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PMID: 17616639 Published · ppublish English Comparative Study Evaluation Study Journal Article Research Support, N.I.H., Extramural Research Support, N.I.H., Intramural Research Support, Non-U.S. Gov't

IL-2 immunotoxin denileukin diftitox reduces regulatory T cells and enhances vaccine-mediated T-cell immunity.

Blood ·Vol. 110 ·No. 9 ·2007-11-01 ·Pages 3192-201

Litzinger MT, Fernando R, Curiel TJ, Grosenbach DW, Schlom J, Palena C

Abstract

CD4+CD25+Foxp3+ regulatory T (Treg) cells have been implicated in the lack of effective antitumor immunity. Denileukin diftitox (DAB(389)IL-2), a fusion protein of interleukin 2 (IL-2) and diphtheria toxin, provides a means of targeting Treg cells. In this study, we examined (1) the effect of denileukin diftitox on the deletion of Treg cells in various lymphoid compartments and (2) the dose scheduling of denileukin diftitox in combination with a recombinant poxviral vaccine to enhance antigen-specific immune responses. Treg cells in spleen, peripheral blood, and bone marrow of normal C57BL/6 mice were variously reduced after a single intraperitoneal injection of denileukin diftitox; the reduction was evident within 24 hours and lasted approximately 10 days. Injection of denileukin diftitox 1 day before vaccination enhanced antigen-specific T-cell responses above levels induced by vaccination alone. These studies show for the first time in a murine model (1) the differential effects of denileukin diftitox on Treg cells in different cellular compartments, (2) the advantage of combining denileukin diftitox with a vaccine to enhance antigen-specific T-cell immune responses, (3) the lack of inhibition by denileukin diftitox of host immune responses directed against a live viral vector, and (4) the importance of dose scheduling of denileukin diftitox when used in combination with a vaccine.

MeSH Terms
Animals Cells, Cultured Combined Modality Therapy Diphtheria Toxin/administration & dosage,pharmacology Drug Administration Schedule Female Immunity, Cellular/drug effects Immunotoxins/pharmacology Influenza A virus/immunology Interleukin-2/administration & dosage,pharmacology Lymphocyte Count Mice Mice, Inbred BALB C Mice, Inbred C57BL Mice, Transgenic Poxviridae/immunology Recombinant Fusion Proteins/administration & dosage,pharmacology T-Lymphocytes, Regulatory/cytology,drug effects,immunology Viral Vaccines/immunology,therapeutic use
Chemicals
Diphtheria Toxin Immunotoxins Interleukin-2 Recombinant Fusion Proteins Viral Vaccines denileukin diftitox
Authors & Affiliations
6 authors, click to expand affiliations / ORCID
Litzinger Mary T
Laboratory of Tumor Immunology and Biology, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892, USA.
Fernando Romaine
Curiel Tyler J
Grosenbach Douglas W
Schlom Jeffrey
Palena Claudia
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Article Info
Journal
Blood
Abbr.
Blood
ISSN
0006-4971
DOI
10.1182/blood-2007-06-094615
Published
2007-11-01
Epub
2007-00-06
Pages
3192-201
Language
English
Region
United States
NLM ID
7603509
PMCID
PMC2200901
Subset
IM
Grants
NCI NIH HHS · CA 100425 · United States
FDA HHS · R01 FD003118 · United States
NCI NIH HHS · R01 CA100425 · United States
Intramural NIH HHS · United States
NCI NIH HHS · CA 105207 · United States
NCI NIH HHS · R01 CA105207 · United States
External Links
PubMed source DOI: 10.1182/blood-2007-06-094615 PMC Full Text View journal details
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