title: Applying TLR synergy in immunotherapy: implications in cutaneous leishmaniasis.
abstract: Therapy of intracellular pathogens can be complicated by drug toxicity, drug resistance, and the need for prolonged treatment regimens. One approach that has shown promise is immunotherapy. Leishmaniasis, a vector-borne disease ranked among the six most important tropical infectious diseases by the World Health Organization, has been treated clinically with crude or defined vaccine preparations or cytokines, such as IFN-gamma and GM-CSF, in combination with chemotherapy. We have attempted to develop an improved and defined immunotherapeutic using a mouse model of cutaneous leishmaniasis. We hypothesized that immunotherapy may be improved by using TLR synergy to enhance the parasite-specific immune response. We formulated L110f, a well-established Leishmania poly-protein vaccine candidate, in conjunction with either monophosphoryl lipid A, a TLR4 agonist, or CpG, a TLR9 agonist, or a combination of these, and evaluated anti-Leishmania immune responses in absence or presence of active disease. Only mice treated with L110f plus monophosphoryl lipid A-CpG were able to induce a strong effective T cell response during disease and subsequently cured lesions and reduced parasite burden when compared with mice treated with L110f and either single adjuvant. Our data help to define a correlate of protection during active infection and indicate TLR synergy to be a potentially valuable tool in treating intracellular infections.
authors.affiliation: Infectious Disease Research Institute, Seattle, WA 98104, USA.
authors.forename: Vanitha S
authors.initials: VS
authors.lastname: Raman
authors.forename: Ajay
authors.initials: A
authors.lastname: Bhatia
authors.forename: Alex
authors.initials: A
authors.lastname: Picone
authors.forename: Jacqueline
authors.initials: J
authors.lastname: Whittle
authors.forename: Hilton R
authors.initials: HR
authors.lastname: Bailor
authors.forename: Joanne
authors.initials: J
authors.lastname: O'Donnell
authors.forename: Sowmya
authors.initials: S
authors.lastname: Pattabhi
authors.forename: Jeffrey A
authors.initials: JA
authors.lastname: Guderian
authors.forename: Raodoh
authors.initials: R
authors.lastname: Mohamath
authors.forename: Malcolm S
authors.initials: MS
authors.lastname: Duthie
authors.forename: Steven G
authors.initials: SG
authors.lastname: Reed
mesh_terms: D000276:Adjuvants, Immunologic / Q000008:administration & dosage; D000818:Animals; D000942:Antigens, Bacterial / Q000008:administration & dosage; D001854:Bone Marrow Cells / Q000276:immunology / Q000378:metabolism; D002478:Cells, Cultured; D003598:Cytoskeletal Proteins / Q000502:physiology; D004359:Drug Therapy, Combination; D005260:Female; D018664:Interleukin-12 / Q000096:biosynthesis; D016773:Leishmaniasis, Cutaneous / Q000276:immunology* / Q000382:microbiology / Q000628:therapy*; D008050:Lipid A / Q000008:administration & dosage / Q000031:analogs & derivatives; D008070:Lipopolysaccharides / Q000008:administration & dosage; D051379:Mice; D008807:Mice, Inbred BALB C; D009838:Oligodeoxyribonucleotides / Q000008:administration & dosage; D000071198:Pyrin; D051193:Toll-Like Receptors / Q000819:agonists / Q000502:physiology*
chemical_list: D000276:Adjuvants, Immunologic; D000942:Antigens, Bacterial; C408982:CPG-oligonucleotide; D003598:Cytoskeletal Proteins; D008050:Lipid A; D008070:Lipopolysaccharides; D009838:Oligodeoxyribonucleotides; D000071198:Pyrin; D051193:Toll-Like Receptors; C032774:antigen L; D018664:Interleukin-12; C048436:monophosphoryl lipid A