Portal de Periódicos da CAPES

Update on the current status of peptide immunotherapy

2007; Elsevier BV; Volume: 119; Issue: 4 Linguagem: Inglês

10.1016/j.jaci.2007.02.015

1097-6825

Mark Larché,

Food Allergy and Anaphylaxis Research

The use of synthetic peptide fragments of allergen molecules holds promise for the delivery of effective immunotherapy without IgE-mediated adverse events. Early studies were associated with frequent induction of allergic symptoms after treatment, mostly related to activation of allergen-specific effector T cells with high doses of peptides. More recently, low doses of peptides have been shown to modify clinical and laboratory surrogates without inducing adverse events. Studies are ongoing to define the optimal dose, dose interval, and route of administration. Current results indicate that treatment with peptides modulates the immune response by reducing TH2 responses to allergen and increasing IL-10 production and the activity of allergen-specific regulatory T cells. Further studies are required in larger numbers of subjects and with peptides derived from a variety of allergens. The use of synthetic peptide fragments of allergen molecules holds promise for the delivery of effective immunotherapy without IgE-mediated adverse events. Early studies were associated with frequent induction of allergic symptoms after treatment, mostly related to activation of allergen-specific effector T cells with high doses of peptides. More recently, low doses of peptides have been shown to modify clinical and laboratory surrogates without inducing adverse events. Studies are ongoing to define the optimal dose, dose interval, and route of administration. Current results indicate that treatment with peptides modulates the immune response by reducing TH2 responses to allergen and increasing IL-10 production and the activity of allergen-specific regulatory T cells. Further studies are required in larger numbers of subjects and with peptides derived from a variety of allergens. Strategies to improve the safety of allergen immunotherapy have traditionally focused on reducing the allergenicity of the preparation administered to the patient. The use of peptide fragments, corresponding to T-cell epitopes, to induce immunologic tolerance has been reported in experimental models of both allergic and autoimmune disease.1Larche M. Peptide therapy for allergic diseases: basic mechanisms and new clinical approaches.Pharmacol Ther. 2005; 108: 353-361Crossref PubMed Scopus (24) Google Scholar By virtue of their size and relative lack of secondary and tertiary structure, peptides display reduced ability to cross-link allergen-specific IgE and activate IgE receptor–bearing cells. However, retention of T-cell epitopes allows targeting of allergen-specific T cells for the induction of tolerance. Translation of this approach to the clinic is ongoing, with a number of small clinical studies having been performed over the last decade. At present, 3 allergens have been targeted with this approach (Table I): the cat allergen Fel d 1, the bee venom allergen Api m 1 (phospholipase A2), and the ragweed allergen Amb a 1 (clinical studies of the last have not been reported). Considerable objective evidence has accumulated demonstrating modulation of allergen-specific immune responses after peptide immunotherapy. Evidence supporting clinical benefit has been slower to accumulate, and definitive studies demonstrating reduced symptom scores and medication use combined with improvements in tolerability are still required.Table IClinical studies of peptide immunotherapyFirst authorAllergenNo. of peptides and lengthTotal doseRouteNo. of subjectsMajor outcome measuresReferenceCat allergy NormanFel d 12 × 2730-3000 μgSubcutaneous95Improved symptom scores after cat room challenge2Norman P.S. Ohman J.L. Long A.A. Creticos P.S. Gefter M.A. Shaked Z. et al.Treatment of cat allergy with T-cell reactive peptides.Am J Respir Crit Care Med. 1996; 154: 1623-1628Crossref PubMed Scopus (351) Google Scholar SimonsFel d 12 × 271000 μgSubcutaneous42No change in cutaneous allergen challenge5Simons F.E. Imada M. Li Y. Watson W.T. HayGlass K.T. Fel d 1 peptides: effect on skin tests and cytokine synthesis in cat-allergic human subjects.Int Immunol. 1996; 8: 1937-1945Crossref PubMed Scopus (122) Google Scholar PèneFel d 12 × 2715-4500 μgSubcutaneous31Improved allergen PD20 compared with baseline4Pène J. Desroches A. Paradis L. Lebel B. Farce M. Nicodemus C.F. et al.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: 571-578Abstract Full Text Full Text PDF PubMed Scopus (128) Google Scholar MaguireFel d 12 × 276000 μgSubcutaneous133Improved FEV1 in subjects with reduced baseline FEV16Maguire P. Nicodemus C. Robinson D. Aaronson D. Umetsu D.T. The safety and efficacy of ALLERVAX CAT in cat allergic patients.Clin Immunol. 1999; 93: 222-231Crossref PubMed Scopus (123) Google Scholar OldfieldFel d 112 × 16/175 μgIntradermal24Reduced cutaneous late-phase reaction after allergen challenge7Oldfield W.L. Kay A.B. Larche M. Allergen-derived T cell peptide-induced late asthmatic reactions precede the induction of antigen-specific hyporesponsiveness in atopic allergic asthmatic subjects.J Immunol. 2001; 167: 1734-1739PubMed Google Scholar OldfieldFel d 112 × 16/1790 μgIntradermal24Reduced cutaneous early and late-phase reaction after allergen challenge, TH1/TH2 cytokines reduced, IL-10 increased8Oldfield W.L. Larche M. Kay A.B. Effect of T-cell peptides derived from Fel d 1 on allergic reactions and cytokine production in patients sensitive to cats: a randomised controlled trial.Lancet. 2002; 360: 47-53Abstract Full Text Full Text PDF PubMed Scopus (340) Google Scholar AlexanderFel d 111 × 16/1740.1 μgIntradermal8Reduced airway hyperreactivity and cutaneous late-phase reaction after allergen challenge, increase in CD4+IFN-γ+ cells in skin after allergen challenge9Alexander C. Ying S. Kay B. Larche M. Fel d 1-derived T cell peptide therapy induces recruitment of CD4CD25; CD4 interferon-gamma T helper type 1 cells to sites of allergen-induced late-phase skin reactions in cat-allergic subjects.Clin Exp Allergy. 