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IL-7Rα and L-selectin, but not CD103 or CD34, are required for murine peanut-induced anaphylaxis Maltby, Steven; DeBruin, Erin J; Bennett, Jami; Gold, Matthew J; Tunis, Matthew C; Jian, Zhiqi; Marshall, Jean S; McNagny, Kelly M Aug 31, 2012

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RESEARCH Open AccessIL-7Rα and L-selectin, but not CD103 or CD34, arerequired for murine peanut-induced anaphylaxisSteven Maltby1†, Erin J DeBruin1†, Jami Bennett1†, Matthew J Gold1, Matthew C Tunis2, Zhiqi Jian1,Jean S Marshall2 and Kelly M McNagny1*AbstractBackground: Allergy to peanuts results in severe anaphylactic responses in affected individuals, and has dramaticeffects on society and public policy. Despite the health impacts of peanut-induced anaphylaxis (PIA), relatively littleis known about immune mechanisms underlying the disease. Using a mouse model of PIA, we evaluated micewith deletions in four distinct immune molecules (IL7Rα, L-selectin, CD34, CD103), for perturbed responses.Methods: PIA was induced by intragastric sensitization with peanut antigen and cholera toxin adjuvant, followedby intraperitoneal challenge with crude peanut extract (CPE). Disease outcome was assessed by monitoring bodytemperature, clinical symptoms, and serum histamine levels. Resistant mice were evaluated for total and antigenspecific serum IgE, as well as susceptibility to passive systemic anaphylaxis.Results: PIA responses were dramatically reduced in IL7Rα−/− and L-selectin−/− mice, despite normalpeanut-specific IgE production and susceptibility to passive systemic anaphylaxis. In contrast, CD34−/− and CD103−/−mice exhibited robust PIA responses, indistinguishable from wild type controls.Conclusions: Loss of L-selectin or IL7Rα function is sufficient to impair PIA, while CD34 or CD103 ablation has noeffect on disease severity. More broadly, our findings suggest that future food allergy interventions should focus ondisrupting sensitization to food allergens and limiting antigen-specific late-phase responses. Conversely, therapiestargeting immune cell migration following antigen challenge are unlikely to have significant benefits, particularlyconsidering the rapid kinetics of PIA.Keywords: Anaphylaxis, Animal model, Food allergy, Immunity, Peanut allergyIntroductionFood allergies affect a significant portion of the popula-tion, with direct effects on health and quality of life. Ofall food sensitivities, peanut allergies account for themost fatalities [1] and exposure to peanut antigen inaffected individuals results in severe, rapid, systemic ana-phylactic responses. Despite the severity of peanut ana-phylactic responses, few effective treatments or therapiesexist and most focus on limiting allergen exposure andmanagement of symptoms. While peanut allergy preva-lence is relatively low (estimated ~1-2% of the totalpopulation), the consequences of exposure are high andthe effects of peanut allergy are disproportionately largein society [2,3].In affected individuals, peanut-specific IgE antibodiesbind to FcεR on mast cells and basophils, and are crosslinked by peanut antigens, resulting in rapid release ofimmune mediators including histamine, leukotrienes,prostaglandins and platelet-activating factor followingexposure (as reviewed in [4]). These mediators contrib-ute to a range of pathological symptoms, includingincreased vascular permeability (resulting in localizededema, decreased blood pressure, and rapid decreasein body temperature), diarrhea and vomiting, and fatalrespiratory failure without treatment.To explore mechanisms underlying this pathology,a mouse model of peanut-induced anaphylaxis (PIA)was established, which closely approximates the clinicalsymptoms and pathology observed in peanut-allergic* Correspondence:†Equal contributors1The Biomedical Research Centre, University of British Columbia, Vancouver,BC, CanadaFull list of author information is available at the end of the articleALLERGY, ASTHMA & CLINICAL IMMUNOLOGY© 2012 Maltby et al.; licensee BioMed Central Ltd. This is an Open Access article distributed under the terms of the CreativeCommons Attribution License (, which permits unrestricted use, distribution, andreproduction in any medium, provided the original work is properly cited.Maltby et al. Allergy, Asthma & Clinical Immunology 