Vaccines, Blood & Biologics

Assessing the Mechanism of Immunotherapy for Allergy and Allergic Asthma: Effect of Viral Respiratory Infections on Pathogenesis and Clinical Course of Asthma and Allergy

Principal Investigator: Ronald Rabin, MD
Office / Division / Lab: OVRR / DBPAP / LI

General Overview

One in five Americans have allergies or asthma. Our laboratory regulates biologics intended for diagnosis and treatment of allergies and asthma (most commonly allergenic extracts for "allergy shots"). Only a few allergenic extracts are standardized for potency to insure consistent dosing among manufactured lots of allergenic extracts. Our lot release lab provides reagents to manufacturers to insure uniform potency testing, and validates manufacturers' potency measurements with our own. Currently, allergy extracts contained unmodified allergens, which modify hay fever or asthma, but are not effective for treatment of food allergy, and risk dangerous allergic reactions. FDA is evaluating novel products for treatment of food and environmental allergy, many of which different mechanisms of action. Our research program insures that scientists and reviewers have the appropriate knowledge base to evaluate these novel therapies, and strives to expand the number of allergenic extracts that are standardized for potency.

Our laboratory has two overall projects: The first project explores environmental factors that trigger allergic diseases and asthma. One factor is respiratory syncytial virus (RSV). RSV may infect lower airways of infants, which increases disease severity and may trigger asthma. We seek to understand why, in addition to their location, infection of lower airways with RSV triggers asthma. We use in vitro culture systems to study biological responses to RSV by cells from the upper and lower airways. In particular, we focus on the balance between expression and responses to interferons (IFN), which protect cells from infection, and pro-inflammatory cytokines, which may be detrimental to infection. We propose that characterizing cellular responses to RSV infection will reveal novel insights towards the pathogenesis of allergic asthma.

Our second project is to characterize house dust mite (HDM) allergens. Indoor allergens, including HDM are a second environmental factor that triggers allergic diseases and asthma. HDM allergy is complex because as many as 32 proteins contribute to the allergic response; how many are clinically important is not known. Allergenic extracts used for diagnosis or treatment of HDM allergy may vary widely in their content of allergenic proteins depending on differences in methods of culturing HDM, source materials, or extraction methods. The current method of standardization of HDM extracts for potency does not measure the concentration of individual allergens and cannot detect qualitative or differences in individual allergen content among HDM allergen extracts. We propose that measurement of all clinically relevant allergenic proteins may reveal clinically important differences among HDM preparations that may inform patient care and provide direct benefit to public health. Current methods aren't feasible, so we are developing the use of mass spectrometry to biochemically characterize and standardize HDM extracts. We believe that standardization of HDM extracts by MS will provide a benchmark to standardize other complex allergenic extracts, thus expanding the number of extracts that are standardized for potency.

Scientific Overview

Asthma and atopy are quintessential diseases for which genetics loads the gun and environment pulls the trigger. GWAS studies reveal associations of asthma with polymorphisms in genes associated with type 2 adaptive responses and the epithelial cell barrier. Two viral pathogens that cause the common cold are also environmental factors associated with asthma: respiratory syncytial virus (RSV) and rhinovirus (RV). Both RSV and RV can infect lower airways, and asthma concurrent with either virus is associated with poor expression of types I or III interferons (IFN).

Our laboratory uses in vitro tissue culture models of respiratory epithelium to compare the cellular factors that determine mild versus severe RSV infection, and which components of the IFN response locally contain RSV infection. Human type I IFNs include IFN and twelve subtypes of IFN-alpha, all of which signal through the ubiquitously expressed IFNAR1/2 receptor complex. There are four type III IFNs, all of which signal through a receptor dimer comprised of IFNLR, selectively expressed by cells of epithelial lineage, and IL10RB. Although they signal through distinct receptors, types I and III IFN share a common signaling pathway that induces autocrine and paracrine expression of more than 600 genes, collectively referred to as interferon response genes (ISG). Many ISGs code for proteins that directly inhibit viral replication and protect against spread of viral infection to neighboring cells.

