Enhancement of tumour-specific immune responses in vivo by 'MHC loading-enhancer' (MLE).
BACKGROUND
Class II MHC molecules (MHC II) are cell surface receptors displaying short protein fragments for the surveillance by CD4+ T cells. Antigens therefore have to be loaded onto this receptor in order to induce productive immune responses. On the cell surface, most MHC II molecules are either occupied by ligands or their binding cleft has been blocked by the acquisition of a non-receptive state. Direct loading with antigens, as required during peptide vaccinations, is therefore hindered.


RESULTS
Here we show, that the in vivo response of CD4+ T cells can be improved, when the antigens are administered together with 'MHC-loading enhancer' (MLE). MLE are small catalytic compounds able to open up the MHC binding site by triggering ligand-release and stabilizing the receptive state. Their enhancing effect on the immune response was demonstrated here with an antigen from the influenza virus and tumour associated antigens (TAA) derived from the NY-ESO-1 protein. The application of these antigens in combination with adamantane ethanol (AdEtOH), an MLE compound active on human HLA-DR molecules, significantly increased the frequency of antigen-specific CD4+ T cells in mice transgenic for the human MHC II molecule. Notably, the effect was evident only with the MLE-susceptible HLA-DR molecule and not with murine MHC II molecules non-susceptible for the catalytic effect of the MLE.


CONCLUSIONS
MLE can specifically increase the potency of a vaccine by facilitating the efficient transfer of the antigen onto the MHC molecule. They may therefore open a new way to improve vaccination efficacy and tumour-immunotherapy.
Dickhaut
Katharina
K
Max-Delbrück-Center for Molecular Medicine (MDC), Berlin, Germany.
Hoepner
Sabine
S
Eckhard
Jamina
J
Wiesmueller
Karl-Heinz
KH
Schindler
Luise
L
Jung
Guenther
G
Falk
Kirsten
K
Roetzschke
Olaf
O
D000818:Animals; D015496:CD4-Positive T-Lymphocytes; D019496:Cancer Vaccines / Q000737:chemistry; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D002469:Cell Separation; D018899:CpG Islands; D000949:Histocompatibility Antigens Class II / Q000737:chemistry / Q000276:immunology*; D006801:Humans; D007167:Immunotherapy / Q000379:methods*; D051379:Mice; D008807:Mice, Inbred BALB C; D008822:Mice, Transgenic; D009369:Neoplasms / Q000628:therapy*; D022223:Vaccines, Subunit
D019496:Cancer Vaccines; D000949:Histocompatibility Antigens Class II; D022223:Vaccines, Subunit