Depletion of CD4+CD25+ human regulatory T cells in vivo: kinetics of Treg depletion and alterations in immune functions in vivo and in vitro.
The aim of this study was to investigate whether depletion of CD4(+)CD25(+) regulatory T cells (Treg) from melanoma patients affects immune responses against tumors. By application of recombinant IL-2-diphteria toxin fusion protein, also known as ONTAK, we were able to significantly reduce the frequency of Treg in peripheral blood, whereas other cell populations remained unaffected. The reduction of Treg started immediately after the first bolus of ONTAK with a dose of 5 microg ONTAK per kg bodyweight and lasted for 13 days with subsequent recovery thereafter. Successive ONTAK treatments further reduced the number of circulating Treg. Using the contact sensitizer DCP we show that all patients developed vast eczema after Treg depletion, whereas no or only mild eczematous reactions were detectable before ONTAK treatment. Corresponding induction of DCP-specific CD4(+) and CD8(+) T cells were detectable. Moreover, after immunization of ONTAK treated patients with tumor antigen peptides, MelanA/MART-1 and gp100, significant induction of peptide specific CD8(+) T cells could be observed in 90% of the patients treated. These cells displayed effector functions, as they were able to lyse peptide-pulsed target cells and secreted IFNgamma upon restimulation. In aggregate, our data indicate that ONTAK depletes Treg in vivo significantly, resulting in enhanced immune functions and substantial development of antigen-specific CD8(+) T cells in vaccinated individuals.
Mahnke
Karsten
K
Department of Dermatology, University Hospital Heidelberg, Vossstrasse 11, Heidelberg, Germany. karsten,mahnke@med.uni-heidelberg.de
Schönfeld
Kurt
K
Fondel
Sabine
S
Ring
Sabine
S
Karakhanova
Svetlana
S
Wiedemeyer
Katharina
K
Bedke
Tanja
T
Johnson
Theron Scott
TS
Storn
Volker
V
Schallenberg
Sonja
S
Enk
Alexander Herrmann
AH
D000328:Adult; D000368:Aged; D000951:Antigens, Neoplasm / Q000737:chemistry / Q000276:immunology; D000970:Antineoplastic Agents / Q000009:adverse effects / Q000627:therapeutic use; D015704:CD4 Antigens / Q000276:immunology; D016827:CD8 Antigens / Q000276:immunology; D049109:Cell Proliferation / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D019281:Dimerization; D004167:Diphtheria Toxin / Q000009:adverse effects / Q000627:therapeutic use*; D004305:Dose-Response Relationship, Drug; D004485:Eczema / Q000139:chemically induced; D005260:Female; D005434:Flow Cytometry; D006801:Humans; D007376:Interleukin-2 / Q000009:adverse effects / Q000627:therapeutic use*; D053645:Interleukin-2 Receptor alpha Subunit / Q000276:immunology; D007937:Leukapheresis; D058965:MART-1 Antigen; D008297:Male; D008545:Melanoma / Q000097:blood / Q000276:immunology / Q000517:prevention & control*; D008562:Membrane Glycoproteins / Q000737:chemistry / Q000276:immunology; D008875:Middle Aged; D009363:Neoplasm Proteins / Q000737:chemistry / Q000276:immunology; D011993:Recombinant Fusion Proteins / Q000009:adverse effects / Q000627:therapeutic use; D013601:T-Lymphocytes / Q000166:cytology / Q000187:drug effects* / Q000276:immunology; D013997:Time Factors; D016896:Treatment Outcome; D014611:Vaccination / Q000379:methods*; D058951:gp100 Melanoma Antigen
D000951:Antigens, Neoplasm; D000970:Antineoplastic Agents; D015704:CD4 Antigens; D016827:CD8 Antigens; D004167:Diphtheria Toxin; D007376:Interleukin-2; D053645:Interleukin-2 Receptor alpha Subunit; D058965:MART-1 Antigen; C548667:MLANA protein, human; D008562:Membrane Glycoproteins; D009363:Neoplasm Proteins; C548637:PMEL protein, human; D011993:Recombinant Fusion Proteins; D058951:gp100 Melanoma Antigen; C078456:denileukin diftitox