2012, 8:15 [5]. Mice are sensitized by weekly oral feed-ings of peanut antigen with adjuvant. Subsequent inter-peritoneal challenge with peanut protein results in rapidmast cell degranulation, elevated serum histamine, anddecreases in blood volume and body temperature. Thismodel has been utilized successfully to highlight therole of B cells, CD40 ligand and mast cells and theeffects of therapeutic interventions (blocking histamineand/or platelet activating factor) on peanut-induced ana-phylactic responses [5,6]. In a related fatal PIA model,the importance of mast cells, macrophages, IgG and IgEhave also been reported [7]. Similarly, in an adjuvantbased model of PIA, treatment by a CD4 blockade couldprovide protection from disease, by increasing the fre-quency of Treg [8]. However, no studies have focussed onother adaptive immune molecules, including moleculesregulating immune cell migration or adhesion, in thePIA model.In our study, we provide the first analysis of four im-mune molecules (IL7Rα, L-selectin, CD34, CD103) inthe PIA model, to determine the effect of altered adap-tive responses and cell migration on food-induced ana-phylaxis. IL7Rα (CD127) is expressed on lymphoid cellsand plays key roles in regulating lymphoid development,survival and proliferation [9-11]. L-selectin (CD62L) isconstitutively expressed on leukocytes and involved inneutrophil extravasation [12], lymphocyte rolling andmigration into lymph nodes [13] and pathology asso-ciated with T cell-mediated inflammation in a numberof disease models [14,15]. CD34 is widely used as a clin-ical marker for the enrichment of human hematopoieticstem cells and a marker of pluripotency. However, CD34is also expressed by a range of hematopoietic cells andvascular endothelia and promotes optimal immune cellmigration (particularly for mast cells, eosinophils anddendritic cells) and the maintenance of vascular integrity[16-20]. CD103 (integrin alpha E) is expressed on sub-sets of dendritic cells (DCs) and lymphocytes within thegut tissues, where it acts as an E-cadherin ligand andhas been proposed as a key molecule regulating oral tol-erance (detailed by Scott et al. [21]).Here we have performed a survey of mice deficient inthese immunoreceptors to identify pathways that altersusceptibility to PIA. Our findings demonstrate that ab-lation of either IL7R or L-sel dramatically reduces the se-verity of PIA, whereas ablation of two migration-associated immune genes, Cd34 or Cd103, has no effect.These findings suggest that L-selectin and IL-7R〈 playkey roles in the development of adaptive immuneresponses to peanut antigen, while immune cell migra-tion via CD34 or CD103-dependent mechanisms are notrequired. When considering effective points of inter-vention in PIA, our findings suggest minimal benefit intargeting late-phase immune cell migration.Materials and methodsMiceC57BL/6, CD103 (Cd103−/−) and IL-7 receptor (IL7R−/−)deficient mice were purchased from The Jackson La-boratory. IL7R−/− mice were backcrossed onto a Ly5.1background. L-selectin deficient (L-sel−/−) [22] micewere provided by Dr. H.J. Ziltener and CD34 deficient(Cd34−/−) mice [23] were provided by Dr. T.W. Mak. Allanimals were housed and bred in specific pathogen-freeconditions at The BRC. For all experiments, eight to tenweek old sex-matched mice were used and the Commit-tee on Animal Care at UBC approved all procedures,in accordance with the requirements of the CanadianCouncil on Animal Care.Peanut-induced anaphylaxis (PIA)PIA was induced as previously described [5]. Briefly,mice were sensitized by oral gavage with 1 mg peanutprotein (Kraft Naturals peanut butter) and 10 μg choleratoxin (List Biological Laboratories) in 100μL steriledH2O, weekly for 4 weeks. Control mice received PBSalone. Two weeks after the final sensitization, mice werechallenged by intraperitoneal injection of 5 mg crudede-fatted peanut extract (CPE; Greer Laboratories) in500μL PBS.Clinical scoringSymptoms were evaluated using the scoring systemdescribed previously [5]. Animals were housed indivi-dually and observed for temperature decreases anddevelopment of clinical symptoms for 40 minutes post-challenge. Rectal temperatures were measured using atraceable expanded range digital thermometer (VWR) at10-minute intervals. Clinical scores were assigned from0–5, where 0 = no symptoms, 1 = repetitive