Subcutaneous allergen immunotherapy for allergic disease: Examining efficacy, safety and cost-effectiveness of current and novel formulations

Immunotherapy

Volumn 4, Issue 6, 2012, Pages 601-616

  Cox, Linda ^a   Calderón, Moisés ^b   Pfaar, Oliver ^c  

^a UNIVERSITY OF NORTH FLORIDA   (United States)

^b NATIONAL HEART AND LUNG INSTITUTE   (United Kingdom)

^c Center for Rhinology and Allergology   (Germany)

Author keywords

specific allergen immunotherapy; subcutaneous immunotherapy; sublingual immunotherapy

Indexed keywords

ACETYLCHOLINE; ALLERGEN; HISTAMINE; HOUSE DUST ALLERGEN; HYMENOPTERA VENOM; LATEX; MELACINE; METHACHOLINE; PLACEBO; POLLEN ANTIGEN; POLLINEX; RAGWEED ANTIGEN; TOLAMBA; UNCLASSIFIED DRUG; WART VIRUS VACCINE;

ALLERGIC ASTHMA; ALLERGIC RHINITIS; ALLERGY; ANGIONEUROTIC EDEMA; ATOPIC DERMATITIS; CLINICAL RESEARCH; COST EFFECTIVENESS ANALYSIS; DANDER; DRUG EFFICACY; DRUG FORMULATION; DRUG SAFETY; HUMAN; NONHUMAN; ORAL ALLERGY SYNDROME; PRIORITY JOURNAL; REVIEW; RHINITIS; SUBCUTANEOUS IMMUNOTHERAPY; UNSPECIFIED SIDE EFFECT; URTICARIA;

ALLERGENS; ANIMALS; CLINICAL TRIALS AS TOPIC; COST-BENEFIT ANALYSIS; DESENSITIZATION, IMMUNOLOGIC; HUMANS; HYPERSENSITIVITY; INJECTIONS, SUBCUTANEOUS;

EID: 84863970198     PISSN: 1750743X     EISSN: 17507448     Source Type: Journal    
DOI: 10.2217/imt.12.36     Document Type: Review

References (107)

