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3.  Prostaglandin E2 promotes survival of naive UCB T cells via the Wnt/β-catenin pathway and alters immune reconstitution after UCBT 
Blood Cancer Journal  2014;4(1):e178-.
The outcome of umbilical cord blood transplantation (UCBT) is compromised by low hematopoietic stem cell (HSC) doses leading to prolonged time to engraftment, delayed immunological reconstitution and late memory T-cell skewing. Exposure of UCB to dimethyl-prostaglandin E2 (dmPGE2) increases HSC in vivo. We determined that exposure of UCB T lymphocytes to dmPGE2 modified Wnt signaling resulting in T cell factor (TCF)-mediated transcription. Wnt signaling upregulated interleukin (IL)-7R and IL-2Rβ, resulting in enhanced survival mediated by the homeostatic cytokines IL-7 and IL-15. dmPGE2 also induced components of the Wnt pathway and Wnt receptors, thereby priming UCB T cells to receive signals via Wnt ligands in vivo. We observed that the Wnt transcription factor TCF7 and its target EOMES were elevated in the T cells of patients who received PGE2-treated UCBs. Consistent with the role of Wnt/β-catenin signaling to induce and maintain naive, memory precursors and long-lived central memory CD8+ cells, these patients also had increased fractions of CD8+CD45RO-CD62L+ plus CD8+CD45RO+CD62L+ subsets encompassing these T-cell populations. These effects of the PGE2/Wnt/β-catenin axis may have significant implications for harnessing immunity in the context of UCBT, where impaired immune reconstitution is associated with late memory T-cell skewing.
doi:10.1038/bcj.2013.75
PMCID: PMC3913944  PMID: 24442207
umbilical cord blood transplantation; immune reconstitution; prostaglandin E2; Wnt/β-catenin pathway
4.  Oral Mucosal Expression of HIV-1 Receptors, Co-receptors, and α-defensins: Tableau of Resistance or Susceptibility to HIV Infection? 
Advances in dental research  2006;19(1):49-51.
PMCID: PMC3750741  PMID: 16672549
HIV-1 receptors; DC-SIGN; HIV-1-co-receptors; CCR5; α-defensin-1; gingiva; human
5.  A large single-center experience with allogeneic stem-cell transplantation for peripheral T-cell non-Hodgkin lymphoma and advanced mycosis fungoides/Sezary syndrome 
Annals of Oncology  2011;22(7):1608-1613.
Background: The prognosis for patients with most forms of T-cell lymphoma is poor. Allogeneic hematopoietic stem-cell transplantation (HSCT) may improve the outcome.
Patients and methods: This study examines the outcome of 52 patients who underwent ablative or nonablative allogeneic HSCT for peripheral T-cell lymphoma (PTCL) or advanced mycosis fungoides/Sezary syndrome over a 12-year period at a single institution. We divided the patients into those with predominantly nodal histologies: peripheral T-cell not otherwise specified (PTCL NOS), angioimmunoblastic (AITL), or anaplastic large cell lymphoma, T/null type (systemic) (ALCL), and predominantly extranodal histologies: natural killer (NK)/T cell, enteropathy type, hepatosplenic, subcutaneous panniculitic, mycosis fungoides, or T cell or NK cell other.
Results: Median follow-up of survivors is 49 months. Non-relapse mortality and relapse at 3 years was 27% and 43%, respectively. The incidence of grade II–IV acute graft-versus-host disease (GVHD) was 21%. The incidence of extensive chronic GVHD at 2 years was 27%. The 3-year progression-free survival was 30%: 45% in patients with predominantly nodal histologies (PTCL NOS, AITL, and ALCL) and 6% in patients with predominantly extranodal histologies (P = 0.016). Overall survival at 3 years was 41% for all patients.
Conclusion: Allogeneic HSCT can produce long-term remissions in relapsed/refractory T-cell lymphoma, especially those with nodal histologies.
doi:10.1093/annonc/mdq698
PMCID: PMC3121969  PMID: 21252059
allogeneic transplant; CTCL; GVHD; mycosis fungoides; NK lymphoma; T-cell lymphoma
6.  Preinfusion variables predict the predominant unit in the setting of reduced-intensity double cord blood transplantation 
Bone marrow transplantation  2007;41(6):523-529.
