title: The immunotherapeutic role of regulatory T cells in Leishmania (Viannia) panamensis infection.
abstract: Leishmania (Viannia) parasites are etiological agents of cutaneous leishmaniasis in the New World. Infection is characterized by a mixed Th1/Th2 inflammatory response, which contributes to disease pathology. However, the role of regulatory T cells (Tregs) in Leishmania (Viannia) disease pathogenesis is unclear. Using the mouse model of chronic L. (V.) panamensis infection, we examined the hypothesis that Treg functionality contributes to control of pathogenesis. Upon infection, Tregs (CD4(+)Foxp3(+)) presented with a dysregulated phenotype, in that they produced IFN-γ, expressed Tbet, and had a reduced ability to suppress T cell proliferation in vitro. Targeted ablation of Tregs resulted in enlarged lesions, increased parasite load, and enhanced production of IL-17 and IFN-γ, with no change in IL-10 and IL-13 levels. This indicated that an increased inflammatory response was commensurate with disease exacerbation and that the remaining impaired Tregs were important in regulation of disease pathology. Conversely, adoptive transfer of Tregs from naive mice halted disease progression, lowered parasite burden, and reduced cytokine production (IL-10, IL-13, IL-17, IFN-γ). Because Tregs appeared to be important for controlling infection, we hypothesized that their expansion could be used as an immunotherapeutic treatment approach. As a proof of principle, chronically infected mice were treated with rIL-2/anti-IL-2 Ab complex to expand Tregs. Treatment transitorily increased the numbers and percentage of Tregs (draining lymph node, spleen), which resulted in reduced cytokine responses, ameliorated lesions, and reduced parasite load (10(5)-fold). Thus, immunotherapy targeting Tregs could provide an alternate treatment strategy for leishmaniasis caused by Leishmania (Viannia) parasites.
authors.affiliation: Department of Epidemiology of Microbial Diseases, Yale School of Public Health, New Haven, CT 06520;
authors.forename: Allison
authors.initials: A
authors.lastname: Ehrlich
authors.affiliation: Department of Epidemiology of Microbial Diseases, Yale School of Public Health, New Haven, CT 06520;
authors.forename: Tiago Moreno
authors.initials: TM
authors.lastname: Castilho
authors.affiliation: Department of Epidemiology of Microbial Diseases, Yale School of Public Health, New Haven, CT 06520;
authors.forename: Karen
authors.initials: K
authors.lastname: Goldsmith-Pestana
authors.affiliation: Department of Immunobiology, Yale School of Medicine, New Haven, CT 06520; and.
authors.forename: Wook-Jin
authors.initials: WJ
authors.lastname: Chae
authors.affiliation: Department of Immunobiology, Yale School of Medicine, New Haven, CT 06520; and.
authors.forename: Alfred L M
authors.initials: AL
authors.lastname: Bothwell
authors.affiliation: Institute of Infection Immunology, Centre for Experimental and Clinical Infection Research, TWINCORE, 30625 Hanover, Germany.
authors.forename: Tim
authors.initials: T
authors.lastname: Sparwasser
authors.affiliation: Department of Epidemiology of Microbial Diseases, Yale School of Public Health, New Haven, CT 06520; diane.mcmahon-pratt@yale.edu.
authors.forename: Diane
authors.initials: D
authors.lastname: McMahon-Pratt
mesh_terms: D000818:Animals; D000906:Antibodies / Q000276:immunology / Q000627:therapeutic use; D000936:Antigen-Antibody Complex / Q000627:therapeutic use; D049109:Cell Proliferation; D005260:Female; D016219:Immunotherapy, Adoptive; D050503:Indoleamine-Pyrrole 2,3,-Dioxygenase / Q000037:antagonists & inhibitors; D007249:Inflammation / Q000276:immunology; D007371:Interferon-gamma / Q000096:biosynthesis; D016753:Interleukin-10 / Q000096:biosynthesis; D018793:Interleukin-13 / Q000096:biosynthesis; D020381:Interleukin-17 / Q000096:biosynthesis; D007376:Interleukin-2 / Q000276:immunology / Q000627:therapeutic use; D018334:Leishmania guyanensis / Q000276:immunology*; D007897:Leishmaniasis, Mucocutaneous / Q000276:immunology* / Q000469:parasitology / Q000628:therapy*; D018655:Lymphocyte Count; D051379:Mice; D008807:Mice, Inbred BALB C; D008822:Mice, Transgenic; D059208:Parasite Load; D050378:T-Lymphocytes, Regulatory / Q000276:immunology* / Q000637:transplantation; D016212:Transforming Growth Factor beta / Q000096:biosynthesis
chemical_list: D000906:Antibodies; D000936:Antigen-Antibody Complex; C556062:IL10 protein, mouse; D050503:Indoleamine-Pyrrole 2,3,-Dioxygenase; D018793:Interleukin-13; D020381:Interleukin-17; D007376:Interleukin-2; D016212:Transforming Growth Factor beta; D016753:Interleukin-10; D007371:Interferon-gamma
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