1. Freeman J. Further observations of the treatment of hay fever by hypodermic inoculations of pollen vaccine. Lancet 2, 814-817 (1911
2. Freeman J. Vaccination against hay fever: Report of results during the last three years. Lancet 183(4730), 1178-1180 (1914
3. Noon L. Prophylactic inoculation against hay fever. Lancet 1, 1572-1573 (1911
4. Ancestors of Allergy. Simons FER (Ed.). Global Medical Communications Ltd, New York, USA (1994
5. Jacobsen L. Primary and secondary endpoints in clinical trials. Arb. Paul Ehrlich Inst. Bundesamt Sera Impfstoffe Frankf. AM 96, 96-104; discussion 104-105 (2009
6. Pfaar O, Kleine-Tebbe J, Hörmann K, Klimek L. Allergen-Specific immunotherapy: Which outcome measures are useful in monitoring clinical trials? Immunol. Allergy Clin. North Am. 31(2), 289-309 (2011
7. Canonica GW, Baena-Cagnani CE, Bousquet J et al. Recommendations for standardization of clinical trials with allergen specific immunotherapy for respiratory allergy. A statement of a World Allergy Organization (WAO) Taskforce. Allergy 62(3), 317-324 (2007
8. Pfaar O, Anders C, Klimek L. Clinical outcome measures of specific immunotherapy. Curr. Opin Allergy Clin. Immunol. 9(3), 208-213 (2009
9. Clark J, Schall R. Assessment of combined symptom and medication scores for rhinoconjunctivitis immunotherapy clinical trials. Allergy 62(9), 1023-1028 (2007
10. Grouin JM, Vicaut E, Jean-Alphonse S et al. The average Adjusted Symptom Score, a new primary efficacy end-point for specific allergen immunotherapy trials. Clin. Exp. Allergy 41(9), 1282-1288 (2011
11. Häfner D, Reich K, Matricardi PM, Meyer H, Kettner J, Narkus A. Prospective validation of 'Allergy-Control-SCORE(TM)': A novel symptom-medication score for clinical trials. Allergy 66(5), 629-636 (2011
12. Juniper EF, Guyatt GH. Development and testing of a new measure of health status for clinical trials in rhinoconjunctivitis. Clin. Exp. Allergy 21(1), 77-83 (1991
13. Calderón MA, Casale TB, Togias A, Bousquet J, Durham SR, Demoly P. Allergen-Specific immunotherapy for respiratory allergies: FROM meta-Analysis to registration and beyond. J. Allergy Clin. Immunol. 127(1), 30-38 (2011
14. Calderón MA, Boyle RJ, Penagos M, Sheikh A. Immunotherapy: The meta-Analyses. What have we learned? Immunol. Allergy Clin. North Am. 31(2), 159-173, vii (2011
15. Cox L. Allergen immunotherapy and asthma: Efficacy, safety, and other considerations. Allergy Asthma Proc. 29(6), 580-589 (2008
16. Klimek L, Malling HJ. Specific immunotherapy (hyposensitization) in allergic rhinoconjunctivitis. Meta-Analysis of effectiveness and side effects. HNO 47(7), 602-610 (1999
17. Ross RN, Nelson HS, Finegold I. Effectiveness of specific immunotherapy in the treatment of allergic rhinitis: AN analysis of randomized, prospective, single- or double-Blind, placebo-Controlled studies. Clin. Ther. 22(3), 342-350 (2000
18. Calderón MA, Alves B, Jacobson M, Hurwitz B, Sheikh A, Durham S. Allergen injection immunotherapy for seasonal allergic rhinitis. Cochrane Database Syst. Rev. 1, CD001936 (2007
19. Abramson MJ, Puy RM, Weiner JM. Is allergen immunotherapy effective in asthma? A meta-Analysis of randomized controlled trials. Am. J. Respir. Crit. Care Med. 151(4), 969-974 (1995
20. Abramson MJ, Puy RM, Weiner JM. Allergen immunotherapy for asthma. Cochrane Database Syst. Rev. 4, CD001186 (2003
21. Abramson MJ, Puy RM, Weiner JM. Injection allergen immunotherapy for asthma. Cochrane Database Syst. Rev. 8, CD001186 (2010
22. Ross RN, Nelson HS, Finegold I. Effectiveness of specific immunotherapy in the treatment of asthma: A meta-Analysis of prospective, randomized, double-Blind, placebo-Controlled studies. Clin. Ther. 22(3), 329-341 (2000
23. Golden DB, Moffitt J, Nicklas RA et al. Stinging insect hypersensitivity: A practice parameter update 2011. J. Allergy Clin. Immunol. 127(4), 852-854.e23 (2011
