Role of type 1 and type2 T helper cells in allergic diseases Martien

Henk M. Jansen, Jan D. Bos and Eddy A. Wierenga

1. Kapsenberg, University

Various related a type2 and

of Amsterdam,

characteristics cytokine

interleukin-5.

elevated

of atopic

with the activation secretion

Amsterdam,

allergic

profile,

These cytokines

including

Current

Atopic disorders are associated with elevated levels of allergen-specific IgE in the serum. As demonstrated by radioallergosorbent and skin tests, atopic patients often show immediate IgEmediated allergic reactions to one or more inhalation or food allergens. Experimental allergen challenges show that these immediate reactions are followed by late phase reactions, characterized by local infiltrations of eosinophils, T lymphocytes and dendritic antigen-presenting cells @PCs). There is considerable evidence for the important role of allergen-specific T cells in the pathophysiology of atopic disease. Ig production to an antigen is regulated by T helper (Th) cells with the same antigen specificity [l] and, indeed, recent reports indicate that enhanced allergen-specific IgE production in atopic disease results from selective activation of allergenspecific T helper type 2 (Th2) cells producing interleukin (IL)-4 but little or no interferon (IFN)-y. The occurrence of eosinophilia can be ascribed to the production of high levels of IL-5 by these cells and finally, allergen-specific Th2 cells also participate in late phase and chronic inflammatory reactions. The present review summarizes these data and speculates on the question of why this T-cell subset predominates in atopic disease.

ThZ-cell

subset in atopic

disease

IgE synthesis is induced by IL-4 and this IL-4induced IgE synthesis is suppressed by IFN-), (see also Vercelli and Geha, this issue pp 794-797). These cytokines are secreted by Th cells after recognition of antigen presented by APCs. Freshly isolated T cells and cloned Th cells can produce variable levels of IL-4, IFN-)I and other cytokines after activation. Two extreme types of Th cells, frequently found after random T-cell cloning from mouse spleen tissue, have been defined by Mosmann and colleagues [ 21.

for the

IgE and eosinophilia

in Immunology

Introduction

to be causally

lymphocytes

with

high levels of interleukin-4

role in local inflammatory

Opinion

seem

T helper

are responsible

levels of serum allergen-specific important

disorders

of allergen-specific

The Netherlands

occurrence

of

and play an

reactions.

1992, 4:78&793

Thl cells produce IFN-)I and IL-2 but not IL-4 and IL-5, whereas Th2 cells produce IL-4 and IL-5 but not IFN-y and IL-2. Only Th2 cells with high IL-4/IFN-y production ratios are able to induce IgE production in vitro [3,4]. The extreme Thl cells are inflammatory T cells and are not able to efficiently support Ig production. In contrast to the mouse spleen T lymphocyte clones (TLCs), most TLCs randomly prepared from peripheral blood of healthy humans have intermediate cytokine profiles [ 5,6] and only a small minority show high IL-4/IFN-y production ratios and are able to support in vitro IgE production [6,71. An early indication that Th2-like cells are present in atopic disease was obtained in a study of TLCs specific for the housedust mite (HDM) Dermatopbugoides pteronyssinus prepared from the peripheral blood of patients allergic to HDM and a non-allergic control individual [8,9*]. Most HDM-specific TLCs from the atopic patients were Th2 cells that produced high levels of IL-4 and IL-5 and low levels of IFN-)I and IL-2 after antigen-specific or non-specific stimulation and were able to induce IgE production in B cells from non-allergic individuals [lo]. HDM-specific TLCs from the non-allergic control donor were Thl cells that produced low levels of IL-4 and IL-5 and high levels of IFN-y and IL-2. Interestingly, TLCs specific for tetanus toxoid and Candida albicans prepared from one of these patients, lacking IgE specific for tetanus toxoid and C: albicuns, were Thl cells or T cells with an intermediate cytokine secretion profile, further supporting a causal relationship between Th2-cell responses and IgE production. The concept of predominant Th2-cell activation in atopic disease is supported by more recent studies on T cells specific for HDM, its major allergen Derp I or grass (Loliumperenne) pollen allergen [11*,12*]. In the study of Yssel et al. [12-l, it was shown that, upon non-specific stimulation with TEA and calcium ionophore, Th2 cells produced high levels of IL-4 and IL-5, as well as IL-2 and IFN-y, indicating that

Abbreviations APC-antigen-presenting cell; CM-CSF-granulocyte-macrophage IL-interleukin; PC-prostaglandin; PL-phospholipase; T&T 788