2005; 35: 52-58Crossref PubMed Scopus (102) Google Scholar AlexanderFel d 112 × 16/17131-341 μgIntradermal28Improved nasal symptoms and late asthmatic reaction after allergen challenge11Alexander C. Tarzi M. Larche M. Kay A.B. The effect of Fel d 1-derived T-cell peptides on upper and lower airway outcome measurements in cat-allergic subjects.Allergy. 2005; 60: 1269-1274Crossref PubMed Scopus (110) Google ScholarBee venom allergy MüllerApi m 13: 11, 12, 18397.1 μgSubcutaneous5Improved tolerance of skin allergen challenge and partial protection from live sting challenge13Müller U. Akdis C.A. Fricker M. Akdis M. Blesken T. Bettens F. et al.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: 747-754Abstract Full Text Full Text PDF PubMed Scopus (383) Google Scholar FellrathApi m 13: 45, 53, 60751.1-1551.1 μgSubcutaneous16Increased allergen-specific IgG4, increased IFN-γ and IL-10 in PBMCs14Fellrath J.M. Kettner A. Dufour N. Frigerio C. Schneeberger D. Leimgruber A. et al.Allergen-specific T-cell tolerance induction with allergen-derived long synthetic peptides: results of a phase I trial.J Allergy Clin Immunol. 2003; 111: 854-861Abstract Full Text Full Text PDF PubMed Scopus (140) Google Scholar TarziApi m 14 × 18431.1 μgIntradermal12Reduced cutaneous early and late-phase reaction after allergen challenge, TH1/TH2 cytokines reduced, IL-10 increased, transiently increased IgG415Tarzi M. Klunker S. Texier C. Verhoef A. Stapel S.O. Akdis C.A. et al.Induction of interleukin-10 and suppressor of cytokine signalling-3 gene expression following peptide immunotherapy.Clin Exp Allergy. 2006; 36: 465-474Crossref PubMed Scopus (123) Google ScholarModified with permission from Larché M. Peptide immunotherapy for allergic diseases. Allergy 2007;62:325-31. Open table in a new tab The earliest clinical studies employed a combination of 2 peptides (Allervax Cat, ImmuLogic Corp., Waltham, Mass) from Fel d 1, administered subcutaneously in a variety of dosing regimens. In the first of these to be reported, peptides were administered at weekly intervals and in 3 dose cohorts (7.5 μg, 75 μg, and 750 μg).2Norman P.S. Ohman J.L. Long A.A. Creticos P.S. Gefter M.A. Shaked Z. et al.Treatment of cat allergy with T-cell reactive peptides.Am J Respir Crit Care Med. 1996; 154: 1623-1628Crossref PubMed Scopus (351) Google Scholar After allergen exposure in a cat room, lung and nasal symptom scores were significantly improved in the higher dose cohorts. Despite the use of peptides that had been screened for reduced activity in basophil histamine release assays, numerous adverse events were documented occurring minutes to hours after peptide administration. Some adverse events may have been a result of the relatively long peptides used that may have harbored residual IgE reactivity; however, the majority of events probably occurred as a result of activation of allergen-specific effector T cells resulting in late asthmatic reactions.3Haselden B.M. Kay A.B. Larche M. Immunoglobulin E-independent major histocompatibility complex-restricted T cell peptide epitope-induced late asthmatic reactions.J Exp Med. 1999; 189: 1885-1894Crossref PubMed Scopus (311) Google Scholar The same peptides were evaluated in inhaled allergen challenge studies. A significant increase in PD20 was observed within cohorts receiving higher dose (total dose between 150 μg and 4500 μg) regimens, but this failed to achieve statistical significance when compared with placebo.4Pène J. Desroches A. Paradis L. Lebel B. Farce M. Nicodemus C.F. et al.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: 571-578Abstract Full Text Full Text PDF PubMed Scopus (128) Google ScholarIn a double-blind, placebo-controlled parallel group study, peptides or placebo were administered by weekly subcutaneous injection (4 × 250 μg) to 42 subjects with cat-allergic rhinitis and/or asthma.5Simons F.E. Imada M. Li Y. Watson W.T. HayGlass K.T. Fel d 1 peptides: effect on skin tests and cytokine synthesis in cat-allergic human subjects.Int Immunol. 1996; 8: 1937-1945Crossref PubMed Scopus (122) Google Scholar Treatment was associated with adverse events, primarily late-onset symptoms of rhinitis, asthma, and pruritus. No significant changes were observed in the primary outcome measure (change in wheal and flare reaction) or in late-phase skin responses to allergen challenge. PBMC cytokine secretion profiles did not differ between peptide-treated and placebo-treated subjects.Treatment with Allervax Cat was also associated with a significant clinical improvement in pulmonary function (FEV1) in individuals with reduced baseline FEV1.6Maguire P. Nicodemus C. Robinson D. Aaronson D. Umetsu D.T. The safety and efficacy of ALLERVAX CAT in cat allergic patients.Clin Immunol. 1999; 93: 222-231Crossref PubMed Scopus (123) Google Scholar Furthermore, a significant improvement in the subjective ability to tolerate cats was also observed through a visual analogue evaluation. Importantly, subjects recruited to this study had moderate to severe disease, with many demonstrating high IgE levels. Approximately 30% had failed previous whole allergen immunotherapy, and more than 40% of the group had asthma. Adverse events were common and consisted of occasional IgE-mediated acute reactions and more frequent late-onset symptoms of asthma. Approximately 20% of peptide-treated subjects developed late-onset symptoms after the first peptide administration, but the prevalence of these reactions decreased as dosing continued, indicating the induction of immunologic tolerance.The incidence of late adverse events was related to both peptide dose and the severity of disease in the study group. Subjects with asthma appeared more likely to develop late-onset symptoms and particularly at higher peptide doses.2Norman P.S. Ohman J.L. Long A.A. Creticos P.S. Gefter M.A. Shaked Z. et al.Treatment of cat allergy with T-cell reactive peptides.Am J Respir Crit Care Med. 1996; 154: 1623-1628Crossref PubMed Scopus (351) Google Scholar, 6Maguire P. Nicodemus C. Robinson D. Aaronson D. Umetsu D.T. The safety and efficacy of ALLERVAX CAT in cat allergic patients.Clin Immunol. 