Double cord blood transplantation (DCBT) may overcome the slow hematopoietic recovery and engraftment failure associated with infusion of a single cord blood unit. In DCBT, only one unit typically contributes to long-term hematopoiesis, but little is known about factors affecting cord predominance. As results from a phase I trial suggested that order of infusion may affect cord predominance, we analyzed the effect of preinfusion variables on chimerism patterns of 38 patients enrolled in the initial study and a subsequent phase II trial. All patients were treated with a reduced-intensity conditioning (RIC) regimen of fludarabine, melphalan and thymoglobulin followed by DCBT. Byday100, 66% of patients had hematopoiesis derived from a single cord blood unit. Higher post-thaw total nucleated cell and CD34+ cell dose were associated with cord predominance and in 68% of patients (P = 0.03); the predominant cord blood unit was infused first. Only the post-thaw CD34+ cell dose of the predominant unit predicted time to both neutrophil and platelet engraftment. Although based on a small number of patients, our results identify parameters that may affect cord predominance and engraftment in the setting of DCBT following RIC and suggest possible strategies for selecting infusion order for cord blood units.
doi:10.1038/sj.bmt.1705933
PMCID: PMC2947748  PMID: 18037942
double cord blood transplant; chimerism; engraftment
7.  Dendritic Cells at the Oral Mucosal Interface 
Journal of dental research  2006;85(8):678-689.
The mucosal lining of the respiratory and digestive systems contains the largest and most complex immune system in the body, but surprisingly little is known of the immune system that serves the oral mucosa. This review focuses on dendritic cells, particularly powerful arbiters of immunity, in response to antigens of microbial or tumor origin, but also of tolerance to self-antigens and commensal microbes. Although first discovered in 1868, the epidermal dendritic Langerhans cells remained enigmatic for over a century, until they were identified as the most peripheral outpost of the immune system. Investigators’ ability to isolate, enrich, and culture dendritic cells has led to an explosion in the field. Presented herein is a review of dendritic cell history, ontogeny, function, and phenotype, and the role of different dendritic cell subsets in the oral mucosa and its diseases. Particular emphasis is placed on the mechanisms of recognition and capture of microbes by dendritic cells. Also emphasized is how dendritic cells may regulate immunity/tolerance in response to oral microbes.
PMCID: PMC2254185  PMID: 16861283
dendritic cells; oral mucosa; periodontitis; Porphyromonas gingivalis; cytokines; T-cells
8.  Hemin-induced modifications of the antigenicity and hemin-binding capacity of Porphyromonas gingivalis lipopolysaccharide. 
Infection and Immunity  1996;64(6):2282-2287.
Previous studies have shown that the physical, biochemical, and antigenic properties of the bacterial outer membrane are profoundly influenced by the growth environment. In the present study, the effects of growth in hemin-replete (H+) and hemin-depleted (H-) media on the lipopolysaccharide (LPS) of the oral pathogen Porphyromonas gingivalis were investigated. Our studies show that LPS from P. gingivalis cultured in H+ media (H+LPS) expressed additional low-molecular-mass antigens, as determined by sodium dodecyl sulfate-polyacrylamide gel electrophoresis and Western blot (immunoblot) analysis. Particularly evident was a 26-kDa antigen (26 LPSC) that was lost from the LPS upon transfer of P. gingivalis into H- media. The loss of the 26 LPSC was accompanied by a marked reduction in the hemin-binding capacity of the LPS. The 26 LPSC was refractory to Coomassie blue staining and proteinase K digestion. H+LPS from strain W50/BE1, a nonpigmented pleiotropic strain, lacked the 26 LPSC and did not bind hemin. Polyclonal antiserum raised to whole-cell antigens of P. gingivalis A7436, W83, and HG405 grown in H+ media, but not in H- media, recognized the 26 LPSC in the purified H+LPS from any of the three strains. The immunoreactivities of sera from humans with (n = 24) or without (n = 25) periodontitis to the 26 LPSC and other H+LPS determinants were analyzed by Western blot. Overall, 75% of adult periodontitis patient sera reacted with multiple bands in the H+LPS stepladder, particularly in the range of 14 to 27 kDa. In contrast, only 20% of control sera reacted faintly with H+LPS bands in the range 27 to 34 kDa. The 26 LPSC was recognized by over 40% of sera from adult patients with periodontitis and none of the healthy control sera. Taken together, these results suggest that the antigenicity and hemin-binding properties of P. gingivalis LPS can be modified by growth in H+ media.
PMCID: PMC174067  PMID: 8675338
9.  Resistance of a Tn4351-generated polysaccharide mutant of Porphyromonas gingivalis to polymorphonuclear leukocyte killing. 
Infection and Immunity  1995;63(2):393-401.
