ABSTRACT
To determine the contribution of vascular endothelial growth factor (VEGF) to cerebral edema formation in bacterial meningitis, we used a VEGF neutralizing antibody to block VEGF in rabbits, following induction of meningitis by intracisternal inoculation with 10(9) heat-killed pneumococci. At 8 h, cerebrospinal fluid (CSF) VEGF was significantly elevated in infected untreated animals, and correlated with CSF white blood cell (WBC) count (r=0.56, P=0.004), and brain water content (r=0.42, P=0.04). Blocking of VEGF did not attenuate brain edema, blood-brain barrier disruption, or CSF pleocytosis. The functional role of VEGF in the pathophysiology of BM remains elusive.
Subject(s)
Antibodies, Blocking/administration & dosage , Brain Edema/immunology , Brain Edema/physiopathology , Capillary Permeability/immunology , Meningitis, Pneumococcal/immunology , Meningitis, Pneumococcal/physiopathology , Vascular Endothelial Growth Factor A/antagonists & inhibitors , Vascular Endothelial Growth Factor A/immunology , Animals , Antibodies, Blocking/pharmacology , Antibodies, Monoclonal/administration & dosage , Antibodies, Monoclonal/pharmacology , Antibodies, Monoclonal, Humanized , Bevacizumab , Brain Edema/blood , Brain Edema/cerebrospinal fluid , Cell Movement/immunology , Cisterna Magna , Female , Humans , Injections, Intravenous , Leukocytes/immunology , Leukocytes/pathology , Meningitis, Pneumococcal/blood , Meningitis, Pneumococcal/cerebrospinal fluid , Mice , Rabbits , Vascular Endothelial Growth Factor A/blood , Vascular Endothelial Growth Factor A/cerebrospinal fluid , Water-Electrolyte BalanceABSTRACT
Cryptococcal capsular Ags induce the production of proinflammatory cytokines in patients with cryptococcal meningitis. Despite this, their cerebrospinal fluid typically contains few neutrophils. Capsular glucuronoxylomannan is generally considered to mediate the inhibition of neutrophil extravasation. In the current study, culture supernatant harvested from the nonglucuronoxylomannan-producing strain CAP67 was found to be as potent as supernatant from wild-type strains in preventing migration. We identified capsular mannoprotein (MP)-4 as the causative agent. Purified MP-4 inhibited migration of neutrophils toward platelet-activating factor, IL-8, and fMLP, probably via a mechanism involving chemoattractant receptor cross-desensitization, as suggested by its direct chemotactic activity. Supporting this hypothesis, MP-4 elicited Ca(2+) transients that were inhibited by preincubation with either fMLP, IL-8, or C5a, but not platelet-activating factor, and vice versa. Moreover, MP-4 strongly decreased the neutrophil surface expression of L-selectin and induced shedding of TNF receptors p55/p75, whereas CD11b/18 increased. Finally, MP-4 was clearly detectable in both serum and cerebrospinal fluid of patients suffering from cryptococcal meningitis. These findings identify MP-4 as a novel capsular Ag prematurely activating neutrophils and desensitizing them toward a chemoattractant challenge.
Subject(s)
Antigens, Bacterial/pharmacology , Chemotaxis, Leukocyte/drug effects , Cryptococcus/pathogenicity , Membrane Glycoproteins/pharmacology , Neutrophils/drug effects , Antigens, Bacterial/blood , CD18 Antigens/metabolism , Calcium/metabolism , Cells, Cultured , Chemotactic Factors/pharmacology , Cryptococcosis/blood , Cryptococcus/immunology , Dose-Response Relationship, Drug , Drug Antagonism , Humans , L-Selectin/metabolism , Macrophage-1 Antigen/metabolism , Membrane Glycoproteins/blood , Meningitis, Bacterial/blood , Neutrophils/immunology , Receptors, Immunologic/metabolism , Receptors, Tumor Necrosis Factor/metabolismABSTRACT
In vitro studies suggest that CD4(+) cells with a T helper 2 (Th2) phenotype better support human immunodeficiency virus type 1 (HIV-1) replication than do cells of the Th1 phenotype. As a result, Th2-type immune responses may be substantially affected by HIV-1 coinfection. To test this hypothesis, a comparison was done of proliferation and cytokine production by peripheral blood mononuclear cells from patients with schistosomiasis who were positive or negative for HIV-1. Patients with schistosomiasis with HIV-1 coinfections had significantly lower interleukin (IL)-4 and IL-10 production than did HIV-1-negative individuals. In contrast, interferon-gamma production levels were similar between the 2 groups. Furthermore, in patients with HIV-1, a decrease in CD4(+) T cells was correlated with an increased Th1:Th2 cytokine production ratio. The effect of praziquantel treatment on proliferation and cytokine responses also differed between HIV-1 infection groups. Thus, HIV-1 infection affects immune response patterns of patients with schistosomiasis.
