Conventional immunotherapy using whole allergen extracts has been shown to be an effective, disease-modifying treatment in carefully selected patients with allergic conjunctivo-rhinitis, asthma and bee and wasp venom hypersensitivity. However, this form of therapy is associated with the risk of systemic anaphylaxis, which, when severe, can be life threatening. A potentially significant reduction in the incidence of IgE-mediated events during immunotherapy may be achieved by the use of short peptides corresponding to T cell epitopes which, by virtue of their size, are incapable of cross-linking allergen-specific IgE bound to the surface of mast cells and basophils. Initial clinical studies have demonstrated degrees of efficacy which have, in some cases, been associated with adverse events occurring immediately or several hours after peptide administration. Preliminary data from studies employing shorter peptides (20 amino acids or less) suggest that improved efficacy may be achieved by using peptides of defined major histocompatibility complex-binding specificity administered in an incremental dose fashion comparable to conventional immunotherapy. This review will discuss the concept of peptide immunotherapy and the implications of recent studies.

1.
Durham SR, Walker SM, Varga E-M, Jacobson MR, O’Brien F, Noble W, Till SJ, Hamid QA, Nouri-Aria KT: Long-term clinical efficacy of grass-pollen immunotherapy. N Engl J Med 1999;341:468–475.
2.
Allergen immunotherapy: Therapeutic vaccines for allergic diseases. Geneva: January 27–29. Allergy 1998;53(suppl 44);1–42.
3.
Nacleiro RM: Pathophysiology of perennial allergic rhinitis. Allergy 1997;52:7–13.
4.
Varney V, Jacobson MR, Sudderick R, Robinson DS, Irani A, Varney VA, Schwartz LB, Mackay IS, Kay AB, Durham SR: Immunohistology of the nasal mucosa following allergen-induced rhinitis. Identification of activated T lymphocytes, eosinophils and neutrophils. Am Rev Respir Dis 1992;146:170–176.
5.
Haselden BM, Kay AB, Larché M: Immunoglobulin-independent major histocompatibility complex-restricted T cell peptide epitope-induced late asthmatic reactions. J Exp Med 1999;189:1885–1894.
6.
Kay AB: Concepts of allergy and hypersensitivity; in Kay AB (ed): Allergy and Allergic Diseases. Oxford, Blackwell Science, 1997, vol 1, pp 23–35.
7.
Kon OM, Kay AB: Anti-T cell strategies in asthma. Inflamm Res 1999;48:516–523.
8.
Hamid Q, Boguniewiecz M, Leung DYM: Differential in situ gene expression in acute versus chronic atopic dermatitis. J Clin Invest 1994;94:870–876.
9.
Hoyne GF, Askonas BA, Hetzel C, Thomas WR, Lamb JR: Regulation of house dust mite responses by intranasally administered peptide: Transient activation of CD4+ T cells precedes the development of tolerance in vivo. Int Immunol 1996;8:335–342.
10.
Briner TJ, Kuo MC, Keating KM, Rogers BL, Greenstein JL: Peripheral T-cell tolerance induced in naive and primed mice by subcutaneous injection of peptides from the major cat allergen Fel d 1. Proc Natl Acad Sci USA 1993;90:7608–7612.
11.
Braciale TJ, Morrison LA, Sweetson MT, Sambrook J, Gething MJ, Braciale VL: Antigen presentation pathways to class I and class II MHC-restricted T lymphocytes. Immunol Rev 1987;98:95–114.
12.
Germain RN: The ins and outs of antigen processing and presentation. Nature 1986;322:687–689.
13.
Hunt DF, Michel H, Dinkinson TA, Shabanowitz J, Cox AL, Sakaguchi K, Apella E, Grey HM, Sette A: Peptides presented to the immune system by the murine class II major histocompatibility complex molecule I-Ad. Science 1992;256:1817–1820.
14.
Neefjes JJ, Momburg F: Cell biology of antigen presentation. Curr Opin Immunol 1993;5:27–34.
15.
Schwartz RH: Costimulation of T lymphocytes: The role of CD28, CTLA-4 and B7/BB1 in interleukin-2 production and immunotherapy. Cell 1992;71:1065–1068.
16.
Larché M, Till SJ, Haselden BM, North J, Barkans J, Corrigan CJ, Kay AB, Robinson DS: Costimulation through CD86 is involved in airway antigen-presenting cell and T cell responses to allergen in atopic asthmatics. J Immunol 1998;161:6375–6382.
17.