@ Current

Biology

colony-stimulating factor; HDMhousedust mite; IFN-interferon; helper; TLC-T lymphocyte clone; TNF-tumor necrosis factor. Ltd MN

0952-7915

Thl

allergen-specific Th2 cells are not defective pacity to produce large amounts of Thl-cell

Helper

function

in their cacytokines.

of Th2 cells in IgE production

Apart from select cytokines, IgE production by B cells requires a signal mediated by physical contact with T cells (see also Vercelli and Geha, this issue pp 794-797). This signal can be provided by most CD4+ TLCs [13,14], including HDM-specific Th2-cell clones from atopic patients but, strikingly, not by HDM-specific Thl -cell clones from a non-allergic control donor [9-l. Recent studies suggest that the interaction between CD40 on B cells and a recently described counterstructure on T cells may be involved in contact-mediated help [ 151. Supporting this hypothesis is the fact that physical contact with T cells can be replaced by anti-CD40 monoclonal antibody for the induction of IL-4-dependent IgE synthesis [16]. A.5 in the mouse [17,18], human Thl cells may be cytotoxic for APCs at the high T cell/APC ratios that are commonly used to demonstrate cytotoxicity of CD8+ T cells [9*,19,20-1. The cytotoxic capacity of Thl cells implies that B cells that present antigen to Thl cells are lysed, thereby abrogating Ig production [l&20-]. Indeed, HDM-specific Thl-cell clones from a control donor, but not HDM-specific Th2-cell clones from allergic patients, kill B cells that present HDM antigen on their surface and, thus, cannot be considered as genuine helper cells [ 2 11. This finding may explain the lack of allergen-specific Ig of any isotype in the serum of non-allergic control individuals. These studies strongly suggest that allergen-specific T cells of allergic patients differ from those of non-allergic individuals in that they efficiently support Ig production, in particular IgE, by B cells. This ability follows from their high IL-4/IFN-y production ratios, their capacity to provide contact-mediated B-cell help, and their lack of cytotoxicity towards allergen-presenting B cells.

Th2 cells in inflammation Allergen-specific Th2 cells also participate in local late phase inflammatory reactions. They occur in high frequencies at the sites of inflammation, as demonstrated by the finding that in panels of randomly prepared TLCs from chronic skin lesions of HDM or grass pollen suergic atopic dermatitis patients, rather high percentages of TLCs responded to the respective allergen [2200,2300]. Like those from the peripheral blood, the majority of these allergen-specific TLCs show high IL-4/IFN-y production ratios. Panels of random TLCs from experimental skin lesions induced by epicutaneous application of HDM [ 24.1 or grass pollen allergen [ 23**] also contained considerable percentages of specific T cells with a Th2 cy tokine profile. In a similar study on TLCs from lesions induced by HDM, all the TLCs obtained were HDMspecific Th2-cell clones [25]. It cannot be excluded, however, that these extreme results followed from the

and Th2 cells and allergic

diseases

Kapsenberg

et al.

use of culture medium that contained IL-4 to generate the TLCs, because IL-4 is known to select for outgrowth of Th2 cells, discussed in more detail below. Increased frequencies of Th2 cells have also been cloned from the conjunctiva of atopic patients [26] and it is tempting to speculate that many of these T cells are specific for allergens and participate in the late phase reaction. A drawback of studies with allergen-specific TLCs is that even panels of TLCs may not reliably represent the respective T-cell repertoire in ZJ~ZQ. Of interest, therefore, is a series of experiments by Kay’s group suggesting active partici~ pation of allergen-specific Th2-like cells in the late phase reaction in z&o in the skin [ 27-1, the bronchoalveoku’ space [28] and the nasal mucosa [ Z.$] After challenge with allergen, predominant expression of mRNA encoding Th2-related cytokines was demonstrated by in situ hybridization. The way in which Th2 cells contribute to inflammation remains obscure. A study in the mouse by Mosmdnn‘s group indicates that inflammatory T cells are Thl cells [30] and that the inflammation is mediated by IFN-y [31] and tumor necrosis factor (TNF)-cr [32]. Indeed, Thl cells may be involved in the induction of inflammation. The studies on TICS from chronic or experimentally induced skin lesions indicate the occurrence of a low percentage of TLCs with intermediate or low IL-4/IFN-y production ratios [22**,23**], some of which may even be allergen-specific [ 24.1, More recent and very interesting data (C Hauser, personal communication) suggest, however, that Th2 cells may also have an important role in late phase reactions. Th2 cell induced inflammation is proba bly mediated by IL-4, because contact sensitivity induced by Th2 cells can be blocked by soluble IL-4 receptor but not by the blocking of various other cytokines. The production of eosinophils from bone marrow progenitor cells is regulated by granulocyte-macrophage colony-stimulating factor (GM-CSF) and IL-3, which are produced both by Thl and Th2 cells, and by IL-j, which is selectively produced by Th2 cells. Several findings im plicate an important regulatory role of Th2 cells in the development of eosinophilia: (a) the development of eosinophilia is T-cell dependent; (b) helminth-induced eosinophilia in mice can be prevented by administering anti-IL-5 antibody [33]; and (c) proliferation of human bone marrow eosinophils can readily be induced by Th2 cell derived supernatants and can be completel) blocked with anti-IL-5 antibody but not by Thl cell derived supernatants (EA Wierenga, B Backx, M Snoek et al, unpublished data). In the periphery, the continuous production of all three cytokines by Th2 cells in local infiltrates may contribute to eosinophil infiltration into the sites of inflammation.