24. Ross RN, Nelson HS, Finegold I. Effectiveness of specific immunotherapy in the treatment of Hymenoptera venom hypersensitivity: A meta-Analysis. Clin. Ther. 22(3), 351-358 (2000
25. Bousquet J, Lockey R, Malling HJ. Allergen immunotherapy: Therapeutic vaccines for allergic diseases. A WHO position paper. J. Allergy Clin. Immunol. 102(4 Pt 1), 558-562 (1998
26. Lockey RF, Benedict LM, Turkeltaub PC, Bukantz SC. Fatalities from immunotherapy (IT) and skin testing (ST). J. Allergy Clin. Immunol. 79(4), 660-677 (1987
27. Position paper: IMMUNOTHERAPY. (EAACI) The European Academy of Allergology and Clinical Immunology. Allergy 48(14 Suppl.), 7-35 (1993
28. Nielsen L, Johnsen CR, Mosbech H, Poulsen LK, Malling HJ. Antihistamine premedication in specific cluster immunotherapy: A double-Blind, placebo-Controlled study. J. Allergy Clin. Immunol. 97(6), 1207-1213 (1996
29. Cox L, Larenas-Linnemann D, Lockey RF, Passalacqua G. Speaking the same language: The World Allergy Organization Subcutaneous Immunotherapy Systemic Reaction Grading System. J. Allergy Clin. Immunol. 125(3), 569-574.e7 (2010
30. Bernstein DI, Epstein T, Murphy-Berendts K, Liss GM. Surveillance of systemic reactions to subcutaneous immunotherapy injections: Year 1 outcomes of the ACAAI and AAAAI collaborative study. Ann. Allergy Asthma Immunol. 104(6), 530-535 (2010
31. Epstein TG, Liss GM, Murphy-Berendts K, Bernstein DI. Immediate and delayed-Onset systemic reactions after subcutaneous immunotherapy injections: Acaai/AAAAI surveillance study of subcutaneous immunotherapy - year 2. Ann. Allergy Asthma Immunol. 107(5), 426-431.e1 (2011
32. Cox L, Nelson H, Lockey R et al. Allergen immunotherapy: A practice parameter third update. J. Allergy Clin. Immunol. 127(1 Suppl.), S1-S55 (2011
33. Golden DB, Kelly D, Hamilton RG, Craig TJ. Venom immunotherapy reduces large local reactions to insect stings. J. Allergy Clin. Immunol. 123(6), 1371-1375 (2009
34. Werfel T, Breuer K, Rueff F et al. Usefulness of specific immunotherapy in patients with atopic dermatitis and allergic sensitization to house dust mites: A multi-Centre, randomized, dose-Response study. Allergy 61(2), 202-205 (2006
35. Glover MT, Atherton DJ. A double-Blind controlled trial of hyposensitization to Dermatophagoides pteronyssinus in children with atopic eczema. Clin. Exp. Allergy 22(4), 440-446 (1992
36. Bussmann C, Böckenhoff A, Henke H, Werfel T, Novak N. Does allergen-Specific immunotherapy represent a therapeutic option for patients with atopic dermatitis? J. Allergy Clin. Immunol. 118(6), 1292-1298 (2006
37. Bussmann C, Maintz L, Hart J et al. Clinical improvement and immunological changes in atopic dermatitis patients undergoing subcutaneous immunotherapy with a house dust mite allergoid: A pilot study. Clin. Exp. Allergy 37(9), 1277-1285 (2007
38. Nelson HS, Lahr J, Rule R, Bock A, Leung D. Treatment of anaphylactic sensitivity to peanuts by immunotherapy with injections of aqueous peanut extract. J. Allergy Clin. Immunol. 99(6 Pt 1), 744-751 (1997
39. Enrique E, Malek T, Pineda F et al. Sublingual immunotherapy for hazelnut food allergy: A follow-up study. Ann. Allergy Asthma Immunol. 100(3), 283-284 (2008
40. de Boissieu D, Dupont C. Sublingual immunotherapy for cow's milk protein allergy: A preliminary report. Allergy 61(10), 1238-1239 (2006
41. Jones SM, Pons L, Roberts JL et al. Clinical efficacy and immune regulation with peanut oral immunotherapy. J. Allergy Clin. Immunol. 124(2), 292-300.e97 (2009
42. Buchanan AD, Green TD, Jones SM et al. Egg oral immunotherapy in nonanaphylactic children with egg allergy. J. Allergy Clin. Immunol. 119(1), 199-205 (2007
43. Staden U, Rolinck-Werninghaus C, Brewe F, Wahn U, Niggemann B, Beyer K. Specific oral tolerance induction in food allergy in children: Efficacy and clinical patterns of reaction. Allergy 62(11), 1261-1269 (2007
44. Narisety SD, Skripak JM, Steele P et al. Open-Label maintenance after milk oral immunotherapy for IgE-mediated cow's milk allergy. J. Allergy Clin. Immunol. 124(3), 610-612 (2009