1999; 93: 222-231Crossref PubMed Scopus (123) Google Scholar A weak relationship was also established between levels of allergen-specific serum IgE and the propensity to develop late reactions.6Maguire P. Nicodemus C. Robinson D. Aaronson D. Umetsu D.T. The safety and efficacy of ALLERVAX CAT in cat allergic patients.Clin Immunol. 1999; 93: 222-231Crossref PubMed Scopus (123) Google Scholar Some subjects developed de novo IgE specific for the treatment peptides, and this was associated in some cases with acute adverse events.6Maguire P. Nicodemus C. Robinson D. Aaronson D. Umetsu D.T. The safety and efficacy of ALLERVAX CAT in cat allergic patients.Clin Immunol. 1999; 93: 222-231Crossref PubMed Scopus (123) Google ScholarThus, early clinical experience established that peptide immunotherapy could modify immunologic markers, clinical surrogates, and subjective clinical outcomes in some studies. The development of peptide-specific IgE and the association of late adverse events with peptide dose and disease severity indicated that improved safety and tolerability may be achieved by using smaller peptides with reduced ability to elicit and interact with IgE (the Allervax Cat peptides were 27 amino acids in length, whereas an average CD4 T-cell epitope would be approximately 14 amino acids). Furthermore, evaluation of lower peptide doses in subjects with less severe disease was indicated.A number of clinical studies have been performed more recently by using mixtures of shorter peptides from Fel d 1.3Haselden B.M. Kay A.B. Larche M. Immunoglobulin E-independent major histocompatibility complex-restricted T cell peptide epitope-induced late asthmatic reactions.J Exp Med. 1999; 189: 1885-1894Crossref PubMed Scopus (311) Google Scholar, 7Oldfield W.L. Kay A.B. Larche M. Allergen-derived T cell peptide-induced late asthmatic reactions precede the induction of antigen-specific hyporesponsiveness in atopic allergic asthmatic subjects.J Immunol. 2001; 167: 1734-1739PubMed Google Scholar, 8Oldfield W.L. Larche M. Kay A.B. Effect of T-cell peptides derived from Fel d 1 on allergic reactions and cytokine production in patients sensitive to cats: a randomised controlled trial.Lancet. 2002; 360: 47-53Abstract Full Text Full Text PDF PubMed Scopus (340) Google Scholar, 9Alexander C. Ying S. Kay B. Larche M. Fel d 1-derived T cell peptide therapy induces recruitment of CD4CD25; CD4 interferon-gamma T helper type 1 cells to sites of allergen-induced late-phase skin reactions in cat-allergic subjects.Clin Exp Allergy. 2005; 35: 52-58Crossref PubMed Scopus (102) Google Scholar, 10Smith T.R. Alexander C. Kay A.B. Larche M. Robinson D.S. Cat allergen peptide immunotherapy reduces CD4 T cell responses to cat allergen but does not alter suppression by CD4 CD25 T cells: a double-blind placebo-controlled study.Allergy. 2004; 59: 1097-1101Crossref PubMed Scopus (66) Google Scholar, 11Alexander C. Tarzi M. Larche M. Kay A.B. The effect of Fel d 1-derived T-cell peptides on upper and lower airway outcome measurements in cat-allergic subjects.Allergy. 2005; 60: 1269-1274Crossref PubMed Scopus (110) Google Scholar, 12Verhoef A. Alexander C. Kay A.B. Larche M. T cell epitope immunotherapy induces a CD4(+) T cell population with regulatory activity.PLoS Med. 2005; 2: e78Crossref PubMed Scopus (144) Google Scholar Peptides were administered intradermally to subjects with cat-allergic asthma. Dose-dependent induction of isolated late asthmatic reactions was observed after a single injection of a mixture of 12 peptides, but this was associated with subsequent tolerance to further challenge that lasted several months. Indeed, peptide injection, whether associated with the induction of late reactions or not, resulted in significantly reduced cutaneous late-phase reaction to intradermal allergen challenge. Furthermore, evaluation of PBMC responses to allergen in vitro demonstrated reductions in both TH2 cytokines and IFN-γ.7Oldfield W.L. Kay A.B. Larche M. Allergen-derived T cell peptide-induced late asthmatic reactions precede the induction of antigen-specific hyporesponsiveness in atopic allergic asthmatic subjects.J Immunol. 2001; 167: 1734-1739PubMed Google ScholarThe same 12-peptide mixture was subsequently administered in divided, incremental doses over a 2-week period in a double-blind, placebo-controlled study. Twenty-four subjects with cat-allergic asthma were subjected to cutaneous allergen challenge, inhaled methacholine PC20, and inhaled allergen PD20.8Oldfield W.L. Larche M. Kay A.B. Effect of T-cell peptides derived from Fel d 1 on allergic reactions and cytokine production in patients sensitive to cats: a randomised controlled trial.Lancet. 2002; 360: 47-53Abstract Full Text Full Text PDF PubMed Scopus (340) Google Scholar A total of 90 μg of each peptide was administered. Treatment was associated with a significant reduction in both early and late-phase cutaneous reactions to intradermal challenge with allergen compared with placebo. Reduced allergen-specific proliferative responses and TH1 and TH2 cytokine production were observed in the active treatment group. Production of IL-10 from PBMCs increased. On the basis of visual analogue evaluation, treated individuals were significantly less sensitive to cat exposure after therapy, although perhaps because of small numbers, this did not achieve significance compared with the placebo group. No improvement in PD20 or PC20 was observed.In a related (open) study, a significant improvement in PC20 was observed with a lower dose regimen (total dose, 41.1 μg) with 2-week dose intervals.9Alexander C. Ying S. Kay B. Larche M. Fel d 1-derived T cell peptide therapy induces recruitment of CD4CD25; CD4 interferon-gamma T helper type 1 cells to sites of allergen-induced late-phase skin reactions in cat-allergic subjects.Clin Exp Allergy. 