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U.S. Department of Health and Human Services

Vaccines, Blood & Biologics

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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

Public Health Issue: Allergy and/or asthma affect one in seven Americans. Cytokines are hormones of the immune system secreted by T cells that contribute to these diseases. Longitudinal studies suggest that the respiratory syncytial virus (RSV), manipulates the immune response to either pre-dispose children to the development of allergy or asthma, or increase the risk of those with a genetic predisposition to those diseases. Allergic diseases are frequently treated with therapeutic vaccination (also known as immunotherapy) with an extract from the offending substance. Studies suggest that prophylactic immunotherapy may also be used to in young children to prevent allergic sensitization. Understanding how respiratory viruses such as RSV manipulate the immune system may provide important insight into how allergy develops, and allow rational design of therapies that will interrupt the progression from childhood respiratory disease to asthma.

Research Approach: Respiratory syncytial virus (RSV) and Parainfluenza virus type 3 (PIV3) are members of the Paramyxoviridae family that account for 24% and 11.5%, respectively, of pediatric hospitalizations for respiratory diseases in the U.S. Infantile RSV is most certainly a risk factor for childhood asthma, and may also increase risk for long-standing asthma and sensitization to environmental allergens. RSV and PIV3 both suppress T cell function, and this suppression almost certainly contributes to viral pathogenesis, the high incidence of repeat infections by RSV and PIV3 and a high frequency of secondary bacterial infections. The suppression may also contribute to deviation of T cell responses towards those that predispose to childhood asthma and allergy. Live attenuated vaccines for both viruses are currently being tested in Phase II clinical trials, but immunosuppression may impede the safety and efficacy of the vaccines. We have recently demonstrated that T cell suppression induced by RSV is mediated by the combination of two interferons (IFN) generally associated with protection from viral infections: IFN-alpha and IFN-lambda; Humans have 13 IFN-alpha genes that express 12 isoforms of the protein. Biological activity varies among IFN-alpha isoforms. For example, IFN-alpha1 potently suppresses viral replication and minimally affects T cell function. The converse is true for IFN-alpha10-poor viral suppression and potent T cell suppression. Clearly, vaccines that elicit expression of favorable IFN-alpha isoforms will be more effective and rapidly elicit protective immunity. This research project targets the following questions: Which of the isoforms of IFN-alpha are expressed in response to RSV and other respiratory viruses? Which of the isoforms best protect against viral infection, and which may predispose to type 2 inflammation and thus predispose to allergy or asthma? What are the contact dependent mechanisms by which RSV suppresses T cell function? What are the differences in the innate response between different strains of RSV, particularly clinical strains that are associated with enhanced disease?

Mission Relevance & Outcomes: These studies will support evaluations of the safety and efficacy of new treatments and uses of allergen extracts for prevention and treatment of allergic diseases and asthma.


Scientific Overview

Respiratory syncytial virus (RSV) and Parainfluenza Virus type 3 (PIV3) are members of the Paramyxoviridae family that account for 24% and 11.5%, respectively, of pediatric hospitalizations for respiratory diseases in the U.S. RSV and PIV3 both suppress T cell function, and this suppression almost certainly contributes to viral pathogenesis, the high incidence of repeat infections by RSV and PIV3 and a high frequency of secondary bacterial infections. Live attenuated vaccines for both viruses are currently being tested in Phase II clinical trials, but immunosuppression may impede the safety and efficacy of the vaccines. We have recently demonstrated that T cell suppression induced by RSV is mediated by the combination of two interferons (IFN) generally associated with protection from viral infections: IFN-alpha and IFN-alpha. Humans have 13 IFN-alpha genes that express 12 subtypes of the protein. Biological activity varies among IFN-alpha isoforms. For example, IFN-alpha1 potently suppresses viral replication and minimally affects T cell function. The converse is true for IFN-alpha10—poor viral suppression and potent T cell suppression. Clearly, vaccines that elicit expression of favorable IFN-alpha isoforms will be more effective and rapidly elicit protective immunity. Determining which IFN-alpha isoforms are favorable in both contexts of viral suppression and T cell responses will guide vaccine design, and may immediately provide a useful biomarker for vaccine efficacy.


Publications

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

J Virol 2004 Apr;78(8):4363-9
Suppression of the Induction of Alpha, Beta, and Gamma Interferons by the NS1 and NS2 Proteins of Human Respiratory Syncytial Virus in Human Epithelial Cells and Macrophages.
Spann KM, Tran KC, Chi B, Rabin RL, Collins PL

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