Defensins act as potent adjuvants that promote cellular and humoral immune responses in mice to a lymphoma idiotype and carrier antigens.
Defensins released by neutrophils are able to kill a broad spectrum of microbes. They also induce leukocyte migration in vitro and elicit inflammatory leukocyte responses at s.c. injection sites in mice. In vitro experiments showed that human defensins enhanced concanavalin A-stimulated murine spleen cell proliferation and IFN-gamma production. This led us to examine the effects of human defensins on specific immune responses in vivo. BALB/c mice were immunized with 50 microg of keyhole limpet hemocyanin (KLH) adsorbed to aluminum hydroxide and administered with defensins in aqueous solution. Intraperitoneal administration of defensins significantly increased the production of KLH-specific IgG1, IgG2a and IgG2b antibodies 14 days after immunization. In vitro splenic KLH-specific proliferative responses were higher in mice treated with KLH and defensins than in those treated with KLH alone. Increased IFN-gamma and, to a lesser extent, IL-4 production were also detected in the supernatants of ex vivoKLH-activated spleen cells from mice treated with defensins. Finally, defensins significantly enhanced the antibody response to a syngeneic tumor antigen, lymphoma Ig idiotype and also augmented resistance to tumor challenge. These results indicate that defensins act as potent immune adjuvants by inducing the production of lymphokines, which promote T cell-dependent cellular immunity and antigen-specific Ig production. Thus, defensins appear to function as neutrophil-derived signals that promote adaptive immune responses.
Tani
K
K
Laboratory of Molecular Immunoregulation, National Cancer Institute Frederick Cancer Research and Development Center, Frederick, MD 21702, USA.
Murphy
W J
WJ
Chertov
O
O
Salcedo
R
R
Koh
C Y
CY
Utsunomiya
I
I
Funakoshi
S
S
Asai
O
O
Herrmann
S H
SH
Wang
J M
JM
Kwak
L W
LW
Oppenheim
J J
JJ
D000276:Adjuvants, Immunologic / Q000494:pharmacology*; D000818:Animals; D000951:Antigens, Neoplasm / Q000276:immunology*; D002478:Cells, Cultured; D023082:Defensins; D004305:Dose-Response Relationship, Drug; D004797:Enzyme-Linked Immunosorbent Assay; D005260:Female; D005434:Flow Cytometry; D006433:Hemocyanins / Q000276:immunology; D006801:Humans; D007114:Immunization; D007074:Immunoglobulin G / Q000097:blood; D007075:Immunoglobulin M / Q000032:analysis; D007371:Interferon-gamma / Q000032:analysis; D015847:Interleukin-4 / Q000032:analysis; D017493:Leukocyte Common Antigens / Q000032:analysis; D008223:Lymphoma; D051379:Mice; D008807:Mice, Inbred BALB C; D008809:Mice, Inbred C3H; D011506:Proteins / Q000494:pharmacology*; D013154:Spleen / Q000276:immunology / Q000378:metabolism; D014407:Tumor Cells, Cultured
D000276:Adjuvants, Immunologic; D000951:Antigens, Neoplasm; D023082:Defensins; D007074:Immunoglobulin G; D007075:Immunoglobulin M; D011506:Proteins; D015847:Interleukin-4; D007371:Interferon-gamma; D006433:Hemocyanins; D017493:Leukocyte Common Antigens; C032808:keyhole-limpet hemocyanin