Casolaro V, Georas SN, Song Z, Ono SJ: Biology and genetics of atopic disease. Curr Opin Immunol 1996;8:796–803.
18.
Kumar V, Bhardwaj V, Soares L, Alexander J, Sette A, Sercarz E: Major histocompatibility complex binding affinity of an antigenic determinant is crucial for the differential secretion of interleukin 4/5 or interferon gamma by T cells. Proc Natl Acad Sci USA 1995;92:9510–9514.
19.
Murray JS, Pfeiffer C, Madri J, Bottomly K: Major histocompatibility complex (MHC) control of CD4 T cell subset activation. II. A single peptide induces either humoral or cell-mediated responses in mice of distinct MHC genotype. Eur J Immunol 1992;22:559–565.
20.
Pfeiffer C, Stein J, Southwood S, Ketelaar H, Sette A, Bottomly K: Altered peptide ligands can control CD4 T lymphocyte differentiation in vivo. J Exp Med 1995;181:1569–1574.
21.
Hosken NA, Shibuya K, Heath AW, Murphy KM, O’Garra A: The effect of antigen dose on CD4+ T helper cell phenotype development in a T cell receptor-alpha beta-transgenic model. J Exp Med 1995;182:1579–1584.
22.
Guery JC, Galbiati F, Smiroldo S, Adorini L: Selective development of T helper (Th)2 cells induced by continuous administration of low dose soluble proteins to normal and beta(2)-microglobulin-deficient BALB/c mice. J Exp Med 1996;183:485–497.
23.
O’Garra A: Cytokines induce the development of functionally heterogeneous T helper cell subsets. Immunity 1998;8:275–278.
24.
Van Neerven RJ, Ebner C, Yssel H, Kapsenberg ML, Lamb J: T-cell responses to allergens: Epitope-specificity and clinical relevance. Immunol Today 1996;17:526–534.
25.
Young RP, Dekker JW, Wordsworth BP, Schou C, Pile KD, Matthiesen F, Rosenberg WM, Bell JI, Hopkin JM, Cookson WO: HLA-DR and HLA-DP genotypes and immunoglobulin E responses to common major allergens. Clin Exp Allergy 1994;24:431–439.
26.
Marsh DG, Hsu SH, Roebber M, Ehrlich-Kautzky E, Freidhoff LR, Meyers DA, Pollard MK, Bias WB: HLA-Dw2: A genetic marker for human immune response to short ragweed pollen allergen Ra5. I. Response resulting primarily from natural antigenic exposure. J Exp Med 1982;155:1439–1451.
27.
Scheiner O, Kraft D: Basic and practical aspects of recombinant allergens. Allergy 1995;50:384–391.
28.
van’t Hof W, van Milligen FJ, van den Berg M, Lombardero M, Chapman MD, Aalberse R: Epitope mapping of the cat (Felis domesticus) major allergen Fel d 1 by overlapping synthetic peptides and monoclonal antibodies against native and denatured Fel d 1. Allergy 1993;48:255–261.
29.
Counsell CM, Bond JF, Ohman JR, Greenstein JL, Garman RD: Definition of the human T-cell epitopes of Fel d 1, the major allergen of the domestic cat. J Allergy Clin Immunol 1996;98:884–892.
30.
O’Hehir RE, Verhoef A, Panagiotopoulou E, Keswani S, Hayball JD, Thomas WR, Lamb JR: Analysis of human T cell responses to the group II allergen of Dermatophagoides species: Localization of major antigenic sites. J Allergic Clin Immunol 1993;92:105–110.
31.
Mark PG, Segal DB, Dallaire ML, Garman RD: Human T and B cell immune responses to Fel d 1 in cat-allergic and non-cat-allergic subjects. Clin Exp Allergy 1996;26:1316–1328.
32.
Bungy GA, Rodda S, Roitt I, Brostoff J: Mapping of T cell epitopes of the major fraction of rye grass using peripheral blood mononuclear cells from atopics and non-atopics. II. Isoallergen clone 5A of Lolium perenne group I (Lol p I). Eur J Immunol 1994:24:2098–2103.
33.
Schenk S, Breiteneder H, Susani M, Najafian N, Laffer S, Duchene M, Valenta R, Fischer G, Scheiner O, Kraft D, Ebner C: T cell epitopes of Phl p 1, major pollen allergen of timothy grass (Phleum pratense). Crossreactivity with group I allergens of different grasses. Adv Exp Med Biol 1996;409:141–146.
34.
