Characterization of an IL-2 mimetic with therapeutic potential.
Human interleukin-2 (IL-2) interacts with two types of functional receptors (IL-2R alpha betagamma and IL-2R betagamma) and acts on a broad range of target cells involved in inflammatory reactions and immune responses. IL-2 is also used in different clinical trials aimed at improving the treatment of some cancers and the recovery of CD4 lymphocytes by HIV patients. The therapeutic index of IL-2 is limited by various side effects dominated by the vascular leak syndrome. We have shown that a chemically synthesised fragment of the IL-2 sequence can fold into a helical tetramer likely mimicking the quatemary structure of an hemopoietin. Indeed, peptide p1-30 (containing amino acids 1 to 30, including the sequence corresponding to the entire alpha helix A of IL-2) spontaneously folds into an alpha-helical homotetramer and stimulates the growth of T-cell lines expressing human IL-2R beta, whereas shorter versions of the peptide lack helical structure and are inactive. At the cellular level, p1-30 induces lymphokine-activated killer (LAK) cells and preferentially activates CD8 low lymphocytes and natural killer cells, which constitutively express IL-2R beta. A significant IFN-gamma production is also detected following p1-30 stimulation. A mutant form of p1-30 (Asp20-->Lys) which is likely unable to induce vascular leak syndrome remains capable to generate LAK cells like the original p1-30 peptide. Altogether our data suggest that p1-30 has therapeutic potential.
Eckenberg
R
R
Dept. d'Immunologie, Institut Pasteur, Paris, France.
Rose
T
T
Moreau
J L
JL
Weil
R
R
Gesbert
F
F
Dubois
S
S
Tello
D
D
Bossus
M
M
Gras
H
H
Tartar
A
A
Bertoglio
J
J
Chouaïb
S
S
Jacques
Y
Y
Alzari
P M
PM
Thèze
J
J
D018414:CD8-Positive T-Lymphocytes / Q000187:drug effects / Q000276:immunology; D006801:Humans; D007376:Interleukin-2 / Q000819:agonists / Q000031:analogs & derivatives* / Q000502:physiology / Q000627:therapeutic use*; D015979:Killer Cells, Lymphokine-Activated / Q000187:drug effects / Q000276:immunology; D007694:Killer Cells, Natural / Q000187:drug effects / Q000276:immunology; D015394:Molecular Structure; D010446:Peptide Fragments / Q000737:chemistry / Q000627:therapeutic use; D015375:Receptors, Interleukin-2 / Q000187:drug effects / Q000502:physiology; D015398:Signal Transduction
D007376:Interleukin-2; D010446:Peptide Fragments; D015375:Receptors, Interleukin-2