Factors that bias Th-cell

subset proliferation

For a better understanding of the pathogenesis of atopic disease it is important to trace those factors that lead to the predominant occurrence of Th2 cells. Basically.

789

790

Atopic allergy and other hypersensitivities

predominance of Th2 cells may result from selective outgrowth of this subset by affecting T-cell proliferation and/or from selective modulation of cytokine secretion. Studies in mice provided evidence that the occurrence of the Thl and Th2 phenotypes after repeated antigen challenge is preceded by the occurrence of ThO cells with the same antigen specificity, suggesting that thx x[ tokine profile of responding T cells changes during the course of the immune response [34-1. In vitro studies have indicated several physiological factors that may selectively and directly modulate cytokine secretion by Th cells, such as the nature or the structure of the antigen, the local presence of cytokines, mediators of inflammation or hormones, and the type of APC. Recent studies have shown that minute changes in the amino acid sequence of a peptide may induce the transition of the Th phenotype of the responding T cells [35-l. Various soluble factors are known to interfere with cytokine secretion. IL-4, for instance, inhibits the synthesis of IFN-y by T cells [36,37]. The effects of prostaglandin (PG)El and PGE2 are most impressive; they suppress the secretion of the Thl-related cytokines, IL-2 and IFN-y, without affecting the secretions of Th2 cytokines [38,39-l, (FGM Snijdewint, P Kalinski, EA Wierenga et al., unpublished data). The elevation of intracellular CAMP levels seems a crucial step in suppression of the secretion of these cytokines, because agents such as forskolin and dibutytyl-cAMP that increase levels of intracellular CAMP have a similar effect on the cytokine secretion profiles of T cells [39”,40**]. This finding suggests that other compounds that bind to adenylate cyclase associated receptors may also affect cytokine secretion by T cells. PGEs are produced by several types of APCs, in particular by activated macrophages. In this way certain subsets of APC may selectively modulate cytokine secretion in a direct way. Once the cytokine profile of a specific Th-cell response is biased, further selection is likely to occur in the proliferative phase of the response. A study by Maggi et al. [41*] on human peripheral blood T cells, which confirmed earlier observations in the mouse [42,43], showed that a microenvironment with high levels of IL-4 selectively promotes outgrowth of Th2 cells, whereas high levels of IFN-)I promote the development of Thl cells. Likewise, it has been implicated that IL-10 selectively favours Th2-cell outgrowth in the mouse [44]. So far, the role of IL-10 in the human in this respect is less clear [45]. Proliferation of Th2 cells in response to endogenous IL-4 requires the presence of IL-1 and thus the capacity of IL-l production by different APCs was shown to be another Important factor in further selective proliferation of Th-cell subsets

[461.

The aberrant

ThZ-cell

subset

Current knowledge indicates that the atopic syndrome is a state of predisposition for Th2 cell directed responses

