Maculopapular exanthema (MPE) induced by drugs is a T-cell mediated reaction and effector cells may play an important role in its development. We assessed the effector and cutaneous homing phenotype in peripheral blood cells from allergic patients after drug stimulation. This study included 10 patients and 10 controls. The effector phenotype (CCR7−CD27+/−), chemokine receptors (CCR4 and CCR10), and activation (CD25low) and regulatory markers (CD25high) were measured by flow cytometry in both peripheral blood mononuclear cells (PBMCs) and CD4-T-lymphocytes. Proliferation was determined by 5-(−6)-carboxyfluorescein diacetate succinimidyl ester (CFSE) assay and the migratory capacity by a chemotaxis assay using CCL17 and CCL27. Compared to controls, CCR7−CD27− cells were increased in patients without (p=0.003) and with drug stimulation (p<0.001) and had significantly higher proliferation (p=0.010). CCR10 expression was increased in patients after drug stimulation in total and memory CD27+ T-cells. Lymphocyte migration with CCL27 was higher in patients with drug stimulation (p=0.048), with a decrease in CCR7−CD27− (p<0.0001) and an increase in CCR7−CD27+ (p=0.017). In patients, CD4-T-lymphocytes were significantly activated after drug stimulation (p<0.001). In conclusion, we show that effector memory CD4+ T-cells (CCR7−CD27+) respond specifically to the drug responsible for MPE and confirm previous data about the involvement of CCR10 in cell trafficking to the skin.
BigbyM. Rates of cutaneous reactions to drugs. Arch Dermatol2001; 137:765–70.
2.
Romano A, Blanca M, Torres MJ, Bircher A, Aberer W, Brockow K, Pichler WJ, Demoly P, ENDA, EAACI. Diagnosis of non-immediate reactions to beta-lactam antibiotics. Allergy2004; 59:1153–60.
3.
YawalkarNEgliFHariYNievergeltHBraathenLRPichlerWJ. Infiltration of cytotoxic T-cells in drug-induced cutaneous eruptions. Clin Exp Allergy2000; 30:847–55.
4.
TorresMJMayorgaCFernandezTDCornejo-GarciaJAAntunezCValenzuelaMDel PradoMFRodriguez-PenaRBlancaM. T-cell assessment in allergic drug reactions during the acute phase according to the time of occurrence. Int J Immunopathol Pharmacol2006; 19:119–30.
5.
PosadasSPadialATorresMJ. Delayed reactions to drugs show a Th1 profile and levels of perforin, granzyme B and Fas-L related to disease severity. J Allergy Clin Immunol2002; 109:155–61.
6.
FernandezTDMayorgaCTorresMJCornejo-GarciaJALópezSChavesPRondonCBlancaM. Cytokine and chemokine expression in the skin from patients with maculopapular exanthema to drugs. Allergy2008; 63:712–19.
7.
CampbellJJHaraldsenGPanJ. The chemokine receptor CCR4 in vascular recognition by cutaneous but not intestinal memory T-cells. Nature1999; 400:776–80.
8.
MoedHBoorsmaDMStoofTJvon BlombergBMBruynzeelDPScheperRJGibbsSRustemeyerT. Nickel-responding T-cells are CD4+ CLA+ CD45RO+ and express chemokine receptors CXCR3, CCR4 and CCR10. Br J Dermatol2004; 151:32–41.
9.
D'AmbrosioDPanina-BordignonPSinigagliaF. Chemokine receptors in inflammation: an overview. J Immunol Methods2003; 273:3–13.
10.
MoralesJHomeyBVicariAP. CTACK, a skin-associated chemokine that preferentially attracts skin-homing memory T-cells. PNAS1999; 96:14470–75.
11.
TapiaBPadialASánchez-SabatéEAlvarez-FerreiraJMorelEBlancaMBellonT. CCL27-CCR10 in drug-induced cutaneous reactions: Involvement in SJS and TEN. J Allergy Clin Immunol2004; 114:335–40.
12.
FlierJBoorsmaDMvan BeekPJ. Differential expression of CXCR3 targeting chemokines CXCL10, CXCL9, and CXCL11 in different types of skin inflammation. J Pathol2001; 194:398–405.
13.
SolerDHumphreysTLSpinolaSMCampbellJJ. CCR4 versus CCR10 in human cutaneous Th lymphocyte trafficking. Blood2003; 101:1677–83.
14.
