Abstract |
Pathogenic lymphocytes in the enteric wall of inflammatory bowel disease patients display various abnormalities, including reduced sensitivity to apoptosis. We evaluated a therapeutic approach to elimination of cytotoxic cells, using two IL-2 fusion proteins, a diphtheria toxin (IL2-DT) and a caspase-3 (IL2-cas) conjugate. In models of acute ( dextran sodium sulfate and trinitrobenzene sulfonic acid) and chronic ( dextran sodium sulfate) toxic colitis, therapeutic doses of the fusion proteins improved survival and prevented colon shortening. While both chimeric proteins eradicated CD4(+)CD25(+)Foxp3(+) T cells in mesenteric LN, IL2-DT caused severe lymphopenia. In contrast, IL2-cas was equally protective and increased fractional expression of Foxp3. Similar effects of the fusion proteins were observed in healthy mice: IL2-DT caused lymphopenia and IL2-cas increased fractional expression of FoxP3. The fusion proteins induced apoptosis in CD25(+) T cells in vitro, with lower toxicity of IL2-cas to Foxp3(+) T cells. These data infer that targeted depletion of cells expressing the IL-2 receptor has therapeutic potential in models of inflammatory colitis, despite depletion of CD25(+) Treg. The IL2-cas fusion protein is particularly relevant to inflammatory bowel disease, as direct internalization of toxic moieties overcomes multiple pathways of resistance to apoptosis of colitogenic T cells.
|
Authors | Shai Yarkoni, Yuval Sagiv, Ayelet Kaminitz, Daniel L Farkas, Nadir Askenasy |
Journal | European journal of immunology
(Eur J Immunol)
Vol. 39
Issue 10
Pg. 2850-64
(Oct 2009)
ISSN: 1521-4141 [Electronic] Germany |
PMID | 19735074
(Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
|
Chemical References |
- Diphtheria Toxin
- Forkhead Transcription Factors
- Foxp3 protein, mouse
- Interleukin-2
- Receptors, Interleukin-2
- Recombinant Fusion Proteins
- Trinitrobenzenesulfonic Acid
- Dextran Sulfate
- Caspase 3
|
Topics |
- Animals
- Apoptosis
(drug effects, immunology)
- Body Weight
(drug effects)
- Caspase 3
(administration & dosage, genetics, pharmacology, therapeutic use)
- Cell Proliferation
(drug effects)
- Colon
(drug effects, pathology)
- Dextran Sulfate
(administration & dosage, pharmacology)
- Diphtheria Toxin
(administration & dosage, genetics, pharmacology, therapeutic use)
- Drug Delivery Systems
(methods)
- Forkhead Transcription Factors
(metabolism)
- Inflammatory Bowel Diseases
(chemically induced, drug therapy, immunology, pathology)
- Interleukin-2
(genetics, metabolism)
- Lymph Nodes
(drug effects, immunology, pathology)
- Male
- Mice
- Mice, Inbred BALB C
- Receptors, Interleukin-2
(metabolism)
- Recombinant Fusion Proteins
(genetics, pharmacology, therapeutic use)
- Spleen
(drug effects, immunology, pathology)
- Survival Analysis
- T-Lymphocyte Subsets
(drug effects, immunology, pathology)
- T-Lymphocytes, Regulatory
(drug effects, immunology, metabolism, pathology)
- Trinitrobenzenesulfonic Acid
(administration & dosage, pharmacology)
|