involving high levels of IL-4 and IL-5 secretion. Manifestation of allergic disorders is promoted by frequent exposure to allergen, resulting in tolerance breakthrough. High IgE responses and eosinophilia may also be evident in non-atopic individuals after insect stings or infections with various types of metazoa. With the exception of responses to a few helm&h types, Th2-cell responses promote disease and have to be considered as aberrant. All the responses mediated by Th2 cells may have a similar origin, i.e. result from the modulation of various stages of a cascade of events, starting with the uptake of antigen and activation of the cycle-oxygenase pathway in peripheral APCs. The APCs degrade the antigen and carry it to the draining lymph nodes where it is presented to antigen-specific T cells. There, these APCs simultaneously secrete PGE that, according to the above mentioned mechanism, will induce a Th2-cell profile in the T-cell population that reacts with the antigen. Overexpression of PGE in one or more lymphoid organs is a crucial prerequisite for this hypothesis. In case of insect stings, there is considerable evidence that various compounds, such as phospholipase (PL)A2 in insect venom, are effectively able to induce PGE expression by local APCs, before they migrate into the draining lymph nodes [47]. Indeed, PI&-specific TLCs secrete large amounts of IL-4 with varying levels of IFN-)I [48]. Furthermore, high PGE production is a property of many metazoa species. High IgE production, found when those metazoa species infect lymph nodes, may result from the direct effects of this metazoa-derived PGE on T cells. In turn, atopic disease may be explained by a hyperactive cascade. Resting and activated APCs from atopic patients produce higher levels of PGE than APCs from non-allergic controls [49]. High IgE production in response to inhaled complex allergenic protein entities, such as mite and cockroach excrements or pollen, may be explained by efficient activation of APCs to synthesize PGE, as occurs in response to inhalation of other particulate agents, such as zymosan or latex. Evidence for this cascade hypothesis is still indirect and sufficient validation will require a new series of experiments.

Conclusions Recent in vitro and in situ studies have indicated that high levels of allergen-specific IgE and eosinophilia in atopic disease are causally related with imbalanced cy tokine production by allergen-specific T cells. Allergenspecific T cells also participate in local inflammation. The precise factors that determine imbalanced cytokine production in atopic disease remain to be established. It may be argued that hyperactivation of a cascade involving PGE expression plays a key role, but at present a role for other factors that are able to modulate the type of Thcell responses cannot be excluded in the pathogenesis of atopic allergy.

Thl

References

and recommended

Papers of particular interest, published view, have been highlighted a..: of special inter&t . of outstanding interest .. 1.

reading

within the annual period

diseases

Kapsenberg

et al.

12. .

of re-

SCHREIERMH, TEES R, NORDINAA, BENNERR, BIANCHIATJ, VAN MJ: Functional Aspects of Helper T Cell Clones. Immunohiol 1982, 161:107-138.

ZWIETEN

2.

MOSMANNTR, SCHUMACHERJH, STREET NF, Brlnn R, O’GAFZA A, FONG TAT, BOND MW, MOORE KWM, SHER A, FIORENTINO DF: Diversity of Cytokine Synthesis and Function of Mouse CD4+ T Cells. Immunol Rev 1991, 123209-229.

3.

COFFMAN

Rl., CART-Y J: A T CeU Activity Polyclonal IgE Production and its Inhibition J Immunol 1986, 136~94F-954. g-a.

and Th2 cells and allergic

that Enhances by Interferon-

YSSEL H, JOHNSON KE, SCHNEIDERPV, WIDEMANJ, TERR A, KAS~I~IN R, DE Vru~s JE: T Cell Activation-inducing Epitopes of the House Dust Mite Allergen Der p I. Proliferation and Lymphokine Production Patterns of Der p I-specific CD4+ T Cell Clones. J Immunol 1992, 148:73%745. TLCs specific for HDM major allergen Derp I react with different epitopes and secrete a Th-2.like lymphokine profile after antigewspecific stimulation and after non-specific stimulation with ConA Non-specific stimulation with TPA and calcium ionophore induced secretion of IL-r, as well as IL-2 and IFN y, indicating that these Th2 cells are not deficient in their capacity to secrete high levels of Thl cyokines. 13.

G&SCAN H, GA~ICI~ATJF, AVERSAG, VAPU’ VI~SSELAERP, I)E VRIES JE: Anti-CD40 Monoclonal Antibodies or CD4+ T CeU Clones and IL-4 Induce IgG4 and IgE Switching in Purified Human B Cells via Different Signaling Pathways. ./ hmunol 1991, 147:%13.

14.

PARRONCHI P, TIRI A, MACCHIA D, DE CARJJ M, BI~WWAS P, SIMONELLIC, MAGGI E, DEL PRETE GF, RICCI M, ROMA(;NANI S: Noncognate Contact-dependent B CeU Activation Can Promote IL-4 Dependent In Vitro Human IgE Synthesis. J Immunol 1990, 144:2102-2108.

15.

ARMITAGERJ, FANSLOWWC, STROCKB~NEI,, SATO TA, CI.IFF~R~ KN, MACDUFF BM, ANDERSON DM, GIMPEL SD, DAVIS~SMITH and Biological CharT, MALISZEWKSI CR, ET AL.:Molecular acterization of a Murine Ligand for CD40. Nature 1992, 357:8Cb82.

16.

