title: A novel immunogen to modulate cytokine production and promote immune system reconstitution in HIV-AIDS.
abstract: This 'proof of concept' study was implemented in anticipation of identifying and testing a novel antigen of human origin as a potential immunogen in a paradigm that emphasizes immunomodulation and immune system reconstitution as requisites to the development of an effective human immunodeficiency virus (HIV)-acquired immune deficiency syndrome vaccine. Fifteen HIV-infected, highly active antiretroviral therapy (HAART) naive, otherwise healthy male seropositive patients were stratified by [CD4+] into 3 groups of 5 patients: group 1 >500/mm; group 2 > 250/mm but <500/mm; and group 3 < 250/mm. Five healthy male subjects were used as controls. Replicate peripheral blood mononuclear cell (PBMC) [H]thymidine uptake phytohemaglutinin-stimulated proliferation studies, and serum cytokine assays were carried out in the presence or absence of Kveim antigen at dilutions ranging from 0.001 to 100 μg/mL. Serum cytokines [interleukin-2 (IL-2), IL-4, IL-6, interferon gamma, and tumor necrosis factor alpha] were assayed using standardized methodology. Nonparametric statistical analyses and linear regression analysis were used to test for statistical significance and strength of associations. PBMCs harvested from HIV-infected patients and incubated, ex vivo, demonstrated reproducible, antigen concentration-dependent changes in cytokine production over a range of antigen concentrations (0.001-100 μg/mL) in contrast to antigen-naive PBMCs and controls. Significant correlations were demonstrated between antigen concentration and the amount of cytokines secreted. The magnitude of the cytokine response and the patterns of cytokine secretion were HIV group-specific and could be used to identify and distinguish between the 3 groups of HIV-infected subjects. A shift toward the production of type 1-like (Th1) cytokines characteristically seen in systemic sarcoidosis and associated with effective HAART was seen when patterns of cytokine secretion were compared between antigen exposed and antigen-naive PBMCs. PBMCs harvested from seropositive HIV-infected patients and exposed to the Kveim antigen have the following properties: (1) They demonstrate proliferation and exhibit an antigen concentration-dependent secretion of cytokines. The magnitude of the cytokine response can be used to identify and distinguish between groups of seropositive patients stratified by [CD4+]. (2) These PBMCs secrete cytokines in patterns suggestive of a shift to a type 1-like (Th1) response characteristic of HAART and sarcoidosis as opposed to the type 2-like (Th2) cytokine profile characteristic of HIV-acquired immune deficiency syndrome.
authors.affiliation: Department of Medicine, Los Angeles County, Harbor-UCLA Medical Center and LABioMed Research Institute, Torrance, CA, USA.
authors.forename: Jack L
authors.initials: JL
authors.lastname: Segal
authors.forename: John F
authors.initials: JF
authors.lastname: Thompson
authors.forename: Richard A
authors.initials: RA
authors.lastname: Charter
mesh_terms: D000328:Adult; D000941:Antigens / Q000008:administration & dosage / Q000276:immunology*; D023241:Antiretroviral Therapy, Highly Active / Q000379:methods; D016022:Case-Control Studies; D049109:Cell Proliferation; D016207:Cytokines / Q000097:blood* / Q000276:immunology / Q000378:metabolism; D015658:HIV Infections / Q000188:drug therapy / Q000276:immunology*; D006679:HIV Seropositivity / Q000276:immunology; D006801:Humans; D007731:Kveim Test; D007963:Leukocytes, Mononuclear / Q000378:metabolism*; D016014:Linear Models; D008297:Male; D008875:Middle Aged; D011446:Prospective Studies; D055815:Young Adult
chemical_list: D000941:Antigens; D016207:Cytokines