis based on genome-
`wide single nucleotide polymorphism data supported the findings
`and showed evidence of an association between atopic dermatitis
`and single nucleotide polymorphisms from the IFITM cluster: the
`RAB31, DUSP1, and ADM genes. It is possible that altered expres-
`sion of multiple apoptosis-related and IFN-c–inducible genes is
`responsible for apoptosis of keratinocytes, leading to eczema, and
`influences the development of chronic skin inflammation in pa-
`tients with atopic dermatitis. The study outlines the complexity of
`atopic dermatitis as a heterogeneous and multifactorial disease and
`proposes several potential novel genes that might play a role in the
`pathogenesis and can be used to develop novel treatment modali-
`ties in patients with atopic dermatitis.
`
`upregulated in
`AD skin
`
`upregulated by
`IFN-y in KCa
`439
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`
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`~ ~ ~ ~ ~ ~ ~ ~ ~ ~
`
`BATF
`CCDC109B
`CCLS
`CCL8
`IFl35
`IFITM1
`IFITM2
`LYN
`RAB31
`
`Nine genes that are upregulated in the skin from patients with atopic derma-
`titis (AD) can be induced by IFN-c in keratinocytes (KCs).
`
`Naive T lymphocytes jump-start allergic
`responses
`
`A
`
`B
`
`medium
`0.317
`
`boiled Papain
`
`Papaln
`
`The earliest steps of allergen recognition leading to differenti-
`ation of naive T lymphocytes into TH2 cells are still a matter of
`debate. Allergic responses to protease allergens, such as the
`papaya-derived food allergen papain or parasitic infection, are
`associated with basophil recruitment to draining lymph nodes.
`Basophils have the capacity to present antigen to naive T cells and
`promote TH2 differentiation directly or indirectly through
`production of the cytokine IL-4. How papain induces basophil
`migration to lymph nodes is unknown. In this issue Liang et al
`(p 1377) elucidate a pathway in mice in which naive T lympho-
`cytes first encounter and recognize papain through protease-
`activated receptor 2 (PAR2) and initiate TH2 differentiation. When
`mice were injected subcutaneously with papain, naive T cells
`produced basophil-attracting chemoattractant cytokines and IL-4
`(see Figure), leading to basophil accumulation in the lymph nodes.
`A subset of naive human peripheral blood T lymphocytes
`
`Papain stimulates Il4 gene expression (left) and IL-4 production (repre-
`sented by green fluorescent protein, right) in naive CD4 T lymphocytes.
`
`expressed PAR2 and responded to papain in a manner similar to
`their murine counterparts. These results suggest that there is an
`allergen recognition pathway mediated by naive T lymphocytes
`that express PAR2, which provide an early source of IL-4 upstream
`of basophils and antigen-restricted TH2 differentiation.
`Furthermore, PAR2 antagonism can be explored for the treatment
`of allergic disease.
`
`Cytomegalovirus and common variable
`immunodeficiency: An emerging
`relationship
`
`Patients with common variable immunodeficiency (CVID) ex-
`perience a spectrum of alterations in cellular immunity. Marashi
`et al (p 1349) profiled the global effect of cytomegalovirus (CMV)
`infection on immune effector cells in patients with CVID and im-
`plicated CMV as the driving force behind the CD4/CD8 ratio inver-
`sion characteristic of these patients. A subset of patients with CVID
`experience debilitating inflammatory disease, and the study focused
`on these patients to show that expansions of CMV-specific late
`
`effector CD8+ cells correlated with the presence of inflammatory
`disease. Remarkably, these CD8+ cells proliferated ex vivo in re-
`sponse to CMV antigen without exogenous costimulation, and su-
`pernatants from proliferating cells conferred proliferative capacity
`on CMV-specific CD8+ T cells from healthy control subjects. IFN-c
`and TNF-a were important for this proliferation. The authors pre-
`viously detected CMV antigens at inflammatory sites in these pa-
`tients, providing a plausible explanation for the persistent antigenic
`stimulation that is presumably required to drive this proliferative
`phenotype. Infliximab and ganciclovir have been used to manage
`CVID-related inflammatory disease, and this study provides a
`compelling rationale for a controlled clinical trial. More broadly, it
`emphasizes the global effect of CMV infection on cellular immunity
`and defines a novel system for studies of CD8+ T-cell regulation.
`
`J ALLERGY CLIN IMMUNOL
`
`May 2012 Page 1217
`
`