JABARAHH, GEHA RS, VERCELLID: CD40 and IgE: Synergism between Anti-CD40 Monoclonal Antibody and Interleukin 4 in the Induction of IgE Synthesis by Highly Purified Human B Cells. J Eap Med 1990, 172:1861-1864.

4.

SNAPPERCM PAULWE: Interferon and B CeU Stimulating Factor 1 Reciprocally Regulate by Isotype Production. Science 1987, 236:944-947.

5.

PALL~RDX, DE WAAL MALEFIJT R, YSSEL H, BLANCHARDD, CHRE~EN I, ABRAMSJS, DE VRIESJE, SPITS H: Simultaneous Production of Interleukin-2, Interleukin-4 and Interferon-y by Activated Human CD4 and CDS T Lymphocyte Clones. J Immunol 1988, 141:849-855.

6.

MAGGI E, DEL PRETE GF, MACCH~AD, PARRONCHIP, TIIU A, CHRETIENI, R~CCIM, ROMAGNANIS: Profiles of Lymphoklne Activities and Helper Function for IgE in Human T CeU Clones. Eur J Immunol 1988, l&1045-1050. 17.

7.

PENE J, ROUSSET F, BRI~RE F, CHRETIEN I, PALIARD X, BANCHEREA~J J, SPITS H, DE VIUES JE: IgE Production by Normal Human B Cells Induced by Alloreactive T CeU Clones is Mediated by IL-4 and Suppressed by IFN-y. J Immunol 1988, 141:1218-1224.

TITE JP, JANEWAYCA: Cloned Helper T Cells Kill B Lymphocytes in the Presence of Specific Antigen: Ia Restriction and Cognate vs Noncognate Interactions in Cytolysis. Ezrr J Immunol 1984, 14:87%893.

18.

WIERENGA EA, SNOEK M, DE GR~OT C, CHRETIEN I, Bos JD, JANSEN HM, KA~SENBERGML: Evidence for CompaxtmentalIzation of Functional Subsets of CD4+ T Lymphocytes in Atopic Patients. J Immunol 1990, 144:46514656.

SHIN~HN~AN, HIIANG Y-Y, MITRO)~.~\~A Specific Suppression of Antibody Responses by Soluble Protein-specific, Class IIrestricted Cytolytic T Lymphocyte Clones. Ezrr ,/ Immum~l 1991, 21:23-37.

19.

HAANFN

8.

WIERENGAEA, SNOEK M, JANSEN HM, BOS JD, VAN LIER RAW, KAPSENRERGML: Human Atopen-specific Types 1 and 2 Helper T Cell Clones. J Immunol 1991, 147:2942-2949. Allergen-specihc Th2-cell clones horn allergic patients, in contrast to allergenen-specific Thl-cell clones from non-atopic controls, secrete high levels of IL 4 and IL-5, little or no IFN-y and moderate levels of IL~2. Both types of TLC secrete high levels of GM-CSF and TNF-a and low levels of IL-G.The ThZ-cell clones from the allergic patients support IgE production in z&o for at least three reasons: they secrete high levels of IL-4 and low levels of INF~y; they can provide physical contact-mediated supporr; and they are not cytotoxic for APCs, including allergen specific B cells. 9. .

10.

WIEMNGA

EA, SNOEK M, BOS JD. JANSENHM, KAIJSENBERG ML: Comparison of Diversity and Function of Housedust Mitespecific T Lymphocyte Clones from Atopic and Nonatopic Donors. Eur J Immunol 1990, 20:151%1526.

DEL PRETE GF, DE 0~1.1 M, Rx-cl M, ROMA(;NA~IS: Helper Activity for Immunoglobulin Synthesis of Thl and Th2 Human T CeU Clones: the Help of Thl Clones is Limited by Their Cytolytic Capacity. J Exp Med 1992, 174%09-X13. like mouse Thl~cell clones. human ‘Thl cell clones dre qtotoxlc totAPCs. including antigen presenting R cells. In co~cultures of Thl iells and antigen-presenting H cells dt high T cell B cell ratios. antihod) pro duction by the B cells IS wwely supprcssecl due to cytolys~s h\, the Th I 20. ..

cells.

21.

WII:REN(,A EA. bhUh hi, \ %\ iP’K ti!.lJI,lll, FI., 1% GROO-I (:. I~(+ JD, JANS~S HM, KAPSEN~ERCI ML: Regulation of Immunoglobulin E Synthesis by T CeU Clones. In Adtlances i~zAllergolog) and Clinical Immunology 1st edn. Edited by Godard PII, Uousquet J, Michel FB. Carnforth: The Parthenon Publishmg group; 1992:23-31.