45. Mondoulet L, Dioszeghy V, Vanoirbeek JA, Nemery B, Dupont C, Benhamou PH. Epicutaneous immunotherapy using a new epicutaneous delivery system in mice. Int. Arch. Allergy Immunol. 154(4), 299-309 (2011
46. Bucher X, Pichler WJ, Dahinden CA, Helbling A. Effect of tree pollen specific, subcutaneous immunotherapy on the oral allergy syndrome to apple and hazelnut. Allergy 59(12), 1272-1276 (2004
47. Hansen KS, Khinchi MS, Skov PS, Bindslev-Jensen C, Poulsen LK, Malling HJ. Food allergy to apple and specific immunotherapy with birch pollen. Mol. Nutr. Food Res. 48(6), 441-448 (2004
48. Leynadier F, Herman D, Vervloet D, Andre C. Specific immunotherapy with a standardized latex extract versus placebo in allergic healthcare workers. J. Allergy Clin. Immunol. 106(3), 585-590 (2000
49. Sastre J, Fernandez-Nieto M, Rico P et al. Specific immunotherapy with a standardized latex extract in allergic workers: A double-Blind, placebo-Controlled study. J. Allergy Clin. Immunol. 111(5), 985-994 (2003
50. Tabar AI, Anda M, Bonifazi F et al. Specific immunotherapy with standardized latex extract versus placebo in latex-Allergic patients. Int. Arch. Allergy Immunol. 141(4), 369-376 (2006
51. Bernardini R, Pecora S, Milani M, Burastero SE. Natural rubber latex allergy in children: Clinical and immunological effects of 3 years sublingual immunotherapy. Eur. Ann. Allergy Clin. Immunol. 40(4), 142-147 (2008
52. Cox L, Cohn JR. Duration of allergen immunotherapy in respiratory allergy: When is enough, enough? Ann. Allergy Asthma Immunol. 98(5), 416-426 (2007
53. Guilbert TW, Morgan WJ, Zeiger RS et al. Long-Term inhaled corticosteroids in preschool children at high risk for asthma. N. Engl. J. Med. 354(19), 1985-1997 (2006
54. Durham SR, Walker SM, Varga EM et al. Long-Term clinical efficacy of grass-pollen immunotherapy. N. Engl. J. Med. 341(7), 468-475 (1999
55. Eng PA, Borer-Reinhold M, Heijnen IA, Gnehm HP. Twelve-Year follow-up after discontinuation of preseasonal grass pollen immunotherapy in childhood. Allergy 61(2), 198-201 (2006
56. Eng PA, Reinhold M, Gnehm HP. Long-Term efficacy of preseasonal grass pollen immunotherapy in children. Allergy 57(4), 306-312 (2002
57. Jacobsen L. Preventive aspects of immunotherapy: Prevention for children at risk of developing asthma. Ann. Allergy Asthma Immunol. 87(1 Suppl. 1), 43-46 (2001
58. The discontinuation of Hymenoptera venom immunotherapy. Report from the Committee on Insects. J. Allergy Clin. Immunol. 101(5), 573-575 (1998
59. Golden DBK, Kagey-Sobotka A, Lichtenstein LM. Survey of patients after discontinuing venom immunotherapy. J. Allergy Clin. Immunol. 105(2), 385-390 (2000
60. Lerch E, Müller UR. Long-Term protection after stopping venom immunotherapy: Results of re-Stings in 200 patients. J. Allergy Clin. Immunol. 101(5), 606-612 (1998
61. Des Roches A, Paradis L, Knani J et al. Immunotherapy with a standardized Dermatophagoides pteronyssinus extract. V. Duration of the efficacy of immunotherapy after its cessation. Allergy 51(6), 430-433 (1996
62. Hedlin G, Heilborn H, Lilja G et al. Long-Term follow-up of patients treated with a three-Year course of cat or dog immunotherapy. J. Allergy Clin. Immunol. 96(6 Pt 1), 879-885 (1995
63. Durham SR, Emminger W, Kapp A et al. Long-Term clinical efficacy in grass pollen-Induced rhinoconjunctivitis after treatment with SQ-Standardized grass allergy immunotherapy tablet. J. Allergy Clin. Immunol. 125(1), 131-138.e7 (2010
64. Guerra S, Sherrill DL, Baldacci S et al. Rhinitis is an independent risk factor for developing cough apart from colds among adults. Allergy 60(3), 343-349 (2005
65. Lombardi C, Passalacqua G, Gargioni S et al. The natural history of respiratory allergy: A follow-up study of 99 patients up to 10 years. Respir. Med. 95(1), 9-12 (2001
66. Leynaert B, Neukirch C, Kony S et al. Association between asthma and rhinitis according to atopic sensitization in a population-Based study. J. Allergy Clin. Immunol. 113(1), 86-93 (2004