scratchingof the ear canals, 2 = decreased activity or puffiness ofthe eyes, 3 = periods of motionlessness for >1 minute,4 = no response to whisker stimuli/prodding and 5 =early endpoint triggered by seizures or convulsion.Blood analysis (Histamine, Total IgE and IgE-mediatedCPE binding)Blood was collected via cardiac puncture from anaesthe-tized animals and diluted in 50ul PBS containing 2.5Uof heparin. Plasma was separated by centrifugationand stored at -20C. Histamine levels were determinedusing an enzyme immunoassay kit (Beckman Coulter /Immunotech). Total IgE was assessed by ELISA using amurine total IgE kit (BD Pharmingen, San Diego CA).IgE-mediated CPE binding was assessed using a sand-wich ELISA, similar to the protocol previously described[5]. Briefly, plates were coated with anti-mouse IgE Ab(Southern Biotech) overnight. Diluted serum sampleswere then incubated overnight, coated with biotinylatedMaltby et al. Allergy, Asthma & Clinical Immunology 2012, 8:15 Page 2 of 8 (Greer), followed by streptavidin-alkaline phosphat-ase (Invitrogen) and developed with a commercial ELISAamplification system (Invitrogen). Resulting opticaldensities were adjusted to a standard curve of biotiny-lated CPE.Passive systemic anaphylaxis (PSA)PSA was performed as previously described [24]. Forhistamine assessment, mice were sensitized by intraven-ous injection of 2 μg of anti-DNP IgE (Sigma-Aldrich) in200 μl HBSS. For body temperature assessments, micewere sensitized with 60 μg of anti-DNP IgE (in-house,clone SPE-7) in 200 μl HBSS. Anaphylaxis was inducedthe next day by intravenous injection of 0.5-1.0 mgDNP-HSA in 200μL HBSS. Anaphylaxis severity wasassessed by measuring rectal temperatures at 5-minuteintervals for 60 minutes or assessment of serum hista-mine levels 5 minutes post-injection.Statistical analysisP values were calculated using unpaired two-way Stu-dent’s t test.ResultsReduced PIA pathology in IL7R−/− and L-sel−/− mice, butnot Cd34−/− or Cd103−/− miceInitially, we performed a survey of IL7R−/−, L-sel−/−,Cd34−/− and Cd103−/− mice to determine susceptibilityto PIA. As previously reported, naïve mice challengedwith CPE, regardless of genotype, did not exhibit anysignificant changes in body temperature, clinical symp-toms or histamine levels when compared to controlmice (Figure 1 and data not shown) [5]. To furtherunderstand of B cell and T cells in PIA [5], we assesseddisease susceptibility in IL7R−/− mice, which exhibitmajor defects in lymphoid development [9-11]. In wild-type (Ly5.1) mice, antigen challenge resulted in rapiddecreases in body temperature (Figure 1A), observableclinical symptoms (Figure 1B) and elevated serum his-tamine (Figure 1C). In sharp contrast, IL7R−/− micewere protected from disease, exhibiting limited or nodecrease in body temperature (Figure 1A), no clinicalsymptoms (Figure 1B) and reduced histamine levels(Figure 1C).We next assessed PIA in L-sel−/− mice, as L-selectin isrequired for homing and migration of naïve lymphocytesand inflammatory immune cells in allergic models[13,25-27]. As such, we hypothesized L-selectin plays arole during either the sensitization stage or antigen chal-lenge stage of disease. Following intraperitoneal chal-lenge, L-sel−/− mice exhibited a minimal temperaturedrop (Figure 1D), which recovered by the 40-minuteendpoint, and exhibited lower average clinical scores(Figure 1E), compared to wild type controls. However, atthe endpoint, L-sel−/− mice exhibited elevated levelsof serum histamine (Figure 1F) equivalent to wildtype controls.CD34 plays a key role in mast cell migration and de-velopment of allergic asthma [16,17], so we hypothesizedthat Cd34−/− mice would also be protected from PIA.However, following challenge, Cd34−/− mice exhibitedequivalent decreases in body temperature (Figure 2A),clinical scores (Figure 2B) and serum histamine levels(Figure 2C) to wildtype control mice.CD103 is expressed on immune cells within the gutmucosa and is a marker of DCs that maintain oral toler-ance [21]. Following PIA induction, like Cd34−/− mice,Cd103−/− mice exhibited wildtype decreases in bodytemperature (Figure 2A), clinical symptoms (Figure 2B)and serum histamine levels (Figure 2C). From thisinitial screen, we determined that IL7R〈∀ and L-selectinare critical for PIA, but neither CD34, nor CD103, playmajor roles in the development of