22. ..

RAMB-LINDHAIW~

23. ..

\AN DER HTIJI)EN FL, WIEKCNC;AEA. Boi JD, ~~.\P%DI:K(~ \ll High Frequency of IL-4 Producing CD4 Allergen-specific ‘I

11.

PARRONCHIP, MACCH!AD, PICCINI MP, B~swks P, SIMONELLI C, E, Rlccl M, ANSAR~ AA, ROMAGNANI S: Allergen- and Bacterial Antigen-specilic T-cell Clones Established from Atopic Donors Show a Different Profile of Cytoklne Production. Proc Nat1 Acad Sci USA 1991, 88:45384542. Allergen~specific TLCs prepared from peripheral blood of atopic patients are predominantly Th2-like cells that secrete IL-4 and IL-5 and lit~ de or no IFN-y, whereaz TLCs specific for bacterial antigens, prepared from the same patient secrete both IL~4 and IFN-y. .

JBAG, DE WAAL MALEYIJ’R, ~ Rb.\ PC&l, KRAAK&\NEM. OITENHOF THM, IX: VRIRIES RRP, SPIT’, I I: Selection of a Human T Helper Type l-like T CeU Subset by Mycobacteria. ./ F.rl Med 1991, 174583-592.

MAGGI

of Grass-pollen Atopic Skin. See [23**].

C, FEI~DMANN A, NEI-~%% C. Characterization Reactive T Cell Lines Derived from Lesional Arch Dermatol l&s 1992. 283:71-X?

791

792

Atopic allergy and other hypersensitivities Lymphocytes in Atopic Dermatitis Lesional Skin. J Invest Dermatol 1991, 97:389-394. This report, together with [22**], documents that panels of TLCs randomly prepared from chronic skin lesions of patients with severe atopic dermatitis comprise a relatively high frequency of T cells that react with aeroallergens. These TLCs tend to secrete high levels of IL-4 and little or no IFN-y. Non-allergen-specific TLCs showed variable cytokine secretion patterns after non-specific stimulation. SAGER

N, FELDMANA, SCHILLINGG, KREITSCHP, NEUMANNC: House Dust Mite-specific T CelIs in the Skin of Subjects with Atopic Dermatitis: Frequency and Lymphokine Profile in the Allergen Patch Test. J Allergy Clin Immunol 1992, 89:801-810. In this report TLCs were randomly prepared from skin lesions that were experimentally induced by epicutaneous application of HDM allergen. Tenfold more T cells in these clone panels proliferated specifically to this aeroallergen in vitro, compared with T cells in similar panels pre pared from peripheral blood. The majority of the HDM-specific TICS secreted high levels of IL-G but almost no IFN-y. 24. .

25.

26.

VAN REYSEN FC, BR~JYNZEEL-KOOMEN CAFM, KALTHoFF FS, MAGGI E, ROMAGNANIS, WESTLANDJKI, MUDDE GC: Skinderived Aeroallergen-specific T Cell Clones of the Th2 Phenotype in Patients with Atopic Dermatitis. J Allergy Clin Immunol 1992, 90:184-193. MAGGI E, BISWA~P, DEL PRFX G, PARRONCHIP, MACCHLAD, SIMONELLIC, EMMI L, DE CARLIM, TIRI A, RICCI M, ROMAGNANI S: Accumulation of Th2-like Helper T Cells in the Conjuctiva of Patients with Vernal Conjunctivitis. J Zmmunol 1991, 146:116%1174.

KAY AB, YING S, VARNEYV; GAGA M, DURHAM SR, MOQBEL R, WARDLAWAJ, HAMID Q: Messenger RNA Expression of the Cytokiie Gene Cluster, Interleukin (IL)-3, IL-4, IL-5 and GM-CSF in Allergen-induced Late Phase Reactions in Atopic Subjects. J Exp Med 1991, 173~775-778. The first demonstration of Th2-cell cytokine secretion profiles in situ. Twenty-four hours after intradennal grass pollen challenge, expression of mRNA encoding the Th2-associated cytokines IL-3, IL~4,IL-5 and GMCSF was evident in tissue sections of skin biopsies taken from grass pollen sensitive atopic patients. Only a small amount of mRNA encoding IL-2 was present and mRNA encoding IFN~y was almost absent.

