Impaired plasmacytoid dendritic cell (PDC)-NK cell activity in viremic human immunodeficiency virus infection attributable to impairments in both PDC and NK cell function.

Human immunodeficiency virus (HIV) and hepatitis C virus (HCV) infections impair plasmacytoid dendritic cell (PDC) and natural killer (NK) cell subset numbers and functions, though little is known about PDC-NK cell interactions during these infections. We evaluated PDC-dependent NK cell killing and gamma interferon (IFN-gamma) and granzyme B production, using peripheral blood mononuclear cell (PBMC)-based and purified cell assays of samples from HCV- and HIV-infected subjects. CpG-enhanced PBMC killing and IFN-gamma and granzyme B activity (dependent on PDC and NK cells) were impaired in viremic HIV infection.

Accessory cell dependent NK cell mediated PBMC IFN-gamma production is defective in HIV infection.

HCV and HIV infections impair dendritic cell function. We evaluated the impact of HCV, HIV, and HCV-HIV infection on MDC-NK interactions by analyzing CD3 depleted PBMC for NK cell IFN-gamma in response to IL-12 or poly (I:C). Purified MDC and NK cells were analyzed for TLR ligand-dependent, MDC-dependent NK activity.

CpG-induced IFNgamma expands TLR4-specific IL-18 responses in vivo.

Serum IL-18 responses to LPS increase after pretreatment with CpG-containing DNA. Compared to saline-pretreated controls, mice pretreated with CpG for two days produced 20-fold more serum IL-18 when challenged with lipopolysaccharide (LPS). In contrast, IFNgamma-deficiency or anti-IFNgamma pretreatment reduced CpG-expanded IL-18 responses to LPS by 67 and 83%, respectively.

In vivo and in vitro regulation of type I IFN synthesis by synergistic effects of CD40 and type II IFN.

During cognate interaction with CD40 ligand (CD154)-expressing T cells, Ag-presenting accessory cells are activated for increased cytokine synthetic and costimulatory function. We examined whether CD40 modulates in vivo innate immune function over time, hypothesizing that distinct cytokine responses evolve to delayed microbial exposure. C3H/HeN mice pretreated with activating anti-CD40 Ab (FGK45) produced 10-fold more serum IFN-gamma and IL-12 p70 to delayed, but not synchronous, challenge with LPS.

Fms-like tyrosine kinase 3-based immunoprophylaxis against infection is improved by adjuvant treatment with anti-interleukin-10 antibody.

Fms-like tyrosine kinase 3 ligand (Flt3L) expands dendritic-cell populations in vivo and protects against microbial infection in healthy and immunocompromised hosts. Approaches for optimizing the protective effects of Flt3L in vivo are not well known.METHODS.

Interleukin 12 and interferon-gamma synthetic deficiency is associated with dendritic cell cytopenia after cardiac surgery.

Traumatic or inflammatory injury associates with deactivation of monocytes and impaired synthesis of proinflammatory cytokines. We conducted a prospective, observational study to test whether cardiac surgery additionally impaired dendritic and natural killer (NK) cell functions responsible for innate immune production of interleukin (IL)-12-dependent interferon (IFN)-gamma in response to bacteria or toll-like receptor agonists. Blood samples were taken just before induction of anesthesia and 24 h postoperatively.

Distinct phases in recovery of reconstituted innate cellular-mediated immunity after murine syngeneic bone marrow transplantation.

Defects in immune reconstitution after hematopoietic stem cell transplantation confer extreme infection risk on to the transplant recipient. Perturbations in adaptive immune reconstitution have been well characterized, yet defects in reconstituted innate cellular-mediated immunity remain largely unstudied. Recovery in innate effector cells was defined by using an established murine model of autologous bone marrow transplantation.

Selective impairments in dendritic cell-associated function distinguish hepatitis C virus and HIV infection.

Impaired APC functions may play important roles in chronicity of hepatitis C virus (HCV) and HIV infections. To investigate the separate and combined effects of HCV and HIV infection on immature dendritic cells (DCs), we evaluated myeloid-derived DC (MDC) and plasmacytoid-derived DC (PDC) frequencies and functions, measured by Toll-like receptor ligand-induced IFN-alpha and IL-12, in healthy controls and subjects with chronic HCV, HIV, and HCV-HIV infection. To evaluate the relation between innate and adaptive immunity, we measured HCV-specific IFN-gamma-producing T cell frequency.