2005; 35: 52-58Crossref PubMed Scopus (102) Google Scholar The magnitude of the cutaneous late-phase reaction was significantly reduced after allergen challenge, confirming previous findings. Treatment was associated with an accumulation of both CD25+ cells and CD4+/IFN-γ+ cells in allergen challenge skin sites compared with placebo challenge. Expression of TGF-β mRNA but not IL-10 was increased after therapy.In an attempt to determine optimal dosing regimens, 2 overlapping studies evaluated higher peptide doses (approximately 300 μg of each of 12 peptides from Fel d 1).11Alexander C. Tarzi M. Larche M. Kay A.B. The effect of Fel d 1-derived T-cell peptides on upper and lower airway outcome measurements in cat-allergic subjects.Allergy. 2005; 60: 1269-1274Crossref PubMed Scopus (110) Google Scholar Subjects with cat-allergic asthma were screened by inhaled incremental allergen challenge to establish whether they developed a single early asthmatic response or a dual early and late asthmatic response. Subjects with dual responses were recruited into a small double-blind, placebo-controlled (n = 16; 8 active, 8 placebo) study, whereas those displaying single early responses (n = 12) were recruited into an open study. Both groups received intradermal peptide injections in an incremental fashion (1 to 100 μg per injection). In common with earlier studies, the magnitude of the cutaneous late-phase reaction to intradermal challenge with allergen extract was significantly attenuated. Similarly, the late asthmatic reaction after allergen inhalational challenge was also attenuated (in the group who experienced late-phase responses). In the open study, there was a significant reduction in outcome scores (sneezing, weight of nasal secretions, and nasal blockage) after nasal allergen challenge, together with significant improvements in some rhinitis quality of life questionnaire fields. No change was observed in allergen PD20 or histamine PC20.Studies evaluating the ability of peptide treatment to modulate regulatory T-cell function have shown no change in the function of blood CD4+CD25+ regulatory T cells10Smith T.R. Alexander C. Kay A.B. Larche M. Robinson D.S. Cat allergen peptide immunotherapy reduces CD4 T cell responses to cat allergen but does not alter suppression by CD4 CD25 T cells: a double-blind placebo-controlled study.Allergy. 2004; 59: 1097-1101Crossref PubMed Scopus (66) Google Scholar but revealed the induction of a population of adaptive, allergen-specific CD4+ T cells with functional regulatory capacity.12Verhoef A. Alexander C. Kay A.B. Larche M. T cell epitope immunotherapy induces a CD4(+) T cell population with regulatory activity.PLoS Med. 2005; 2: e78Crossref PubMed Scopus (144) Google ScholarBee venom allergyThree studies of immunotherapy with peptides derived from the major allergen Api m 1 (phospholipase A2) have been reported. In an open study, 5 subjects with bee venom allergy received divided incremental doses of a mixture of 3 peptides at weekly intervals.13Müller U. Akdis C.A. Fricker M. Akdis M. Blesken T. Bettens F. et al.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: 747-754Abstract Full Text Full Text PDF PubMed Scopus (383) Google Scholar Patients received 397.1 μg of each of 3 peptides subcutaneously. Patients receiving conventional bee venom immunotherapy were used as controls. After treatment, subcutaneous allergen challenge was tolerated without systemic allergic symptoms. Three of 5 subjects also tolerated a wild bee sting challenge without reaction. The remaining 2 subjects developed mild systemic allergic reactions. Allergen challenge was associated with a marked increase in serum levels of allergen-specific serum IgG4.After encouraging results in a murine model of bee venom sensitivity, subjects with bee venom allergy were treated with 3 synthetic polypeptides (long synthetic peptides ranging in length from 45 to 60 residues) covering the whole Api m 1 molecule according to a RUSH protocol.14Fellrath J.M. Kettner A. Dufour N. Frigerio C. Schneeberger D. Leimgruber A. et al.Allergen-specific T-cell tolerance induction with allergen-derived long synthetic peptides: results of a phase I trial.J Allergy Clin Immunol. 2003; 111: 854-861Abstract Full Text Full Text PDF PubMed Scopus (140) Google Scholar Subjects initially received approximately 250 μg in incremental divided doses at 30 minute intervals. As many as 5 maintenance injections were subsequently given with total doses reaching approximately 750 to 1150 μg. Some mild adverse events were reported. IFN-γ, IL-10, and allergen-specific IgG4 levels increased. Peptide-specific IgE was induced in some patients. In contrast with studies using shorter peptides, no significant change in skin sensitivity to intradermal allergen challenge was observed.Most recently, four 18–amino acid peptides with high affinity for commonly expressed MHC class II molecules were administered to individuals with bee venom allergy with mild disease in a controlled, open-label, single-blind study.15Tarzi M. Klunker S. Texier C. Verhoef A. Stapel S.O. Akdis C.A. et al.Induction of interleukin-10 and suppressor of cytokine signalling-3 gene expression following peptide immunotherapy.Clin Exp Allergy. 