Helper T Cells. Evidence from Bulk Cultures and Limiting Dilution Cloning for Precursors of Thl and Th2 Cells. J Immunol 1990, 144:1629-1639. This report provides evidence for the commitment in vivo of Th cells to the Thl and Th2 phenotypes. T-lymphocyte clones from non-immunized mice secrete both IL-2 and IL-4. T-cell clones prepared from mice immunized with the helmith Nz@ostroneylus hrusiliensis tend to be Th2 cells with a high IL-4/IL~2 secretion ratio, whereas the T-cell clones prepared from mice immunized with Brucellu abortus tend to be Thl cells with a low IL-4/IL-2 secretion ratio. SOWWAY P, FISII S, PASSMOREH, GEFIER M, COFFEE R, MANSER T: Regulation of the Immune Response to Peptide Antigens: Differential Induction of Immediate Hypersensitivity and T Cell Proliferation Due to Changes in Either Peptide Structure or Major Histocompatibility Complex Haplotypes. .I Exp Med 1992, 174:847-858. The peptide structure of antigen determines the type of effector cell in the immune response. A peptide, and most of its sequence variants, induces immediate hypersensitivity in mice. However, some variants, which may differ by as little as a single amino acid residue, do not, although they may still induce peptide-specific IgG and/or 1gM product tion. 35 .

36.

VERCELLID, JABARAHH, LAUENEKRP, GEHA Rs: IL-4 Inhibits the Synthesis of IFN-y and Induces the Synthesis of IgE in Human Mixed Lymphocyte Cultures. J Immunol 1990, 144:57&573.

37.

CHRETIENI, PENE J, BRIEREF, DE WAALMALEFIJTR, ROUSSETF, DE VRIESJE: Regulation of Human IgE Synthesis. I. Human IgE Synthesis In Vi&o is Determined by the Reciprocal Antagonistic Effects of Interleukin 4 and Interferon-y. Eur J Immunol 1990, 20:243-251.

38.

NOVAK TJ, ROTHENEIERGEV: CAMP Inhibits Induction of Interleukin 2 but Not of Interleukin 4 in T Ceils. Proc Nut1 Acud Sci USA 1990, 87~9353-9357.

27. ..

28.

ROBINSONDS, HAMII) W, YING S, TSICOPO~ILOSA, BARKANSJ, BENTLEYAM, CORRIGAN C, DURHAM SR, KAY AB: Predominant ‘Ih2-like Bronchoalveolar T-lymphocyte Population in Atopic Asthma. New En@ J Med 1992, 326:298-304.

29.

DURHAMSR, YING S, VARNAY VA, JACOBSON MR, SL~~DEFXKRM, MACCAYIS, KAY AB, HAMID QA: Cytokine Messenger RNA Expression for IL-S, IL-4, IL-5 and GM-CSF in the Nasal Mucosa after Local Allergen Provocation: Relationship to Tissue Eosinophilia. J Immunol 1992, 148:239&2394.

30.

CHER D, MOSMANNTR: Two Types of Murine Helper T CelI Clone. II Delayed Type Hypersensitivity is Mediated by Thl Clones. J Immunol 1987, 138:368%3694.

31.

FONG TAT, MOSMANNTR: The Role of IFN-gamma in Delayed Type Hypersensitivity Mediated by Thl Clones. J Immunol 1989, 143:2887-2893.

32.

PIGUET PF, GRAU GE, HAUSER C, VA.SSALLI P: Tumor Necrosis Factor is a Critical Mediator in Hapten-induced Irritant and Contact-hypersensitivity Reactions. J Eq Med 1991, 173~673-679.

33.

COFFMAN RL, SEYMOUR BWP, HUDAK S, JACKSON J, RENNICK D: Antibody to Interleukin-5 Inhibits Hehninth-induced EosinophIla in Mice. Science 1989, 245:30%310.

34. ..

STREET NE,

B~rz M, Fox BS: Prostaglandin E2 Inhibits Production of Thl Lymphokines but not of Th2 Lymphokines. J Immunol 1991, 146:10%113. This paper, together with [381, demonstrates that an increase in introcellular levels of CAMP in T cells, induced either by the physiological mediators PGEl and PGE2 or by artificial drugs, results in suppression of the mitogen-induced secretion of the Thl cytokines, IL-2 and IFN-y, whereas the secretion of the Th2 cytokines, IL-4 and IL-5, is unaffected or increased. 39. ..

VANDER PouwKRAAN TEM, VANKOOTEN C, RENSINKI, AARDEN IA: Interleukin (IL)-4 Production by Human T Cells: Differential Regulation of IL-4 versus IL-2 Production. Eur J Immmunol 1992, 22~1237-1241. This report demonstrates that in peripheral blood T cells the highest levels of II.-4 production are found after stimulation with combinations of antibodies to CD2 and CD28. Agents that increase the intracellular CAMP levels inhibited IL-2 production but did not affect IL-4 production. In contrast, PMA almost completely inhibited IL-4 production, whereas 1~~2 production was enhanced by almost tenfold. The authors speculate that the intracellular protein kinase A/protein kinase C balance regulates the IL-4/11.-2 production ratio. 40. ..