In addition to IFNs, viral pathogens simultaneously induce expression of NF-kB dependent pro-inflammatory cytokines. For example, IL-6 drives STAT3 mediated IL-17 expression, which in turn drives canonical NF-B mediated expression of IL-6, CXCL8 and CCL2--a positive feedback loop that contributes to immune-mediated pathology of viral lower respiratory infections. Because the same pattern recognition receptors (RIG-I or MDA5) activate IFN and proinflammatory cytokine expression, they may be considered a point of bifurcation. Properly balanced, viral infection is locally contained. Improperly balanced, prolonged expression of IFNs or more likely, high expression of pro-inflammatory cytokines mediates autoinflammatory tissue destruction and promotes allergic sensitization or asthma.

Of interest, some allergenic proteins mimic or enhance the pro-inflammatory response. For example, Der p 2, a house dust mite (HDM) allergen, enhances TLR signaling and NF-kB activation in response to LPS. Because they are ubiquitous in American homes, infants are exposed to HDM early. In genetically susceptible individuals, HDM are among the first environmental allergens to elicit allergic disease, and may initiate the allergic march towards multiple allergies and allergic asthma.

We focus on factors that determine successful local immunity to respiratory viruses, and that shift the response from one that is primarily anti-viral towards a one that is pro-inflammatory. Our Specific Aims are:

1. Define cellular factors that direct the balance between expression of IFN versus pro-inflammatory cytokines in response to viral infection.
2. Define non-redundant functions of types I versus type III IFNs, and of individual IFN subtypes
3. Mass Spectrometry for characterization and rapid, quantitative, and definitive standardization of potency of house dust mite allergenic extracts



Ann Allergy Asthma Immunol 2017 May;118(5):531-6
Allergenic extracts to diagnose and treat sensitivity to insect venoms and inhaled allergens.
Khurana T, Bridgewater JL, Rabin RL

Clin Exp Allergy 2017 May;47(5):604-17
Mass spectrometry to complement standardization of house dust mite and other complex allergenic extracts.
Spiric J, Reuter A, Rabin RL

Front Immunol 2017 Apr 21;8:459
Type I and Type III interferons display different dependency on mitogen-activated protein kinases to mount an antiviral state in the human gut.
Pervolaraki K, Stanifer ML, Munchau S, Renn LA, Albrecht D, Kurzhals S, Senis E, Grimm D, Schroder-Braunstein J, Rabin RL, Boulant S

Virology 2017 Apr;504:63-72
Respiratory syncytial virus infection induces a subset of types I and III interferons in human dendritic cells.
Hillyer P, Mane VP, Chen A, Dos Santos MB, Schramm LM, Shepard RE, Luongo C, Le Nouen C, Huang L, Yan L, Buchholz UJ, Jubin RG, Collins PL, Rabin RL

Allergy 2017 Jul;72(7):1035-42
Allergen Exposure Chambers (AEC): harmonizing current concepts and projecting the needs for the future--an EAACI position paper.
Pfaar O, Calderon MA, Andrews CP, Angjeli E, Bergmann KC, Bonlokke JH, de Blay F, Devillier P, Ellis AK, Gerth van Wijk R, Hohlfeld J, Horak F, Jutel M, Jacobs RL, Jacobsen L, Kaul S, Larche M, Larenas-Linnemann D, Mosges R, Nolte H, Patel P, Peoples L, Rabin RL, Rather C, Salapatek AM, Sigsgaard T, Thaarup S, Yang J, Zieglmayer P, Zuberbier T, Demoly P

Cell Immunol 2016 Dec;310:156-64
Early treatment with reverse transcriptase inhibitors significantly suppresses peak plasma IFNalpha in vivo during acute simian immunodeficiency virus infection.
George J, Renn L, Verthelyi D, Roederer M, Rabin RL, Mattapallil JJ

J Interferon Cytokine Res 2016 Oct;36(10):589-98
Distinct patterns of expression of transcription factors in response to interferon beta and interferon lambda1.
Novatt H, Theisen TC, Massie T, Massie T, Simonyan V, Voskanian-Kordi A, Renn LA, Rabin RL