2006; 36: 465-474Crossref PubMed Scopus (123) Google Scholar A total dose of 431.1 μg of each of the 4 peptides was administered to 12 individuals, with untreated subjects matched for disease severity acting as controls. No adverse events were observed. In common with studies using cat allergen peptides, treatment with bee venom peptides was associated with reduced PBMC proliferative and TH1/TH2 cytokine responses. A concomitant increase in IL-10 production was observed. Late-phase skin reactions to allergen were significantly reduced. A transient but significant increase in allergen-specific IgG4 and IgG was also observed.In summary, translation of peptide immunotherapy from encouraging murine models and early human studies continues. Optimal dose schedules have yet to be established, but early indications are that unlike whole allergen immunotherapy, higher doses may not always be more effective (Fig 1). Subjects with more severe disease may experience treatment-related adverse events at higher peptide doses. Low doses that do not elicit adverse events are able to induce immunologic tolerance and to modify surrogate clinical markers. Adverse events appear to be related to residual IgE reactivity in larger peptides and to activation of allergen-specific effector T cells at high peptide doses. Therapeutic effects appear to be associated with the induction of allergen-specific regulatory T cells and can be achieved at doses low enough to avoid adverse events. Further studies are required to define optimal dose, dose interval, and route of administration. Strategies to improve the safety of allergen immunotherapy have traditionally focused on reducing the allergenicity of the preparation administered to the patient. The use of peptide fragments, corresponding to T-cell epitopes, to induce immunologic tolerance has been reported in experimental models of both allergic and autoimmune disease.1Larche M. Peptide therapy for allergic diseases: basic mechanisms and new clinical approaches.Pharmacol Ther. 2005; 108: 353-361Crossref PubMed Scopus (24) Google Scholar By virtue of their size and relative lack of secondary and tertiary structure, peptides display reduced ability to cross-link allergen-specific IgE and activate IgE receptor–bearing cells. However, retention of T-cell epitopes allows targeting of allergen-specific T cells for the induction of tolerance. Translation of this approach to the clinic is ongoing, with a number of small clinical studies having been performed over the last decade. At present, 3 allergens have been targeted with this approach (Table I): the cat allergen Fel d 1, the bee venom allergen Api m 1 (phospholipase A2), and the ragweed allergen Amb a 1 (clinical studies of the last have not been reported). Considerable objective evidence has accumulated demonstrating modulation of allergen-specific immune responses after peptide immunotherapy. Evidence supporting clinical benefit has been slower to accumulate, and definitive studies demonstrating reduced symptom scores and medication use combined with improvements in tolerability are still required. Modified with permission from Larché M. Peptide immunotherapy for allergic diseases. Allergy 2007;62:325-31. The earliest clinical studies employed a combination of 2 peptides (Allervax Cat, ImmuLogic Corp., Waltham, Mass) from Fel d 1, administered subcutaneously in a variety of dosing regimens. In the first of these to be reported, peptides were administered at weekly intervals and in 3 dose cohorts (7.5 μg, 75 μg, and 750 μg).2Norman P.S. Ohman J.L. Long A.A. Creticos P.S. Gefter M.A. Shaked Z. et al.Treatment of cat allergy with T-cell reactive peptides.Am J Respir Crit Care Med. 1996; 154: 1623-1628Crossref PubMed Scopus (351) Google Scholar After allergen exposure in a cat room, lung and nasal symptom scores were significantly improved in the higher dose cohorts. Despite the use of peptides that had been screened for reduced activity in basophil histamine release assays, numerous adverse events were documented occurring minutes to hours after peptide administration. Some adverse events may have been a result of the relatively long peptides used that may have harbored residual IgE reactivity; however, the majority of events probably occurred as a result of activation of allergen-specific effector T cells resulting in late asthmatic reactions.3Haselden B.M. Kay A.B. Larche M. Immunoglobulin E-independent major histocompatibility complex-restricted T cell peptide epitope-induced late asthmatic reactions.J Exp Med. 1999; 189: 1885-1894Crossref PubMed Scopus (311) Google Scholar The same peptides were evaluated in inhaled allergen challenge studies. A significant increase in PD20 was observed within cohorts receiving higher dose (total dose between 150 μg and 4500 μg) regimens, but this failed to achieve statistical significance when compared with placebo.4Pène J. Desroches A. Paradis L. Lebel B. Farce M. Nicodemus C.F. et al.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: 571-578Abstract Full Text Full Text PDF PubMed Scopus (128) Google Scholar In a double-blind, placebo-controlled parallel group study, peptides or placebo were administered by weekly subcutaneous injection (4 × 250 μg) to 42 subjects with cat-allergic rhinitis and/or asthma.5Simons F.E. Imada M. Li Y. Watson W.T. HayGlass K.T. Fel d 1 peptides: effect on skin tests and cytokine synthesis in cat-allergic human subjects.Int Immunol. 1996; 8: 1937-1945Crossref PubMed Scopus (122) Google Scholar Treatment was associated with adverse events, primarily late-onset symptoms of rhinitis, asthma, and pruritus. No significant changes were observed in the primary outcome measure (change in wheal and flare reaction) or in late-phase skin responses to allergen challenge. PBMC cytokine secretion profiles did not differ between peptide-treated and placebo-treated subjects. Treatment with Allervax Cat was also associated with a significant clinical improvement in pulmonary function (FEV1) in individuals with reduced baseline FEV1.6Maguire P. Nicodemus C. Robinson D. Aaronson D. Umetsu D.T. The safety and efficacy of ALLERVAX CAT in cat allergic patients.Clin Immunol. 