MACGI E, PARRONCHIP, MANETTIR, SIMONELUC, PICCINNIMP, RUGIU FS, DE CARLI M, Rtccl M, ROMAGNANIS: Reciprocal Regulatory Effects of IFN-y and IL-4 on the In Vitro Development of Human Thl and Th2 Clones. J Immunol 1992, 148:2142-2147. The demonstration that, as previously reported in the mouse model, IL-4 directs the outgrowth of IL-4~producing Th2 cells, whereas IFN-y directs the outgrowth of INF-y-producing human Thl cells in vitro.

41. .

42. SCHLJMACHER JD,

FONG

TAT, Bkss H, FIORENTINO DF, LEVERAHJA, MOSMANN TR: Heterogeneity of Mouse

GAJEWSKITF, JOYCE J, FITCH IW Antiproliferative Effect of INF-y in Immune Regulation. III. DIfferentiaI Selection of Thl and Th2 Murine Helper T Lymphocyte Clones Using

Thl

44.

45.

46.

diseases Kapsenberg

et a/.

47.

HOFFMANT, BRANW C, LIZZIOEF, LEE C, HANSONM, TINC K, KIM YJ, ABRAHAMSEN T, PLIR~J, Bom1 MD: Functional Consequences of Phospholipase A2 Activation in Human Monocytes. Adza Ex/, Med Biol 19’90, 279:125-136.

48.

SWAINSL, WEINBERGAD, ENGLISHM, HIISTON G: CD4+ T Cell Subsets. Lymphokine Secretion of Memory Cells and of Effector Cells that Develop from Precursors In Vitro. J Immunol 1990, 144:178%1799.

CARBAUJDOJM, CAK~ALLIW-PERRIG N, TERRES G, HEUSSER CH, BLUER K: Bee Venom Phospholipase A2-specific T Cell Clones from Human Allergic and Non-allergic Individuals: Cytokine Pattern Change in Response to Antigen Concentration. Eur J Immunol 1992, 22:1357-1363.

-t9.

DE WAAI.~~ALECFIJT R, HAANENJBAG, Spurs H, RONCAROLO MG, TE VEDE AA, FIGD~R CG, JOHNSONK, KAYA-ELEIN R, YSSELH, DE VRlESJE: IL-10 and Vial IL-10 Strongly Reduce Antigenspecific Human T CelI Proliferation by Diminishing the Antigen-presenting Capacity of Monocytes via Downregulation of Class II MHC Expression. J Exp Med 1992, in press.

JA~~OHT, HIISPITH BN, IATCHMAN YE, FZCROFT R, BROSTOFF J: Depressed Lymphocyte Transformation and the Role of Prostaglandins in Atopic Dermatitis. Clin f@ fmmunol1990, 79:380-384

ML Kapsenberg and EA Wierenga, laboratov of Cell Biology and I listology, University of Amsterdam, Academisch M&s& Centrum, Meibergdreef 15, 1105 AZ Amsterdam, The Netherlands.

Recombinant IL-2 and Recombinant IFN-y. J Immunoll989, 143:15-22. 43.

and Th2 ceils and allergic

SWAINSL, WEINBERG AD, ENGLISH M, HUTTONG: IL-4 Directs the Development of ‘IX-2-like Helper Effector Cells. J Immunol 19!90, 145:37963806.

CHANG T-I., SHEA CM, UNOSTE S, THOMPSONRC, BOOM WH, hBAs AK: Heterogeneity of Helper/Inducer T Lymphocytes. III. Responses of IL-2- and IL-4-producing (Thl and Th2) Clones to Antigens Presented by Different Accessory Cells. J Immunol 1990, 145:2803-2808.

HM Jansen, Department of Pulmonology, I!niversity of Amsterdam, Academisch Medisch Centrum, Meibergdreef 9, 1105 AZ Amsterdam, The Netherlands. JD Bos, Department of Dermatology, llniversity of Amsterdam, Academisch Medisch Centmm, Meibergdreef 9, 1105 AZ Amsterdam, The Netherlands.

793

Role of type 1 and type 2 T helper cells in allergic diseases.

Various characteristics of atopic allergic disorders seem to be causally related with the activation of allergen-specific T helper lymphocytes with a ...
808KB Sizes 0 Downloads 0 Views