Distinct modulatory effects of LPS and CpG on IL-18-dependent IFN-gamma synthesis.

Innate cellular production of IFN-gamma is suppressed after repeated exposure to LPS, whereas CpG-containing DNA potentiates IFN-gamma production. We compared the modulatory effects of LPS and CpG on specific cellular and cytokine responses necessary for NK-cell dependent IFN-gamma synthesis. C3H/HeN mice pretreated with LPS for 2 days generated 5-fold less circulating IL-12 p70 and IFN-gamma in response to subsequent LPS challenge than did challenged control mice.

Modulation of T-cell costimulation as immunotherapy or immunochemotherapy in experimental visceral leishmaniasis.

CD40 ligand (CD40L)-deficient C57BL/6 mice failed to control intracellular Leishmania donovani visceral infection, indicating that acquired resistance involves CD40-CD40L signaling and costimulation. Conversely, in wild-type C57BL/6 and BALB/c mice with established visceral infection, injection of agonist anti-CD40 monoclonal antibody (MAb) induced killing of approximately 60% of parasites within liver macrophages, stimulated gamma interferon (IFN-gamma) secretion, and enhanced mononuclear cell recruitment and tissue granuloma formation. Comparable parasite killing was also induced by MAb blockade (inhibition) of cytotoxic T lymphocyte antigen-4 (CTLA-4) which downregulates separate CD28-B7 T-cell costimulation.

Immunoenhancement combined with amphotericin B as treatment for experimental visceral leishmaniasis.

To determine if stimulation of Th1-cell-associated immune responses, mediated by interleukin 12 (IL-12) and gamma interferon (IFN-gamma), enhance the antileishmanial effect of amphotericin B (AMB), Leishmania donovani-infected BALB/c mice were first treated with (i) exogenous IL-12 to induce IFN-gamma, (ii) agonist anti-CD40 monoclonal antibody (MAb) to maintain IL-12 and induce IFN-gamma, or (iii) anti-IL-10 receptor (IL-10R) MAb to blockade suppression of IL-12 and IFN-gamma. In animals with established visceral infection, low-dose AMB alone (two injections of 1 mg/kg of body weight; total dose, 2 mg/kg) killed 15 to 29% of liver parasites; by themselves, the immunointerventions induced 16 to 33% killing. When the interventions were combined, the leishmanicidal activities increased 3.

Determinants of response to interleukin-10 receptor blockade immunotherapy in experimental visceral leishmaniasis.

In established Leishmania donovani visceral infection in normal mice, anti-interleukin (IL)-10 receptor (IL-10R) monoclonal antibody (MAb) treatment induced intracellular parasite killing within liver macrophages. IL-10R blockade maintained IL-12 protein 40, markedly increased interferon (IFN)-gamma serum levels, and enhanced tissue inducible nitric oxide synthase (iNOS) expression and granuloma assembly. Optimal MAb-induced killing, including synergism with antimony chemotherapy, required endogenous IL-12 and/or IFN-gamma and at least one IFN-gamma-regulated macrophage mechanism-iNOS or phagocyte oxidase.

Vaccine-induced protection against Helicobacter pylori in mice lacking both antibodies and interleukin-4.

To test the hypothesis that a Th2 response to Helicobacter pylori is necessary for protection and to address the possibility that humoral and Th2 cellular responses may compensate for each other, we generated mice deficient in both interleukin-4 (IL-4) and antibodies. The immunized double-knockout mice were protected from H. pylori challenge, as were the parental strains and wild-type C57BL/6 mice.

Vaccine-induced reduction of Helicobacter pylori colonization in mice is interleukin-12 dependent but gamma interferon and inducible nitric oxide synthase independent.

Previous studies with mice have shown that major histocompatibility complex class II (MHC-II) is required for protection from Helicobacter pylori, while MHC-I and antibodies are not. Thus, CD4(+) T cells are presumed to play an essential role in protective immunity via secretion of cytokines. To determine which cytokines are associated with a reduction of bacterial load in immunized mice, gastric cytokine expression was examined by semiquantitative reverse transcription-PCR in protected (defined as > or =2-log-unit decrease in bacterial load) and unprotected mice 4 weeks after challenge.