1999; 93: 222-231Crossref PubMed Scopus (123) Google Scholar Furthermore, a significant improvement in the subjective ability to tolerate cats was also observed through a visual analogue evaluation. Importantly, subjects recruited to this study had moderate to severe disease, with many demonstrating high IgE levels. Approximately 30% had failed previous whole allergen immunotherapy, and more than 40% of the group had asthma. Adverse events were common and consisted of occasional IgE-mediated acute reactions and more frequent late-onset symptoms of asthma. Approximately 20% of peptide-treated subjects developed late-onset symptoms after the first peptide administration, but the prevalence of these reactions decreased as dosing continued, indicating the induction of immunologic tolerance. The incidence of late adverse events was related to both peptide dose and the severity of disease in the study group. Subjects with asthma appeared more likely to develop late-onset symptoms and particularly at higher peptide doses.2Norman P.S. Ohman J.L. Long A.A. Creticos P.S. Gefter M.A. Shaked Z. et al.Treatment of cat allergy with T-cell reactive peptides.Am J Respir Crit Care Med. 1996; 154: 1623-1628Crossref PubMed Scopus (351) Google Scholar, 6Maguire P. Nicodemus C. Robinson D. Aaronson D. Umetsu D.T. The safety and efficacy of ALLERVAX CAT in cat allergic patients.Clin Immunol. 1999; 93: 222-231Crossref PubMed Scopus (123) Google Scholar A weak relationship was also established between levels of allergen-specific serum IgE and the propensity to develop late reactions.6Maguire P. Nicodemus C. Robinson D. Aaronson D. Umetsu D.T. The safety and efficacy of ALLERVAX CAT in cat allergic patients.Clin Immunol. 1999; 93: 222-231Crossref PubMed Scopus (123) Google Scholar Some subjects developed de novo IgE specific for the treatment peptides, and this was associated in some cases with acute adverse events.6Maguire P. Nicodemus C. Robinson D. Aaronson D. Umetsu D.T. The safety and efficacy of ALLERVAX CAT in cat allergic patients.Clin Immunol. 1999; 93: 222-231Crossref PubMed Scopus (123) Google Scholar Thus, early clinical experience established that peptide immunotherapy could modify immunologic markers, clinical surrogates, and subjective clinical outcomes in some studies. The development of peptide-specific IgE and the association of late adverse events with peptide dose and disease severity indicated that improved safety and tolerability may be achieved by using smaller peptides with reduced ability to elicit and interact with IgE (the Allervax Cat peptides were 27 amino acids in length, whereas an average CD4 T-cell epitope would be approximately 14 amino acids). Furthermore, evaluation of lower peptide doses in subjects with less severe disease was indicated. A number of clinical studies have been performed more recently by using mixtures of shorter peptides from Fel d 1.3Haselden B.M. Kay A.B. Larche M. Immunoglobulin E-independent major histocompatibility complex-restricted T cell peptide epitope-induced late asthmatic reactions.J Exp Med. 1999; 189: 1885-1894Crossref PubMed Scopus (311) Google Scholar, 7Oldfield W.L. Kay A.B. Larche M. Allergen-derived T cell peptide-induced late asthmatic reactions precede the induction of antigen-specific hyporesponsiveness in atopic allergic asthmatic subjects.J Immunol. 2001; 167: 1734-1739PubMed Google Scholar, 8Oldfield W.L. Larche M. Kay A.B. Effect of T-cell peptides derived from Fel d 1 on allergic reactions and cytokine production in patients sensitive to cats: a randomised controlled trial.Lancet. 2002; 360: 47-53Abstract Full Text Full Text PDF PubMed Scopus (340) Google Scholar, 9Alexander C. Ying S. Kay B. Larche M. Fel d 1-derived T cell peptide therapy induces recruitment of CD4CD25; CD4 interferon-gamma T helper type 1 cells to sites of allergen-induced late-phase skin reactions in cat-allergic subjects.Clin Exp Allergy. 2005; 35: 52-58Crossref PubMed Scopus (102) Google Scholar, 10Smith T.R. Alexander C. Kay A.B. Larche M. Robinson D.S. Cat allergen peptide immunotherapy reduces CD4 T cell responses to cat allergen but does not alter suppression by CD4 CD25 T cells: a double-blind placebo-controlled study.Allergy. 2004; 59: 1097-1101Crossref PubMed Scopus (66) Google Scholar, 11Alexander C. Tarzi M. Larche M. Kay A.B. The effect of Fel d 1-derived T-cell peptides on upper and lower airway outcome measurements in cat-allergic subjects.Allergy. 2005; 60: 1269-1274Crossref PubMed Scopus (110) Google Scholar, 12Verhoef A. Alexander C. Kay A.B. Larche M. T cell epitope immunotherapy induces a CD4(+) T cell population with regulatory activity.PLoS Med. 2005; 2: e78Crossref PubMed Scopus (144) Google Scholar Peptides were administered intradermally to subjects with cat-allergic asthma. Dose-dependent induction of isolated late asthmatic reactions was observed after a single injection of a mixture of 12 peptides, but this was associated with subsequent tolerance to further challenge that lasted several months. Indeed, peptide injection, whether associated with the induction of late reactions or not, resulted in significantly reduced cutaneous late-phase reaction to intradermal allergen challenge. Furthermore, evaluation of PBMC responses to allergen in vitro demonstrated reductions in both TH2 cytokines and IFN-γ.7Oldfield W.L. Kay A.B. Larche M. Allergen-derived T cell peptide-induced late asthmatic reactions precede the induction of antigen-specific hyporesponsiveness in atopic allergic asthmatic subjects.J Immunol. 2001; 167: 1734-1739PubMed Google Scholar The same 12-peptide mixture was subsequently administered in divided, incremental doses over a 2-week period in a double-blind, placebo-controlled study. Twenty-four subjects with cat-allergic asthma were subjected to cutaneous allergen challenge, inhaled methacholine PC20, and inhaled allergen PD20.8Oldfield W.L. Larche M. Kay A.B. Effect of T-cell peptides derived from Fel d 1 on allergic reactions and cytokine production in patients sensitive to cats: a randomised controlled trial.Lancet. 