A small peptide (CEL-1000) derived from the beta-chain of the human major histocompatibility complex class II molecule induces complete protection against malaria in an antigen-independent manner.
CEL-1000 (DGQEEKAGVVSTGLIGGG) is a novel potential preventative and therapeutic agent. We report that CEL-1000 confers a high degree of protection against Plasmodium sporozoite challenge in a murine model of malaria, as shown by the total absence of blood stage infection following challenge with 100 sporozoites (100% protection) and by a substantial reduction (400-fold) of liver stage parasite RNA following challenge with 50,000 sporozoites. CEL-1000 protection was demonstrated in A/J (H-2(a)) and C3H/HeJ (H-2(k)) mice but not in BALB/c (H-2(d)) or CAF1 (A/J x BALB/c F(1) hybrid) mice. In CEL-1000-treated and protected mice, high levels of gamma interferon (IFN-gamma) in serum and elevated frequencies of hepatic and splenic CD4+ IFN-gamma-positive T cells were detected 24 h after administration of an additional dose of CEL-1000. Treatment of A/J mice that received CEL-1000 with antibodies against IFN-gamma just prior to challenge abolished the protection, and a similar treatment with antibodies against CD4+ T cells partially reduced the level of protection, while treatment with control antibodies or antibodies specific for interleukin-12 (IL-12), CD8+ T cells, or NK cells had no effect. Our data establish that the protection induced by CEL-1000 is dependent on IFN-gamma and is partially dependent on CD4+ T cells but is independent of CD8+ T cells, NK cells, and IL-12 at the effector phase and does not induce a detectable antibody response.
Charoenvit
Yupin
Y
CEL-SCI Corporation, 8229 Boone Blvd., Suite 802, Vienna, VA 22182, USA.
Brice
Gary T
GT
Bacon
David
D
Majam
Victoria
V
Williams
Jackie
J
Abot
Esteban
E
Ganeshan
Harini
H
Sedegah
Martha
M
Doolan
Denise L
DL
Carucci
Daniel J
DJ
Zimmerman
Daniel H
DH
D000595:Amino Acid Sequence; D000818:Animals; D000918:Antibody Specificity; D000953:Antigens, Protozoan / Q000276:immunology*; D000962:Antimalarials / Q000494:pharmacology*; D016207:Cytokines / Q000097:blood; D004797:Enzyme-Linked Immunosorbent Assay; D005260:Female; D005802:Genes, MHC Class II / Q000235:genetics*; D007371:Interferon-gamma / Q000276:immunology; D007700:Kinetics; D008099:Liver / Q000737:chemistry / Q000469:parasitology; D008288:Malaria / Q000276:immunology / Q000469:parasitology / Q000517:prevention & control*; D051379:Mice; D008807:Mice, Inbred BALB C; D008969:Molecular Sequence Data; D010962:Plasmodium berghei / Q000276:immunology; D010967:Plasmodium yoelii / Q000276:immunology; D012313:RNA / Q000737:chemistry / Q000302:isolation & purification; D020133:Reverse Transcriptase Polymerase Chain Reaction
D000953:Antigens, Protozoan; D000962:Antimalarials; D016207:Cytokines; D012313:RNA; D007371:Interferon-gamma