Allergy 2016 Oct;71(10):1414-24
Standardization of allergen products: 3. validation of candidate european pharmacopoeia standard methods for quantification of major birch allergen bet v 1.
Kaul S, Zimmer J, Dehus O, Costanzo A, Daas A, Buchheit KH, Asturias JA, Barber D, Carnes J, Chapman M, Dayan-Kenigsberg J, Doring S, Fuhrer F, Hanschmann KM, Holzhauser T, Ledesma A, Moingeon P, Nony E, Pini C, Plunkett G, Reese G, Sandberg E, Sander I, Strecker D, Valerio C, van Ree R, Vieths S

J Virol 2015 Aug 1;89(15):7567-83
Different temporal effects of Ebola virus VP35 and VP24 proteins on the global gene expression in human dendritic cells.
Ilinykh PA, Lubaki NM, Widen SG, Renn LA, Theisen TC, Rabin RL, Wood TG, Bukreyev A

J Virol 2014 Jun;88(11):6453-69
Human metapneumovirus SH and G glycoproteins inhibit macropinocytosis-mediated entry into human dendritic cells and reduce CD4+ T cell activation.
Le Nouen C, Hillyer P, Brock LG, Winter CC, Rabin RL, Collins PL, Buchholz UJ

Hum Immunol 2013 Dec;74(12):1524-30
Attenuated expression of interferon-beta and interferon-lambda1 by human alternatively activated macrophages.
Fiky AE, Perreault R, McGinnis GJ, Rabin RL

Eur J Immunol 2013 Dec;43(12):3197–208
Subtypes of type I IFN differentially enhance cytokine expression by suboptimally stimulated CD4(+) T cells.
Hillyer P, Raviv N, Gold DM, Dougherty D, Liu J, Johnson TR, Graham BS, Rabin RL

PLoS One 2013;8(2):e56527
Interferon-alpha Is the Primary Plasma Type-I IFN in HIV-1 Infection and Correlates with Immune Activation and Disease Markers.
Hardy GA, Sieg S, Rodriguez B, Anthony D, Asaad R, Jiang W, Mudd J, Schacker T, Funderburg NT, Pilch-Cooper HA, Debernardo R, Rabin RL, Lederman MM, Harding CV

Immunol Cell Biol 2012 Sep;90(8):774-83
Expression profiles of human interferon-alpha and interferon-lambda subtypes are ligand- and cell-dependent.
Hillyer P, Mane VP, Schramm LM, Puig M, Verthelyi D, Chen A, Zhao Z, Navarro MB, Kirschman KD, Bykadi S, Jubin RG, Rabin RL

J Interferon Cytokine Res 2012 Sep;32(9):407-15
High-throughput quantitative real-time polymerase chain reaction array for absolute and relative quantification of rhesus macaque types I, II, and III interferon and their subtypes.
Schramm LM, Kirschman KD, Heuer M, Chen AA, Verthelyi D, Puig M, Rabin RL

J Allergy Clin Immunol 2012 Apr;129(4):1014-9
The US Food and Drug Administration review of the safety and effectiveness of nonstandardized allergen extracts.
Slater JE, Menzies SL, Bridgewater J, Mosquera A, Zinderman CE, Ou AC, Maloney D, Cook CM, Rabin RL

J Leukoc Biol 2012 Jan;91(1):147-58
TLR9 and TLR7 agonists mediate distinct type I IFN responses in humans and nonhuman primates in vitro and in vivo.
Puig M, Tosh KW, Schramm LM, Grajkowska LT, Kirschman KD, Tami C, Beren J, Rabin RL, Verthelyi D

J Immunol 2011 Sep 1;187(5):2540-7
Mycobacterium tuberculosis Triggers Host Type I IFN Signaling To Regulate IL-1{beta} Production in Human Macrophages.
Novikov A, Cardone M, Thompson R, Shenderov K, Kirschman KD, Mayer-Barber KD, Myers TG, Rabin RL, Trinchieri G, Sher A, Feng CG

J Allergy Clin Immunol 2011 Aug;128(2):434
Comments on cow's milk allergy and diphtheria, tetanus, and pertussis vaccines.
Slater JE, Rabin RL, Martin D

PLoS Pathog 2011 Jun;7(6):e1002105
Low CCR7-Mediated Migration of Human Monocyte Derived Dendritic Cells in Response to Human Respiratory Syncytial Virus and Human Metapneumovirus.
Le Nouën C, Hillyer P, Winter CC, McCarty T, Rabin RL, Collins PL, Buchholz UJ