2002; 360: 47-53Abstract Full Text Full Text PDF PubMed Scopus (340) Google Scholar A total of 90 μg of each peptide was administered. Treatment was associated with a significant reduction in both early and late-phase cutaneous reactions to intradermal challenge with allergen compared with placebo. Reduced allergen-specific proliferative responses and TH1 and TH2 cytokine production were observed in the active treatment group. Production of IL-10 from PBMCs increased. On the basis of visual analogue evaluation, treated individuals were significantly less sensitive to cat exposure after therapy, although perhaps because of small numbers, this did not achieve significance compared with the placebo group. No improvement in PD20 or PC20 was observed. In a related (open) study, a significant improvement in PC20 was observed with a lower dose regimen (total dose, 41.1 μg) with 2-week dose intervals.9Alexander C. Ying S. Kay B. Larche M. Fel d 1-derived T cell peptide therapy induces recruitment of CD4CD25; CD4 interferon-gamma T helper type 1 cells to sites of allergen-induced late-phase skin reactions in cat-allergic subjects.Clin Exp Allergy. 2005; 35: 52-58Crossref PubMed Scopus (102) Google Scholar The magnitude of the cutaneous late-phase reaction was significantly reduced after allergen challenge, confirming previous findings. Treatment was associated with an accumulation of both CD25+ cells and CD4+/IFN-γ+ cells in allergen challenge skin sites compared with placebo challenge. Expression of TGF-β mRNA but not IL-10 was increased after therapy. In an attempt to determine optimal dosing regimens, 2 overlapping studies evaluated higher peptide doses (approximately 300 μg of each of 12 peptides from Fel d 1).11Alexander C. Tarzi M. Larche M. Kay A.B. The effect of Fel d 1-derived T-cell peptides on upper and lower airway outcome measurements in cat-allergic subjects.Allergy. 2005; 60: 1269-1274Crossref PubMed Scopus (110) Google Scholar Subjects with cat-allergic asthma were screened by inhaled incremental allergen challenge to establish whether they developed a single early asthmatic response or a dual early and late asthmatic response. Subjects with dual responses were recruited into a small double-blind, placebo-controlled (n = 16; 8 active, 8 placebo) study, whereas those displaying single early responses (n = 12) were recruited into an open study. Both groups received intradermal peptide injections in an incremental fashion (1 to 100 μg per injection). In common with earlier studies, the magnitude of the cutaneous late-phase reaction to intradermal challenge with allergen extract was significantly attenuated. Similarly, the late asthmatic reaction after allergen inhalational challenge was also attenuated (in the group who experienced late-phase responses). In the open study, there was a significant reduction in outcome scores (sneezing, weight of nasal secretions, and nasal blockage) after nasal allergen challenge, together with significant improvements in some rhinitis quality of life questionnaire fields. No change was observed in allergen PD20 or histamine PC20. Studies evaluating the ability of peptide treatment to modulate regulatory T-cell function have shown no change in the function of blood CD4+CD25+ regulatory T cells10Smith T.R. Alexander C. Kay A.B. Larche M. Robinson D.S. Cat allergen peptide immunotherapy reduces CD4 T cell responses to cat allergen but does not alter suppression by CD4 CD25 T cells: a double-blind placebo-controlled study.Allergy. 2004; 59: 1097-1101Crossref PubMed Scopus (66) Google Scholar but revealed the induction of a population of adaptive, allergen-specific CD4+ T cells with functional regulatory capacity.12Verhoef A. Alexander C. Kay A.B. Larche M. T cell epitope immunotherapy induces a CD4(+) T cell population with regulatory activity.PLoS Med. 2005; 2: e78Crossref PubMed Scopus (144) Google Scholar Bee venom allergyThree studies of immunotherapy with peptides derived from the major allergen Api m 1 (phospholipase A2) have been reported. In an open study, 5 subjects with bee venom allergy received divided incremental doses of a mixture of 3 peptides at weekly intervals.13Müller U. Akdis C.A. Fricker M. Akdis M. Blesken T. Bettens F. et al.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: 747-754Abstract Full Text Full Text PDF PubMed Scopus (383) Google Scholar Patients received 397.1 μg of each of 3 peptides subcutaneously. Patients receiving conventional bee venom immunotherapy were used as controls. After treatment, subcutaneous allergen challenge was tolerated without systemic allergic symptoms. Three of 5 subjects also tolerated a wild bee sting challenge without reaction. The remaining 2 subjects developed mild systemic allergic reactions. Allergen challenge was associated with a marked increase in serum levels of allergen-specific serum IgG4.After encouraging results in a murine model of bee venom sensitivity, subjects with bee venom allergy were treated with 3 synthetic polypeptides (long synthetic peptides ranging in length from 45 to 60 residues) covering the whole Api m 1 molecule according to a RUSH protocol.14Fellrath J.M. Kettner A. Dufour N. Frigerio C. Schneeberger D. Leimgruber A. et al.Allergen-specific T-cell tolerance induction with allergen-derived long synthetic peptides: results of a phase I trial.J Allergy Clin Immunol. 2003; 111: 854-861Abstract Full Text Full Text PDF PubMed Scopus (140) Google Scholar Subjects initially received approximately 250 μg in incremental divided doses at 30 minute intervals. As many as 5 maintenance injections were subsequently given with total doses reaching approximately 750 to 1150 μg. Some mild adverse events were reported. IFN-γ, IL-10, and allergen-specific IgG4 levels increased. Peptide-specific IgE was induced in some patients. In contrast with studies using shorter peptides, no significant change in skin sensitivity to intradermal allergen challenge was observed.Most recently, four 18–amino acid peptides with high affinity for commonly expressed MHC class II molecules were administered to individuals with bee venom allergy with mild disease in a controlled, open-label, single-blind study.15Tarzi M. Klunker S. Texier C. Verhoef A. Stapel S.O. Akdis C.A. et al.Induction of interleukin-10 and suppressor of cytokine signalling-3 gene expression following peptide immunotherapy.Clin Exp Allergy. 