ovalbumin and Lymphoma--Non-Hodgkin

Cancer-induced immunotolerance mediated by inducible Treg (iTreg) is a major obstacle to cancer immunotherapy. In a basic study of immunotolerance, injection of an endogenous superantigen, i.e. the minor lymphocyte stimulatory (Mls)-1(a), into specific TCR Vbeta8.1-Tg mice enabled generation of anergic CD25(-) iTreg, the immunosuppressive function of which was maintained by IL-10 production via p38-MAPK activation. Interestingly, although p38-chemical inhibitor (p38-inhibitor) is capable of breaking CD25(-) iTreg-induced immunotolerance, the p38-inhibitor had hardly any immunotolerance breaking effect when CD25(+) Treg were present, suggesting that depletion of CD25(+) Treg is necessary for p38-inhibitor to be effective. Peptide OVA(323-339) iv.-injection into its specific TCR-Tg (OT-II) mice also induced adaptive tolerance by iTreg. Peptide immunotherapy with p38-inhibitor after CD25(+) Treg-depletion was performed in an OVA-expressing lymphoma E.G7-bearing tolerant model established by adoptive transfer of OT-II CD25(-) iTreg, which resulted in suppression of tumor growth. Similarly, the antitumor immunity induced by peptide immunotherapy in colon carcinoma CT26-bearing mice, in which the number of IL-10-secreting iTreg is increased, was augmented by treatment with p38-inhibitor after CD25(+) Treg-depletion and resulted in inhibition of tumor progression. These results suggest that simultaneous inhibition of two distinct Treg-functions may be important to the success of cancer immunotherapy.

Topics: Adaptor Proteins, Signal Transducing; Amino Acid Sequence; Animals; Clonal Anergy; Forkhead Transcription Factors; Imidazoles; Immunotherapy; Immunotherapy, Adoptive; Interleukin-10; Interleukin-2 Receptor alpha Subunit; Lymphocyte Depletion; Lymphoma, Non-Hodgkin; Mice; Mice, Inbred Strains; Mice, Transgenic; Minor Lymphocyte Stimulatory Antigens; Molecular Sequence Data; Neoplasm Proteins; Ovalbumin; p38 Mitogen-Activated Protein Kinases; Peptide Fragments; Pyridines; Receptors, Antigen, T-Cell, alpha-beta; Superantigens; T-Lymphocytes, Regulatory; Toll-Like Receptor 9; Tumor Escape