Expansion of circulating Foxp3+)D25bright CD4+ T cells during specific venom immunotherapy.
BACKGROUND
Venom immunotherapy (VIT) induces long-lasting immune tolerance to hymenoptera venom antigens, but the underlying mechanisms are not yet clarified. Regulatory T cells are thought to play an important role in allergic diseases and tolerance induction during specific immunotherapy.


OBJECTIVE
Characterize longitudinally the impact of VIT on the pool of circulating regulatory T cells.


METHODS
Fourteen hymenoptera venom-allergic patients with severe reactions (grades III-IV) were studied before, 6 and 12 months after starting ultra-rush VIT. Freshly isolated peripheral blood mononuclear cells were surface stained with a panel of markers of T cell differentiation and intracellularly for CTLA-4 and Foxp3 and analysed by flow cytometry. foxp3 mRNA was quantified by real-time PCR. VIT responses were assessed by measuring specific IgG4 and IgE levels. Eleven individuals with no history of insect venom allergy were studied as controls.


RESULTS
VIT induces a significant progressive increase in both the proportion and the absolute numbers of regulatory T cells defined as CD25bright and/or Foxp3+ CD4+ T cells. These changes are not related to alterations in the expression of activation markers or imbalances in the naïve/memory T cell compartments. foxp3 mRNA levels also increased significantly during VIT. Of note, the increase in circulating regulatory T cell counts significantly correlates with the venom-specific IgG4/IgE ratio shift.


CONCLUSIONS
VIT is associated with a progressive expansion of circulating regulatory T cells, supporting a role for these cells in tolerance induction.
Pereira-Santos
M C
MC
Unidade de Imunologia Clínica, Instituto de Medicina Molecular, Faculdade de Medicina, Universidade de Lisboa, Lisboa, Portugal. mcgalvaos@fm.ul.pt
Baptista
A P
AP
Melo
A
A
Alves
R R
RR
Soares
R S
RS
Pedro
E
E
Pereira-Barbosa
M
M
Victorino
R M M
RM
Sousa
A E
AE
D000293:Adolescent; D000328:Adult; D000368:Aged; D000818:Animals; D000941:Antigens / Q000276:immunology; D001514:Bee Venoms / Q000276:immunology* / Q000627:therapeutic use; D015704:CD4 Antigens / Q000032:analysis; D003888:Desensitization, Immunologic / Q000379:methods*; D005260:Female; D051858:Forkhead Transcription Factors / Q000032:analysis / Q000235:genetics / Q000378:metabolism; D006801:Humans; D006927:Hymenoptera / Q000276:immunology*; D006969:Hypersensitivity, Immediate / Q000188:drug therapy / Q000276:immunology*; D007108:Immune Tolerance; D007073:Immunoglobulin E / Q000097:blood; D007074:Immunoglobulin G / Q000097:blood; D007156:Immunologic Memory; D007299:Insect Bites and Stings / Q000188:drug therapy / Q000276:immunology*; D053645:Interleukin-2 Receptor alpha Subunit / Q000032:analysis; D018655:Lymphocyte Count; D008297:Male; D008875:Middle Aged; D050378:T-Lymphocytes, Regulatory / Q000276:immunology*; D014862:Wasp Venoms / Q000276:immunology* / Q000627:therapeutic use
D000941:Antigens; D001514:Bee Venoms; D015704:CD4 Antigens; C418974:FOXP3 protein, human; D051858:Forkhead Transcription Factors; D007074:Immunoglobulin G; D053645:Interleukin-2 Receptor alpha Subunit; D014862:Wasp Venoms; D007073:Immunoglobulin E