2006; 36: 465-474Crossref PubMed Scopus (123) Google Scholar A total dose of 431.1 μg of each of the 4 peptides was administered to 12 individuals, with untreated subjects matched for disease severity acting as controls. No adverse events were observed. In common with studies using cat allergen peptides, treatment with bee venom peptides was associated with reduced PBMC proliferative and TH1/TH2 cytokine responses. A concomitant increase in IL-10 production was observed. Late-phase skin reactions to allergen were significantly reduced. A transient but significant increase in allergen-specific IgG4 and IgG was also observed.In summary, translation of peptide immunotherapy from encouraging murine models and early human studies continues. Optimal dose schedules have yet to be established, but early indications are that unlike whole allergen immunotherapy, higher doses may not always be more effective (Fig 1). Subjects with more severe disease may experience treatment-related adverse events at higher peptide doses. Low doses that do not elicit adverse events are able to induce immunologic tolerance and to modify surrogate clinical markers. Adverse events appear to be related to residual IgE reactivity in larger peptides and to activation of allergen-specific effector T cells at high peptide doses. Therapeutic effects appear to be associated with the induction of allergen-specific regulatory T cells and can be achieved at doses low enough to avoid adverse events. Further studies are required to define optimal dose, dose interval, and route of administration. Three studies of immunotherapy with peptides derived from the major allergen Api m 1 (phospholipase A2) have been reported. In an open study, 5 subjects with bee venom allergy received divided incremental doses of a mixture of 3 peptides at weekly intervals.13Müller U. Akdis C.A. Fricker M. Akdis M. Blesken T. Bettens F. et al.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: 747-754Abstract Full Text Full Text PDF PubMed Scopus (383) Google Scholar Patients received 397.1 μg of each of 3 peptides subcutaneously. Patients receiving conventional bee venom immunotherapy were used as controls. After treatment, subcutaneous allergen challenge was tolerated without systemic allergic symptoms. Three of 5 subjects also tolerated a wild bee sting challenge without reaction. The remaining 2 subjects developed mild systemic allergic reactions. Allergen challenge was associated with a marked increase in serum levels of allergen-specific serum IgG4. After encouraging results in a murine model of bee venom sensitivity, subjects with bee venom allergy were treated with 3 synthetic polypeptides (long synthetic peptides ranging in length from 45 to 60 residues) covering the whole Api m 1 molecule according to a RUSH protocol.14Fellrath J.M. Kettner A. Dufour N. Frigerio C. Schneeberger D. Leimgruber A. et al.Allergen-specific T-cell tolerance induction with allergen-derived long synthetic peptides: results of a phase I trial.J Allergy Clin Immunol. 2003; 111: 854-861Abstract Full Text Full Text PDF PubMed Scopus (140) Google Scholar Subjects initially received approximately 250 μg in incremental divided doses at 30 minute intervals. As many as 5 maintenance injections were subsequently given with total doses reaching approximately 750 to 1150 μg. Some mild adverse events were reported. IFN-γ, IL-10, and allergen-specific IgG4 levels increased. Peptide-specific IgE was induced in some patients. In contrast with studies using shorter peptides, no significant change in skin sensitivity to intradermal allergen challenge was observed. Most recently, four 18–amino acid peptides with high affinity for commonly expressed MHC class II molecules were administered to individuals with bee venom allergy with mild disease in a controlled, open-label, single-blind study.15Tarzi M. Klunker S. Texier C. Verhoef A. Stapel S.O. Akdis C.A. et al.Induction of interleukin-10 and suppressor of cytokine signalling-3 gene expression following peptide immunotherapy.Clin Exp Allergy. 2006; 36: 465-474Crossref PubMed Scopus (123) Google Scholar A total dose of 431.1 μg of each of the 4 peptides was administered to 12 individuals, with untreated subjects matched for disease severity acting as controls. No adverse events were observed. In common with studies using cat allergen peptides, treatment with bee venom peptides was associated with reduced PBMC proliferative and TH1/TH2 cytokine responses. A concomitant increase in IL-10 production was observed. Late-phase skin reactions to allergen were significantly reduced. A transient but significant increase in allergen-specific IgG4 and IgG was also observed. In summary, translation of peptide immunotherapy from encouraging murine models and early human studies continues. Optimal dose schedules have yet to be established, but early indications are that unlike whole allergen immunotherapy, higher doses may not always be more effective (Fig 1). Subjects with more severe disease may experience treatment-related adverse events at higher peptide doses. Low doses that do not elicit adverse events are able to induce immunologic tolerance and to modify surrogate clinical markers. Adverse events appear to be related to residual IgE reactivity in larger peptides and to activation of allergen-specific effector T cells at high peptide doses. Therapeutic effects appear to be associated with the induction of allergen-specific regulatory T cells and can be achieved at doses low enough to avoid adverse events. Further studies are required to define optimal dose, dose interval, and route of administration.