peanut-specificimmunity or resulting anaphylactic responses followingantigen exposure.Wildtype levels of total and antigen-specific IgE in IL7R−/−and L-sel−/− miceAs disease progression was impaired in IL7R−/− andL-sel−/− mice, we also assessed total IgE production andpeanut-specific IgE binding in these animals. Surpris-ingly, despite decreased disease severity and histaminerelease, both IL7R−/− and L-sel−/− mice exhibited normalor increased total plasma IgE levels, compared to wild-type controls (Figure 3A,B) and normal levels of IgE-mediated CPE binding (Figure 3C,D). Thus, reduceddisease severity in IL7R−/− and L-sel−/− mice is inde-pendent of the ability to produce peanut-specific IgEresponses and may reflect lower affinity IgE productionor otherwise impaired immune responses.L-sel−/− and IL7R−/− mice are fully susceptible to passivesystem anaphylaxis (PSA)L-selectin and IL7R〈∀-deficient animals exhibiteddecreased susceptibility to PIA, which could resultfrom impaired immune sensitization or impaired ana-phylactic responses. To test the latter possibility, weassessed the susceptibility of L-sel−/− and IL7R−/− mice to aPSA model. Mice were loaded with anti-DNP IgE and chal-lenged with DNP-HSA. After challenge, both L-sel−/− andIL7R−/− exhibited marked decreases in body temperature,which recovered to initial body temperatures, similarto their respective wildtype Bl/6 and Ly5.1 controls(Figure 4A,D) and individual maximal temperaturedecreases were indistinguishable across genotypes(Figure 4B,E). Further, assessment of serum histamine levelsMaltby et al. Allergy, Asthma & Clinical Immunology 2012, 8:15 Page 3 of 8 minutes post-challenge revealed equivalent levels of hista-mine release in all animals tested (Figure 4C,F). These find-ings demonstrate that while L-sel−/− and IL7R〈∀ mice areprotected from PIA, both strains are capable of mounting arobust systemic anaphylactic response when loaded withequivalent levels of antigen-specific IgE.DiscussionPeanut-induced anaphylaxis is a severe medical condi-tion, with major effects on individual patient health andsocial policy. Despite this, we lack a basic understandingof unique underlying mechanisms of the disease. Recentstudies using a mouse model of PIA have highlightedLy 5.1 IL7R -/- ControlPeanutAverage Clinical Score*N.D N.DCBALy 5.1 IL7R -/-050010001500ControlPeanutHistamine (nM)*FEDBl/6 L-Sel -/- ControlPeanut*Average Clinical ScoreN.D N.DBl/6 L-Sel -/-050010001500ControlPeanutHistamine (nM)Figure 1 IL-7Rα and L-selectin, are required for murine peanut-induced anaphylaxis. Mice were initially sensitized using peanut antigenand cholera toxin via oral gavage for 4 consecutive weeks. Two weeks following the final sensitization, mice were challenged i.p. with crudepeanut extract. Body temperature (A, D) and average observed clinical scores (B, E) monitored every 10 minutes for 40 minutes post-injection.Following the 40-minute endpoint, blood levels of histamine were assayed (C, F). Control mice were challenged with peanut immediately beforemonitoring. (IL7R−/− and Ly5.1 n = 3, representative of 4 experiments; L-Sel−/− n = 8, Bl/6 n = 7, and control micen = 3, representative of 5 experiments; *represents p < 0.05; **represents p < 0.01; Error bars = SEM).3934353637383332Temperature (C)0 10 403020Time post challengeCd34-/-Wild typeCD103-/-Wild type Cd34-/- CD103-/-Average Clinical Score1. (nM)Wild type CD103-/-Cd34-/-900CBAFigure 2 CD103 or CD34 are not required for murine peanut-induced anaphylaxis. Mice were sensitized with peanut antigen and choleratoxin via oral gavage for 4 consecutive weeks and were challenged i.p. with crude peanut extract 2 weeks following the final sensitization. Bodytemperature decreases (A) and average clinical scores (B) monitored every 10 minutes; observed for 40 minutes post-injection. Following the40-minute endpoint, blood levels of histamine were assayed (C). (Cd34−/− n = 10, Cd103−/− n = 4, Bl/6 n = 10, representative of 2–3 experiments.