SallustoFLenigDFosterRLippMLanzavecchiaA. Two subsets of memory T-lymphocytes with distinct homing potentials and effector functions. Nature1999; 401:708–12.
15.
CampbellJJMurphyKEKunkelEJ. CCR7 expression and memory T-cell diversity in humans. J Immunol2001; 166:877–84.
16.
StubbeMVanderheydeNGoldmanMMarchantA. Antigen-specific central memory CD4+ T-lymphocytes produce multiple cytokines and proliferate in vivo in humans. J Immunol2006; 177:8185–90.
17.
BaarsPAMauriceMMRepMHooibrinkBvan LierRA. Heterogeneity of the circulating human CD4+ T-cell population. Further evidence that the CD4+CD45RA-CD27- T-cell subset contains specialized primed T-cells. J Immunol1995; 154:17–25.
18.
TerakiYShioharaT. IFN-gamma-producing effector CD8+ T cells and IL-10-producing regulatory CD4+ T cells in fixed drug eruption. J Allergy Clin Immunol2003; 112:609–15.
19.
AntúnezCTorresMJMayorgaCCornejo-GarcíaJASantamaría-BabiLFBlancaM. Different cytokine production and activation marker profiles in circulating cutaneous-lymphocyte-associated antigen T-cells from patients with acute or chronic atopic dermatitis. Clin Exp Allergy2004; 34:559–66.
20.
ImaiTYoshidaTBabaMNishimuraMKakizakiMYoshieO. Molecular cloning of a novel T-cell-directed CC chemokine expressed in thymus by signal sequence trap using Epstein-Barr virus vector. J Biol Chem1996; 271:21514–21.
21.
Baecher-AllanCBrownJAFreemanGJHaflerDA. CD4+CD25high regulatory cells in human peripheral blood. J Immunol2001; 167:1245–53.
22.
TsugeIOkumuraAKondoYItomiSKakamiMKawamuraMNakajimaYKomatsubaraRUrisuA. Allergen-specific T-cell response in patients with phenytoin hypersensitivity; simultaneous analysis of proliferation and cytokine production by carboxyfluorescein succinimidyl ester (CFSE) dilution assay. Allergol Int2007; 56:149–55.
FritschRDShenXSimsGPHathcockKSHodesRJLipskyPE. Stepwise differentiation of CD4 memory T-cells defined by expression of CCR7 and CD27. J Immunol2005; 175:6489–97.
25.
TakataHTakiguchiM. Three memory subsets of human CD8+ T-cells differently expressing three cytolytic effector molecules. J Immunol2006; 177:4330–40.
26.
FritschRDShenXIlleiGGYarboroCHPrussinCHathcockKSHodesRJLipskyPE. Abnormal differentiation of memory T-cells in Systemic Lupus Erythematosus. Arthritis Rheum2006; 54:2184–97.
27.
GamadiaLERemmerswaalEBWeelJFBemelmanFvan LierRATen BergeIJ. Primary immune responses to human CMV: a critical role for IFN-gamma-producing CD4+ T-cells in protection against CMV disease. Blood2003; 101:2686–92.
28.
PowellDJJrDudleyMERobbinsPFRosenbergSA. Transition of late-stage effector T-cells to CD27+ CD28+ tumor-reactive effector memory T-cells in humans after adoptive cell transfer therapy. Blood2005; 105:241–50.
29.
MacallanDCWallaceDZhangYDe LaraCWorthATGhattasHGriffinGEBeverleyPCToughDF. Rapid turnover of Effector-Memory CD4+ T-cells in Healthy Humans. J Exp Med2004; 200:255–60.
30.
TapiaBMorelEMartín-DíazMADíazRAlves-FerreiraJRubioPPadialABellónT. Up-regulation of CCL17, CCL22 and CCR4 in drug-induced maculopapular exanthema. Clin Exp Allergy2007; 37:704–13.
31.
IellemAMarianiMLangRRecaldeHPanina-BordignonPSinigagliaFD'AmbrosioD. Unique chemotactic response profile and specific expression of chemokine receptors CCR4 and CCR8 by CD4(+)CD25(+) regulatory T-cells. J Exp Med2001; 194:847–53.
32.
CavaniANasorriFOttavianiCSebastianiSDe PitàOGirolomoniG. Human CD25+ regulatory T-cells maintain immune tolerance to nickel in healthy, nonallergic individuals. J Immunol2003; 171:5760–68.