67. Toren K, Olin AC, Hellgren J, Hermansson BA. Rhinitis increase the risk for adult-Onset asthma - a Swedish population-Based case-Control study (MAP-Study). Respir. Med. 96(8), 635-641 (2002
68. Johnstone DE, Dutton A. The value of hyposensitization therapy for bronchial asthma in children - a 14 year study. Pediatrics 42(5), 793-802 (1968
69. Jacobsen L, Niggemann B, Dreborg S et al. Specific immunotherapy has long-Term preventive effect of seasonal and perennial asthma: 10 year follow-up on the PAT study. Allergy 62(8), 943-948 (2007
70. Moller C, Dreborg S, Ferdousi HA et al. Pollen immunotherapy reduces the development of asthma in children with seasonal rhinoconjunctivitis (the PAT-Study). J. Allergy Clin. Immunol. 109(2), 251-256 (2002
71. Niggemann B, Jacobsen L, Dreborg S et al. Five-Year follow-up on the PAT study: Specific immunotherapy and long-Term prevention of asthma in children. Allergy 61(7), 855-859 (2006
72. Polosa R, Li Gotti F, Mangano G et al. Effect of immunotherapy on asthma progression, BHR and sputum eosinophils in allergic rhinitis. Allergy 59(11), 1224-1228 (2004
73. Polosa R, Al-Delaimy WK, Russo C, Piccillo G, Sarva M. Greater risk of incident asthma cases in adults with allergic rhinitis and effect of allergen immunotherapy: A retrospective cohort study. Respir. Res. 6, 153 (2005
74. Novembre E, Galli E, Landi F et al. Coseasonal sublingual immunotherapy reduces the development of asthma in children with allergic rhinoconjunctivitis. J. Allergy Clin. Immunol. 114(4), 851-857 (2004
75. Des Roches A, Paradis L, Menardo JL, Bouges S, Daures JP, Bousquet J. Immunotherapy with a standardized Dermatophagoides pteronyssinus extract. VI. Specific immunotherapy prevents the onset of new sensitizations in children. J. Allergy Clin. Immunol. 99(4), 450-453 (1997
76. Pajno GB, Barberio G, De Luca F, Morabito L, Parmiani S. Prevention of new sensitizations in asthmatic children monosensitized to house dust mite by specific immunotherapy. A six-Year follow-up study. Clin. Exp. Allergy 31(9), 1392-1397 (2001
77. Purello-D'Ambrosio F, Gangemi S, Merendino RA et al. Prevention of new sensitizations in monosensitized subjects submitted to specific immunotherapy or not. A retrospective study. Clin. Exp. Allergy 31(8), 1295-1302 (2001
78. Marogna M, Spadolini I, Massolo A, Canonica GW, Passalacqua G. Randomized controlled open study of sublingual immunotherapy for respiratory allergy in real-Life: Clinical efficacy and more. Allergy 59(11), 1205-1210 (2004
79. American Academy of Allergy, Asthma and Immunology (AAAAI). The Allergy Report: SCIENCE Based Findings on the Diagnosis and Treatment of Allergic Disorders, 1996-2001. American Academy of Allergy, Asthma and Immunology (AAAAI), Milwaukee, WI, USA (2001
80. Sullivan PW, Ghushchyan VH, Slejko JF, Belozeroff V, Globe DR, Lin SL. The burden of adult asthma in the United States: Evidence from the Medical Expenditure Panel Survey. J. Allergy Clin. Immunol. 127(2), 363-369.e3 (2011
81. Soni A. Allergic Rhinitis: TRENDS in Use and Expenditures, 2000 to 2005. Statistical Brief #204. Agency for Healthcare Research and Quality, Bethesda, MD, USA (2008
82. Cox L, Jacobsen L. Comparison of allergen immunotherapy practice patterns in the United States and Europe. Ann. Allergy Asthma Immunol. 103(6), 451-459; quiz 459-461, 495 (2009
83. Lockey RF, Hankin CS. Health economics of allergen-Specific immunotherapy in the United States. J. Allergy Clin. Immunol. 127(1), 39-43 (2011
84. Ariano R, Berto P, Tracci D, Incorvaia C, Frati F. Pharmacoeconomics of allergen immunotherapy compared with symptomatic drug treatment in patients with allergic rhinitis and asthma. Allergy Asthma Proc. 27(2), 159-163 (2006
85. Hankin CS, Cox L, Lang D et al. Allergen immunotherapy and health care cost benefits for children with allergic rhinitis: A large-Scale, retrospective, matched cohort study. Ann. Allergy Asthma Immunol. 104(1), 79-85 (2010