Ebner C, Szepfalusi Z, Ferreira F, Jilek A, Valenta R, Parronchi P, Maggi E, Romagnani S, Scheiner O, Kraft D: Identification of multiple T cell epitopes on Bet v I, the major birch pollen allergen, using specific T cell clones and overlapping peptides. J Immunol 1993;150:1047–1054.
35.
Carballido JM, Carballido-Perrig N, Kagi MK, Meloen MH, Wuthrich B, Heusser CH, Blaser K: T cell epitope specificity in human allergic and nonallergic subjects to bee venom phospholipase A2. J Immunol 1993;150:3582–3591.
36.
van Neerven FJ, van de Pol MM, van Milligen FJ, Jansen H, Aalberse R, Kapsenberg ML: Characterization of cat dander-specific T lymphocytes from atopic patients. J Immunol 1994;152:4203–4210.
37.
Katsuki T, Shimojo N, Honma K, Tsunoo H, Kohno Y, Niimi H: Establishment and characterization of ovalbumin-specific T cell lines from patients with egg allergy. Int Arch Allergy Immunol 1996;109:344–351.
38.
Parronchi P, Sampognaro S, Annunziato F, Brugnolo F, Radbruch A, Di Modugno F, Ruffilli A, Romagnani S, Maggi E: Influence of both TCR repertoire and severity of the atopic status on the cytokine secretion profile of Parietaria officinalis-specific T cells. Eur J Immunol 1998;28:37–46.
39.
Norman PS, Ohman JL Jr, Long AA, Creticos PS, Gefter MA, Shaked Z, Wood RA, Eggleston PA, Hafner KB, Rao P, Lichtenstein LM, Jones NH, Nicodemus CF: Treatment of cat allergy with T-cell reactive peptides. Am J Respir Crit Care Med 1996;154:1623–1628.
40.
Maguire P, Nicodemus N, Robinson D, Aaronson D, Umetsu DT: The safety and efficacy of ALLERVAX CAT in cat allergic patients. Clin Immunol 1999;33:222–231.
41.
Charron D, Fauchet R, Albert E, Cambon Thomsen A, Degos L, Hors J, Piazza A, Schreuder I: Genetic diversity of HLA, functional and medical implication; in Charron D (ed): XIIth International Histocompatibility Workshop and Conference. Paris, EDK, 1996, pp 669–671.
42.
Texier C, Pouvelle S, Busson M, Hervé M, Charron D, Ménez A, Maillère B:HLA-DR restricted peptide candidates for bee venom immunotherapy. J Immunol 2000;164:3177–3184.
43.
Ohman JL, Kendall S, Lowell FC: IgE antibody to cat allergens in an allergic population. J Allergy Clin Immunol 1977;60:317–319.
44.
Marcotte GV, Braun CM, Norman PS, Nicodemus CF, Kagey-Sobotka A, Lichtenstein LM, Essayan DM: Effects of peptide therapy on ex vivo T-cell responses. J Allergy Clin Immunol 1998;101:506–513.
45.
Simons FE, Imada M, Li Y, Watson WT, HayGlass KT: Fel d 1 peptides: Effect on skin tests and cytokine synthesis in cat-allergic human subjects. Int Immunol 1996;8:1937–1945.
46.
Pene J, Desroches A, Paradis L, Lebel B, Farce M, Nicodemus CF, Yssel H, Bousquet J: Immunotherapy with Fel d 1 peptides decreases IL-4 release by peripheral blood T cells of patients allergic to cats. J Allergy Clin Immunol 1998;102:571–578.
47.
Muller U, Akdis CA, Fricker M, Akdis M, Blesken T, Bettens F, Blaser K: Successful immunotherapy with T-cell epitope peptides of bee venom phospholipase A2 induces specific T-cell anergy in patients allergic to bee venom. J Allergy Clin Immunol 1998;101:747–754.
48.
Oldfield WLG, Shirley KE, Haselden BM, Larché M, Kay AB: Attenuation of late cutaneous reactions and asthmatic reactions following administration of short allergen-derived T cell peptide epitopes. J Allergy Clin Immunol 2000;104:A1111.
49.
Lamb JR, Skidmore BJ, Green N, Chiller JM, Feldmann M: Induction of tolerance in influenza virus-immune T lymphocyte clones with synthetic peptides of influenza hemagglutinin. J Exp Med 1983;157:1434–1447.
50.
O’Hehir RE, Yssel H, Verma S, de Vries JE, Spits H, Lamb JR: Clonal analysis of differential lymphokine production in peptide and superantigen induced T cell anergy. Int Immunol 1991;3:819–826.
51.