PLoS Pathog 2011 Apr;7(4):e1001336
Respiratory Syncytial Virus Interferon Antagonist NS1 Protein Suppresses and Skews the Human T Lymphocyte Response.
Munir S, Hillyer P, Le Nouën C, Buchholz UJ, Rabin RL, Collins PL, Bukreyev A

J Immunol 2010 Dec 1;185(11):6646-63
CCR2 identifies a stable population of human effector memory CD4(+) T cells equipped for rapid recall response.
Zhang HH, Song K, Rabin RL, Hill BJ, Perfetto SP, Roederer M, Douek DC, Siegel RM, Farber JM

PLoS One 2010 Nov 29;5(11):e15017
Effects of human respiratory syncytial virus, metapneumovirus, parainfluenza virus 3 and influenza virus on CD4+ T cell activation by dendritic cells.
Le Nouën C, Hillyer P, Munir S, Winter CC, McCarty T, Bukreyev A, Collins PL, Rabin RL, Buchholz UJ

Ann Pharmacother 2009 May;43(5):967-72
Anaphylactic reaction to anakinra in a rheumatoid arthritis patient intolerant to multiple nonbiologic and biologic disease-modifying antirheumatic drugs.
Desai D, Goldbach-Mansky R, Milner JD, Rabin RL, Hull K, Pucino F, Colburn N

Virology 2009 Mar 1;385(1):169-82
Infection and maturation of monocyte-derived human dendritic cells by human respiratory syncytial virus, human metapneumovirus, and human parainfluenza virus type 3.
Le Nouën C, Munir S, Losq S, Winter CC, McCarty T, Stephany DA, Holmes KL, Bukreyev A, Rabin RL, Collins PL, Buchholz UJ

J Biomol Tech 2008 Dec;19(5):342-7
Systematic method for determining an ideal housekeeping gene for real-time PCR analysis.
Mane VP, Heuer MA, Hillyer P, Navarro MB, Rabin RL

Clin Exp Immunol 2008 Jul;153(1):19-30
The nexus between atopic disease and autoimmunity: a review of the epidemiological and mechanistic literaturedouble dagger.
Rabin RL, Levinson AI

J Leukoc Biol 2006 Jun;79(6):1328-38
HIV regulation of the IL-7R: a viral mechanism for enhancing HIV-1 replication in human macrophages in vitro.
Zhang M, Drenkow J, Lankford CS, Frucht DM, Rabin RL, Gingeras TR, Venkateshan C, Schwartzkopff F, Clouse KA, Dayton AI

J Virol 2006 May;80(10):5032-40
Alpha and lambda interferon together mediate suppression of CD4 T cells induced by respiratory syncytial virus.
Chi B, Dickensheets HL, Spann KM, Alston MA, Luongo C, Dumoutier L, Huang J, Renauld JC, Kotenko SV, Roederer M, Beeler JA, Donnelly RP, Collins PL, Rabin RL

Int Immunol 2006 Mar;18(3):485-93
Human T cell cytokine responses are dependent on multidrug resistance protein-1.
Zhang J, Alston MA, Huang H, Rabin RL

Arb Paul Ehrlich Inst Bundesamt Sera 2006;(95):191-3
Recombinant and modified allergens: the U.S. perspective.
Rabin RL

Proc Natl Acad Sci U S A 2005 May 31;102(22):7916-21
Characterization of subsets of CD4+ memory T cells reveals early branched pathways of T cell differentiation in humans.
Song K, Rabin RL, Hill BJ, De Rosa SC, Perfetto SP, Zhang HH, Foley JF, Reiner JS, Liu J, Mattapallil JJ, Douek DC, Roederer M, Farber JM

Virology 2005 Feb 20;332(2):491-7
Targeted lysis of HIV-infected cells by natural killer cells armed and triggered by a recombinant immunoglobulin fusion protein: implications for immunotherapy.
Gupta N, Arthos J, Khazanie P, Steenbeke TD, Censoplano NM, Chung EA, Cruz CC, Chaikin MA, Daucher M, Kottilil S, Mavilio D, Schuck P, Sun PD, Rabin RL, Radaev S, Van Ryk D, Cicala C, Fauci AS


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