86. Hankin CS, Cox L, Lang D et al. Allergy immunotherapy among Medicaid-Enrolled children with allergic rhinitis: Patterns of care, resource use, and costs. J. Allergy Clin. Immunol. 121(1), 227-232 (2008
87. Wang Z, Hankin CS, Cox L, Bronstone A. Allergen immunotherapy significantly reduces healthcare costs among U.S. adults with allergic rhinitis: A retrospective matched cohort study jointly funded by the AAAAI and ACAAI. Presented at: ANNUAL Meeting of the American Academy of Allergy, Asthma, and Immunology. San Francisco, CA, USA, 18-22 March 2011 (Poster presentation
88. Strunk RC, Sternberg AL, Szefler SJ, Zeiger RS, Bender B, Tonascia J. Long-Term budesonide or nedocromil treatment, once discontinued, does not alter the course of mild to moderate asthma in children and adolescents. J. Pediatr. 154(5), 682-687 (2009
89. Worm M, Lee HH, Kleine-Tebbe J et al. Development and preliminary clinical evaluation of a peptide immunotherapy vaccine for cat allergy. J. Allergy Clin. Immunol. 127(1), 89-97.e14 (2011
90. Larché M. Peptide and recombinant immunotherapy. Immunol. Allergy Clin. North Am. 31(2), 377-389, xi (2011
91. Casale TB, Stokes JR. Immunomodulators for allergic respiratory disorders. J. Allergy Clin. Immunol. 121(2), 288-296 (2008
92. Creticos PS, Schroeder JT, Hamilton RG et al. Immunotherapy with a ragweed-Toll-Like receptor 9 agonist vaccine for allergic rhinitis. N. Engl. J. Med. 355(14), 1445-1455 (2006
93. Cox LS. How safe are the biologicals in treating asthma and rhinitis? Allergy Asthma Clin. Immunol. 5(1), 4 (2009
94. DuBuske LM, Frew AJ, Horak F et al. Ultrashort-Specific immunotherapy successfully treats seasonal allergic rhinoconjunctivitis to grass pollen. Allergy Asthma Proc. 32(3), 239-247 (2011
95. Keles S, Karakoc-Aydiner E, Ozen A et al. A novel approach in allergen-Specific immunotherapy: Combination of sublingual and subcutaneous routes. J. Allergy Clin. Immunol. 128(4), 808-815.e7 (2011
96. Senti G, Prinz Vavricka BM, Erdmann I et al. Intralymphatic allergen administration renders specific immunotherapy faster and safer: A randomized controlled trial. Proc. Natl Acad. Sci. USA 105(46), 17908-17912 (2008
97. Freeman J. 'Rush inoculation', with special reference to hay fever treatment. Lancet 1, 744-747 (1930
98. Norman PS. Immunotherapy: Past and present. J. Allergy Clin. Immunol. 102, 1-10 (1998
99. Frankland AW, Augustin R. Prophylaxis of summer hay-Fever and asthma: A controlled trial comparing crude grass-pollen extract with isolated main protein component. Lancet 1, 1055-1057 (1954
100. Johnstone DE. Study of the role of antigen dosage in the treatment of pollenosis and pollen asthma. J. Dis. Child. 94(1), 1-5 (1957
101. Johnstone DE, Dutton A. The value of hyposensitization therapy for bronchial asthma in children - a 14 year study. Pediatrics 42, 793-802 (1968
102. Lowell FC, Franklin W. A double-Blind study of the effectiveness and specificity of injection therapy in ragweed hay fever. N. Engl. J. Med. 273, 675-679 (1965
103. Ishizaka K, Ishizaka T, Terry WD. Antigenic structure of gamma-E-Globulin and reaginic antibody. J. Immunol. 99, 849-858 (1967
104. Ishizaka K, Ishizaka T. Identification of gamma-E antibodies as a carrier of reaginic activity. J. Immunol. 99, 1187-1199 (1967
105. Ewbank PA, Murray J, Sanders K, Curran-Everett D, Dreskin S, Nelson HS. A double-Blind placebo-Controlled immunotherapy dose-Response study with standardized cat extract. J. Allergy Clin. Immunol. 111, 155-161 (2003
106. Nanda A, O'Connor M, Anand M et al. Dose dependence and time course of the immunologic response to administration of standardized cat allergen extract. J. Allergy Clin. Immunol. 114, 1339-1344 (2004
107. Francis J, James L, Paraskevopoulos G et al. Grass pollen immunotherapy: il-10 induction and suppression of late responses precedes IgG4 inhibitory antibody activity. J. Allergy Clin. Immunol. 121, 1120-1125.e2 (2008)