TY - JOUR
T1 - Nanoparticle formulated alpha-galactosylceramide activates NKT cells without inducing anergy
AU - Thapa, Prakash
AU - Zhang, Guodong
AU - Xia, Chengfeng
AU - Gelbard, Alexander
AU - Overwijk, Willem W.
AU - Liu, Chengwen
AU - Hwu, Patrick
AU - Chang, David Z.
AU - Courtney, Amy
AU - Sastry, Jagannadha K.
AU - Wang, Peng G.
AU - Li, Chun
AU - Zhou, Dapeng
N1 - Funding Information:
We thank Bhanu Prakash Pappu, Yeonseok Chung and Chen Dong for advice and discussion. This project is supported by M.D. Anderson Cancer Center (D.Z. and C.L.), Ohio State University (P.G.W.) and NIH grant AI42694 and 46969 (K.J.S.), and CA123195-01 (P.G.W.). C.L. is supported by John S. Dunn Foundation. D.Z. is recipient of a Developmental Award from Baylor-UTHouston Center for AIDS Research AIDS Research Core Support Grant (AI36211).
PY - 2009/5/26
Y1 - 2009/5/26
N2 - Activation of innate immunity is critical for vaccine development and immunotherapy, through triggering antigen specific immune responses. Natural killer T (NKT) cells are a unique type of innate immune cells which exert potent anti-viral and anti-metastasis function, through producing interferon-γ and activating dendritic cells to present tumor antigens to CD8 T cells. alpha-Galactosylceramide, a synthetic antigen for NKT cells, is an adjuvant for protein antigens which can induce protective immunity against cancer and viral diseases, and has been proven to be safe and immune stimulatory in human cancer and hepatitis patients. Current existing problem for alpha-galactosylceramide is its induction of anergy of NKT cells, due to the non-selective presentation of alpha-galactosylceramide antigen by B cells. We hypothesized that nanoparticle formulated alpha-galactosylceramide may be selectively presented by dendritic cells and macrophages, but not B cells, thus avoiding anergy induction in NKT cells. We have prepared poly-lactic acid based nanoparticles conjugated with alpha-galactosylceramide, examined their stimulation of NKT cells in vitro and in vivo in mice, and showed that nanoparticle formulated alpha-galactosylceramide stimulates NKT cells. In contrast to soluble alpha-galactosylceramide, which caused NKT anergy after single stimulation, nanoparticle formulated alpha-galactosylceramide repeatedly stimulates NKT cells without inducing anergy. Mechanistic studies showed that nanoparticle formulated alpha-galactosylceramide is efficiently presented by mouse CD11c + population containing dendritic cells, and CD11b + population containing macrophages, but very poorly by B220 + population containing B cells. Hence, nanoparticle formulated alpha-galactosylceramide is an attractive immunomodulator for immunotherapy and vaccine development. Future studies will be focused on its application as adjuvant for protein and/or peptide antigens.
AB - Activation of innate immunity is critical for vaccine development and immunotherapy, through triggering antigen specific immune responses. Natural killer T (NKT) cells are a unique type of innate immune cells which exert potent anti-viral and anti-metastasis function, through producing interferon-γ and activating dendritic cells to present tumor antigens to CD8 T cells. alpha-Galactosylceramide, a synthetic antigen for NKT cells, is an adjuvant for protein antigens which can induce protective immunity against cancer and viral diseases, and has been proven to be safe and immune stimulatory in human cancer and hepatitis patients. Current existing problem for alpha-galactosylceramide is its induction of anergy of NKT cells, due to the non-selective presentation of alpha-galactosylceramide antigen by B cells. We hypothesized that nanoparticle formulated alpha-galactosylceramide may be selectively presented by dendritic cells and macrophages, but not B cells, thus avoiding anergy induction in NKT cells. We have prepared poly-lactic acid based nanoparticles conjugated with alpha-galactosylceramide, examined their stimulation of NKT cells in vitro and in vivo in mice, and showed that nanoparticle formulated alpha-galactosylceramide stimulates NKT cells. In contrast to soluble alpha-galactosylceramide, which caused NKT anergy after single stimulation, nanoparticle formulated alpha-galactosylceramide repeatedly stimulates NKT cells without inducing anergy. Mechanistic studies showed that nanoparticle formulated alpha-galactosylceramide is efficiently presented by mouse CD11c + population containing dendritic cells, and CD11b + population containing macrophages, but very poorly by B220 + population containing B cells. Hence, nanoparticle formulated alpha-galactosylceramide is an attractive immunomodulator for immunotherapy and vaccine development. Future studies will be focused on its application as adjuvant for protein and/or peptide antigens.
KW - Biodegradable nanoparticle
KW - Dendritic cells
KW - Natural killer T cells
KW - Phagocytosis
KW - T cell anergy
KW - alpha-galactosylceramide
UR - http://www.scopus.com/inward/record.url?scp=67349171859&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=67349171859&partnerID=8YFLogxK
U2 - 10.1016/j.vaccine.2009.01.047
DO - 10.1016/j.vaccine.2009.01.047
M3 - Article
C2 - 19200815
AN - SCOPUS:67349171859
SN - 0264-410X
VL - 27
SP - 3484
EP - 3488
JO - Vaccine
JF - Vaccine
IS - 25-26
ER -