Abstract. The plasma protein fibronectin is an important opsonin in wound repair and host defense. To better understand the process of fibronectin-mediated phagocytosis, we have transfectod K562 cells, which endogenously express 0~5fll, with a,f13. In these transfectants, antibodies to t~fl3 block phagocytosis of fibronectin-opsonized beads completely, even though half the ingestion occurs through endogenous 0t5/3~ receptors, c~5/31-mediated adhesion to fibronectincoated surfaces is unaffected by c~j33 ligation. Neither av/$5 nor O/M/~2 ligation affects O~5/~1 phagocytic function in transfectants expressing these receptors. Pharmacologic data suggest that o~v/~3 ligation suppresses the phagocytic competence of high affinity ot5/$1 receptors through a signal transduction pathway, perhaps involving protein kinase C. In addition to its significance for phagocytosis, otv/33 regulation of o~5/31 function may be significant for its roles in cell migration, metastasis, and angiogenesis. MACROPHAGE interaction with fibronectin (Fn) 1 is recognized as an important aspect of host defense and wound repair. Fibronectin opsonlzation is necessary for macrophage recognition and phagocytosis of particulate debris released from tissues after bum and trauma (23,41,53,58), resolution of bacteremia during sepsis (48, 53), and clearance of fibrin during disseminated intravascular coagulation (9,11,60). In addition, macrophage adhesion to fibronectin-coated surfaces affects a variety of macrophage functions including chemotaxis (25, 50), differentiation (8), secretion (7,45), and phagocytosis via immunologic receptors (12,52,66). Nonetheless, the moleculax nature of the interactions leading to these critical macrophage functions is unknown.Studies which have examined fibronectin receptors on macrophages in detail have demonstrated an unexpectedly large number of integrin and non-integrin fibronectin-binding proteins (10,13,16,17,29,42,59,63). Four integrin receptors with fibronectin binding capability have been identified on mononuclear phagocytes. Fibronectin binding to VLA-5 (ot5/~1), the vitronectin receptor (otJ~3) and the Leukocyte Response Integrin (LRI) appears dependent on the RGD adhesion sequence (13, 16, 29); (VLA-4 (~,) binds fibronectin independent of this sequence (28). Additional macrophage integrins ~J~5, VLA-3 (ot3/~,), and OtM/~2, may also Please address all correspondence to Dr. Eric J. Brown, Infectious Diseases, Campus Box 8051, Washington University School of Medicine, St. Louis, MO 63110. bind fibronectin (1%42,59,63). To add to the complexity of fibronectin binding by macrophages, several of these receptors can recognize alternative, potentially competing ligands. Moreover, a~/31 and perhaps other of these integrins can assume two affinity states for fibronectin (26). The existence of these distinct but related receptors for the same ligand suggest that they may have different roles in macrophage function. The purpose of the present work was to begin to determine how these various receptors contributed to adhe...
ClincalTrials.gov identifier: http://www.clinicaltrials.gov/ct2/show/NCT00280033?term= NCT00280033&rank=1 NCT00280033 .
To improve immune responses to influenza vaccine, a trivalent inactivated vaccine containing 60 µg of the HA of each component (A/H3N2, A/H1N1, B) was compared to a licensed vaccine containing 15 µg of the HA of each. More local and systemic reactions were reported by subjects given the high dosage but only local pain and myalgias were significantly increased. The high dosage vaccine induced a higher frequency of serum antibody increases (≥4 fold) in both hemagglutination-inhibiting (HAI) and neutralization tests for all three vaccine viruses in the total group as well as subjects vaccinated and those not vaccinated the previous year. Mean titers of antibody attained, the magnitude of antibody increases and the frequencies of persons with final HAI antibody titers ≥1:32, ≥1:64, and ≥1:128 were all greater for the high dosage group in both serologic tests, for all groups, and for all vaccine viruses. These increased immune responses should provide increased protection against influenza in the elderly. KeywordsInfluenza; vaccines; elderly IntroductionTrivalent inactivated influenza vaccines (TIV) are effective for prevention of influenza and its complications among the elderly. However, there is a need to improve these vaccines because the degree of protection is variable and sometimes low [1,2]. One option for improving TIV is to increase vaccine dosage so as to increase serum antibody responses to the hemagglutinin (HA) as measured in hemagglutination-inhibiting (HAI) and neutralization (neut) tests. Increasing antibody to the HA in serum correlates with increasing protection against infection and illness after exposure to influenza and available information indicates that this antibody is the primary mediator of immunity to infection [3,5].A number of studies have shown that increasing the dosage of TIV will induce an increase in the serum antibody response [6][7][8][9][10][11][12][13][14][15][16][17][18]. Dosages as high as 135 µg of each HA in TIV (containing an A/H3N2, A/H1N1 and B virus strain) have been shown to be safe in elderly subjects and to induce significantly greater serum antibody responses as dosage was increased [15,17]. In a recent study, we tested the 2000-2001 formulation of licensed trivalent vaccine containing the standard 15 µg of the HA of each component as well as unlicensed concentrations of the same vaccine containing 30 ug and 60 ug of each HA; the increased dosage was well tolerated and induced an increased antibody response [16]. To confirm this finding and to evaluate a high dosage vaccine designed for clinical development, a larger number of elderly subjects were given a new 60 µg per HA TIV. The gelatin and thimerosal components in licensed vaccine were removed and only the three viral components used in [2004][2005] Materials and Methods Study DesignThis was a multi-site, phase II, randomized, double-blind, stratified study. The primary hypothesis was that the new TIV containing 60 µg of each antigen would be well tolerated and induce a significantly greater serum HAI ...
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