Akdis CA, Akdis M, Blesken T, Wymann D, Alkan SS, Muller U, Blaser K: Epitope-specific T cell tolerance to phospholipase A2 in bee venom immunotherapy and recovery by IL-2 and IL-15 in vitro. J Clin Invest 1996;98:1676–1683.
52.
Akdis CA, Blesken T, Akdis M, Wuthrich B, Blaser K: Role of interleukin 10 in specific immunotherapy. J Clin Invest 1998;102:98–106.
53.
O’Hehir RE, Lamb JR: Induction of specific clonal anergy in human T lymphocytes by Staphylococcus aureus enterotoxins. Proc Natl Acad Sci USA 1990;87:8884–8888.
54.
O’Hehir RE, Aguilar BA, Schmidt TJ, Gollnick SO, Lamb JR: Functional inactivation of Dermatophagoides spp. (house dust mite) reactive human T cell clones. Clin Exp Allergy 1991;21:209–215.
55.
Yssel H, Fasler S, Lamb J, de Vries JE: Induction of non-responsiveness in human allergen-specific type 2 helper cells. Curr Opin Immunol 1994;6:847–852.
56.
LaSalle JM, Tolentino PJ, Freeman GJ, Nadler LM, Hafler DA: Early signaling defects in human T cells anergized by T cell presentation of autoantigen. J Exp Med 1992;176:177–186.
57.
Faith A, Akdis CA, Akdis M, Simon HU, Blaser K: Defective TCR stimulation in anergized type 2 T helper cells correlates with abrogated p561ck and ZAP-70 tyrosine kinase activities. J Immunol 1997;159:53–60.
58.
Lake RA, O’Hehir RE, Verhoef A, Lamb JR: CD28 mRNA rapidly decays when activated T cells are functionally anergized with specific peptide. Int Immunol 1993;5:461–466.
59.
Hoyne GF, Askonas BA, Hetzel C, Thomas WR: Regulation of house dust mite responses by intranasally administered peptide: Transient activation of CD4+ T cells precedes the development of tolerance in vivo. Int Immunol 1996;8:335–342.
60.
Lowrey JL, Savage ND, Palliser D, Corsin-Jimenez M, Forsyth LM, Hall G, Lindey S, Stewart GA, Tan KA, Hoyne GF, Lamb JR: Induction of tolerance via the respiratory mucosa. Int Arch Allergy Immunol 1998;116:93–102.
61.
Suhr C, Sprent J: T-cell apoptosis detected in situ during positive and negative selection in the thymus. Nature 1994;372:100–103.
62.
Chen Y, Inobe JL, Marks R, Gonnella P, Kuchroo VK, Weiner HL: Peripheral deletion of antigen-reactive T cells in oral tolerance. Nature 1995;376:177–180.
63.
Hoyne GF, Jarnicki AG, Thomas WR, Lamb JR: Characterization of the specificity and duration of T cell tolerance to intranasally administered peptides in mice: A role for intramolecular epitope suppression. Int Immunol 1997;9:1165–1173.
64.
Hoyne GF, Callow MG, Kuo MC, Thomas WR: Inhibition of T-cell responses by feeding peptides containing major and cryptic epitopes: Studies with the Der p I allergen. Immunology 1994;83:190–195.
65.
Hoyne GF, Dallman MJ, Lamb JR: Linked suppression in peripheral T cell tolerance to the house dust mite derived allergen Der p 1. Int Arch Allergy Immunol 1999;118:122–124.
66.
Secrist H, Chelen CJ, Wen Y, Marshall JD, Umetsu DT: Allergen immunotherapy decreases interleukin 4 production in CD4+ T cells from allergic individuals. J Exp Med 1993;178:2123–2130.
67.
Jutel M, Pichler WJ, Skrbic D, Urwyler A, Dahinden C, Muller UR: Bee venom immunotherapy results in decrease of IL-4 and IL-5 and increase of IFN-gamma secretion in specific allergen-stimulated T cell cultures. J Immunol 1995;154:4187–4194.
68.
McHugh SM, Deighton J, Stewart AG, Lachmann PJ, Ewan PW: Bee venom immunotherapy induces a shift in cytokine responses from a TH-2 to a TH-1 dominant pattern: Comparison of rush and conventional immunotherapy. Clin Exp Allergy 1995;25:828–838.
69.
Hamid QA, Schotman E, Jacobson MR, Walker SM, Durham SR: Increases in IL-12 messenger RNA+ cells accompany inhibition of allergen-induced late skin responses after successful grass pollen immunotherapy. J Allergy Clin Immunol 1997;99:254–260.
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