*represents p < 0.05; **represents p < 0.01; Error bars = SEM).Maltby et al. Allergy, Asthma & Clinical Immunology 2012, 8:15 Page 4 of 8 role of B cells in peanut allergy development orfocussed on potential therapeutic interventions [5-7].However, the importance of other specific immunemolecules and immune processes underlying this diseaseare not well understood. In the current study, we used aseries of knockout mice to survey the importance ofcytokine receptors and adhesion/trafficking molecules insusceptibility to food allergy with the goal of identifyingnovel pathways as points of therapeutic intervention.We were surprised to find that ablation of CD34 hadno effect on PIA, since this molecules has previouslybeen shown to play critical roles in a variety of immunecell mediated disease models [16,18,28,29]. One possibleexplanation is that after priming is complete, cell traf-ficking no longer plays a role in the effector phase ofPIA due to the short timeline of disease (~1 hour).Although CD34 facilitates the migration of severalhematopoietic effector lineages (mast cells, eosinophilsand DCs) and Cd34−/− mice are protected in models ofasthma, ulcerative colitis and hypersensitivity pneumon-itis, this likely reflects a delay, but not a block, in theability of CD34+ effector cells to migrate [16,18,28,29].Thus, given sufficient time for priming, it is likely thatthese mice “catch up” to their wildtype counterparts andare equally susceptible to the acute phase of an anaphyl-actic response.CD103 is an E-cadherin ligand proposed to specifytissue localization of CD103+ DCs and mucosal T cellswithin the gut [30-34]. CD103+ DCs promote both Tregdevelopment and Teff cell homing [30,32], and play a keyrole in maintaining oral tolerance and gut homeostasis.Notably, while CD103 is a marker of Treg subsets, recent050100150200250Plasma IgE (ng/ml)050100150200250300350400Plasma IgE (ng/ml)Total Plasma IgE Bound crude peanut extract050100150200250Bound crude peanut (ng/ml)050100150200250300350Bound crude peanut (ng/ml)∗∗∗Wild type L-Selectin -/- Wild type L-Selectin -/-Wild type IL7R α -/-Wild type IL7R α -/-A CB DFigure 3 Total and antigen-specific IgE in plasma of IL7R−/− and L-sel−/− mice. Following peanut sensitization and challenge, blood levelsof total IgE (A, B) and IgE-mediated CPE binding (C, D) were assayed at the 40 minute endpoint. (IL7R−/− n = 3 and Ly5.1 n = 4, representative of3 experiments; L-Sel−/− n = 5 and Bl/6 n = 7, representative of 4 experiments; ***represents p < 0.001; Error bars = SEM).Maltby et al. Allergy, Asthma & Clinical Immunology 2012, 8:15 Page 5 of 8 has demonstrated that CD103 does not play anessential role in Treg mediated functions in the gut.Mullaly et al., demonstrated that CD103 was notrequired for immune responses during helminth infec-tion, and that mice which lack CD103 have normallevels of Treg in the mesenteric lymphnodes or laminapropria [35]. CD103 is also a marker of pro-regulatoryDCs, however very little work has focused on the func-tional role of CD103 on these cells. Therefore we andothers [21], hypothesized that Cd103 ablation wouldexacerbate disease, if pro-regulatory DCs modulate dis-ease severity. Our findings demonstrate, however, thatloss of CD103 has no effect on PIA disease severity and,thus, we propose that CD103 is a valuable marker of DCand Treg subsets in the gut, but does not play an essentialrole in the development or maintenance of oral tolerance.Our findings demonstrate that disease severity isreduced when adaptive immune responses are impaired.This is particularly evident in IL7R−/− mice, whichexhibit severe defects in lymphoid development and sur-vival, resulting in lymphopenia, low thymic cellularityand impaired antibody production [9-11]. Surprisingly,despite severe defects, IL7R−/− mice produce normalserum Ig levels [36] and in the PIA model had wildtype(or elevated) levels of both total IgE and antigen-specificIgE. Nevertheless, IL7R−/− mice exhibited reduced circu-lating histamine levels following peanut challenge. Thisapparent discrepancy may reflect a severely limited anti-body repertoire in IL7R−/− mice [37]. Without effectiveIL-7R signalling, distal regions of the immunoglobulinheavy chain loci become inaccessible, resulting in limitedB cell repertoires and, likely, lower affinity antibody pro-duction [37]. In vivo, lower affinity antibodies likelyfail to induce a robust histamine release (despite normalIgE levels), resulting in an absence of clinical symptomsin the PIA model. This finding is consistent with theknown role of adaptive immunity in allergic responses,and the importance of B cells reported in this model [5].Bl/6L-sel  -/-*Ly5.1IL7R -/-*****TemperatureTemperatureTime (min)Time (min)Max Temp DecreaseMax Temp DecreaseHistamine @ 5 min (uM)Histamine @ 5 min (uM)ADCFEBFigure 4 Equivalent passive systemic anaphylaxis induction in L-sel−/− and IL7R−/− mice. Mice were initially injected i.v. with anti-DNPIgE to simulate sensitization. The next day, mice were injected i.v. with DNP-HSA to induce passive systemic anaphylaxis. Body temperaturemeasurements in L-sel−/− (A) and IL7R−/− (D) mice were taken at 5-minute intervals for 60 minutes post-injection. We identified maximalindividual temperature decreases (B, E) and assessed serum histamine levels (C, F) in animals sacrificed 5 minutes post-injection. (n = 4-5,*represents p < 0.05; **represents p < 0.01; Error bars = SEM).Maltby et al. Allergy, Asthma & Clinical Immunology 2012, 8:15 Page 6 of 8 degree of protection from PIA was more subtlein L-sel−/− mice, which exhibit an attenuated response.L-selectin is involved in adaptive immunity both in naïveT cell homing and the migration of mature Ag-specificT cells during inflammation [12-14,26,27]. L-sel−/− micemount a normal antibody response [14], but are pro-tected in a number of acute inflammatory and T-cellmediated models of delayed-type hypersensitivity reactionand experimental allergic encephalomyelitis [14,15,25-27].Intriguingly, despite reduced disease pathology in L-sel−/−mice, no difference in blood histamine or IgE levelswas observed following PIA-induction, suggesting thatthey may represent an asymptomatic sensitization topeanut allergen [38]. Our findings also suggest thatprotection in L-sel−/− mice is via a histamine-independent mechanism, (most likely regulating T cellor neutrophil recruitment and migration). Intriguingly,despite the reduced susceptibility to PIA, both IL7R−/−and L-sel−/− mice exhibited normal susceptibility topassive systemic anaphylaxis.In summary, we have shown that targeting L-selectinor IL7R〈∀ function is sufficient to reduce PIA responses,while loss of CD34 or CD103 has no effect on diseaseseverity. More broadly, these findings suggest that inter-ventions targeting initial immune sensitization are morelikely to meet with therapeutic success, by suppressingeffective antigen-specific antibody production and inhi-biting late-phase anaphylaxis/mast cell responses. Con-versely, therapies inhibiting immune cell migrationfollowing antigen challenge are unlikely to have signifi-cant benefits, particularly considering the rapid kineticsof peanut-induced anaphylaxis.Conflict of interestNo conflict of interest is declared by any authors of this manuscript.Authors’ contributionsSM and JB designed and performed all experiments and wrote themanuscript. EDB coordinated reagent procurement and initiation of theproject, participated in experiment harvests and edited the manuscript. MJG,MCT, and ZJ performed selected assays and edited the manuscript. JSM andKMM supervised trainees, edited the manuscript, and provided reagents. Allauthors read and approved the final manuscript.AcknowledgementsWe are grateful to Takahide Murakami for genotyping, Hermann J. Ziltenerfor providing IL7R−/− and Lsel−/− mice, Helen Merkens and Kimberley Allanfor technical support, and the BRC Animal Care Facility for animal handling.This work was funded by grants from the Canadian Group on Food AllergyResearch (CanGoFar; Grant #07B1), the AllerGen Network NCE and theCanadian Institutes of Health Research (CIHR; MOP-84545). SM wassupported through a CIHR and Heart and Stroke Foundation of CanadaFellowship from the Centre for Blood Research (CBR), JB was supported bythe Multiple Sclerosis Society of Canada, EJD was supported through aNSERC Postgraduate Scholarship and a UBC 4-Year Fellowship and MJGholds a fellowship from the CIHR/Michael Smith Foundation for HealthResearch (MSFHR) Transplantation Training Program. 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Allergy,Asthma & Clinical Immunology 2012 8:15.Submit your next manuscript to BioMed Centraland take full advantage of: • Convenient online submission• Thorough peer review• No space constraints or color figure charges• Immediate publication on acceptance• Inclusion in PubMed, CAS, Scopus and Google Scholar• Research which is freely available for redistributionSubmit your manuscript at et al. Allergy, Asthma & Clinical Immunology 2012, 8:15 Page 8 of 8


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