In this study, we describe the development of an efficient transpositional mutagenesis system for Porphyromonas gingivalis using the Bacteroides fragilis transposon Tn4351. Using this system, we have isolated and characterized a Tn4351-generated mutant of P. gingivalis A7436, designated MSM-1, which exhibits enhanced resistance to polymorphonuclear leukocyte (PMN) phagocytosis and killing. P. gingivalis MSM-1 was initially selected based on its colony morphology; MSM-1 appeared as a mucoid, beige-pigmented colony. Analysis of P. gingivalis MSM-1 by electron microscopy and staining with ruthenium red revealed the presence of a thick ruthenium red-staining layer that was twice the thickness of this layer observed in the parent strain. P. gingivalis MSM-1 was found to be more hydrophilic than strain A7436 by hydrocarbon partitioning. Analysis of phenol-water extracts prepared from P. gingivalis A7436 and MSM-1 by Western (immunoblot) analysis and immunodiffusion with hyperimmune sera raised against A7436 and MSM-1 revealed the loss of a high-molecular-weight anionic polysaccharide component in extracts prepared from MSM-1. P. gingivalis MSM-1 was also found to be more resistant to PMN phagocytosis and intracellular killing than the parent strain, as assessed in a fluorochrome phagocytosis microassay. These differences were statistically significant (P < 0.05) when comparing PMN phagocytosis in nonimmune serum and intracellular killing in nonimmune and immune sera. P. gingivalis MSM-1 was also more resistant to killing by crude granule extracts from PMNs than was P. gingivalis A7436. These results indicate that the increased evasion of PMN phagocytosis and killing exhibited by P. gingivalis MSM-1 may result from alterations in polysaccharide-containing antigens.
PMCID: PMC173008  PMID: 7822002
10.  Influence of immunization on Porphyromonas gingivalis colonization and invasion in the mouse chamber model. 
Infection and Immunity  1992;60(4):1447-1454.
The effects of immunization with invasive or noninvasive Porphyromonas (Bacteroides) gingivalis strains on the pathogenesis of infection in a mouse chamber model were examined. BALB/c mice were immunized by a single injection of heat-killed P. gingivalis invasive strain A7436 or W83 or noninvasive strain 33277, HG405, or 381 directly into subcutaneous chambers. P. gingivalis-specific antibody was detected in chamber fluid 21 days postimmunization, and mice were subsequently challenged by injection of exponential-phase P. gingivalis into chambers. Immunization with A7436 or W83 followed by challenge with A7436 protected mice against secondary abscess formation and death; however, P. gingivalis persisted in chambers for up to 14 days postchallenge. Immunization with noninvasive strain 33277, HG405, or 381 followed by challenge with invasive strain A7436 or W83 protected mice against secondary lesion formation and death. P. gingivalis was cultured from 33277- or HG405-immunized and nonimmunized animals to day 14. All P. gingivalis strains induced an immunoglobulin G response, as measured by an enzyme-linked immunosorbent assay and Western immunoblotting of P. gingivalis whole-cell and outer membrane protein preparations. Western blot analyses indicated that sera from mice immunized with different invasive and noninvasive strains recognized common P. gingivalis antigens. In summary, immunization with invasive P. gingivalis A7436 and W83 or noninvasive P. gingivalis 33277, HG405, and 381 protected mice from secondary lesion formation and death after challenge with invasive P. gingivalis A7436 or W83. P. gingivalis-specific antibody did not, however, inhibit the colonization of P. gingivalis within chambers.
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PMCID: PMC257017  PMID: 1312515
11.  Antibody-dependent alternate pathway of complement activation in opsonophagocytosis of Porphyromonas gingivalis. 
Infection and Immunity  1991;59(6):2105-2109.
It has been suggested that the ability of Porphyromonas gingivalis to proteolyse complement, as well as its production of a capsule, contributes to resistance to phagocytosis by polymorphonuclear leukocytes. In this report, the opsonic role of serum complement and its activation pathways were investigated, using individual sera heat treated or depleted of factors B, C2, and C1q and the divalent cations Mg2+ and Ca2+. A fluorochrome microassay was used to quantitate phagocytosis of P. gingivalis A7436 by human polymorphonuclear leukocytes. Heat treatment of rabbit antiserum to P. gingivalis (RaPg) (56 degrees C, 30 min) resulted in a reduction in phagocytosis from 100% to 55% +/- 5%, while heat treatment of chronic adult periodontal disease serum abrogated phagocytosis. The heat-labile activity of RaPg was fully restored with MgEGTA-chelated rabbit serum but not EDTA- or EGTA-chelated rabbit serum. The addition of serum depleted of factor B but not C2 or C1q restored most of the heat-labile activity; however, the factor B-depleted serum was suspect, due to low-level opsonization of zymosan (inhibitable by EDTA but not MgEGTA). Adding C1q at 80 micrograms/ml to serum depleted of C1q restored much but not all of the activity lost through heat treatment or through depletion of C1q. A large part of opsonic activity with C2- and C1q-depleted sera was enhanced by the addition of 4 x 10(-3) M Mg2+. The data indicate that although opsonophagocytosis of P. gingivalis A7436 is dependent on the classical complement pathway, a significant contribution is made by an antibody-dependent alternate pathway.
PMCID: PMC257972  PMID: 2037371
12.  Phagocytosis of virulent Porphyromonas gingivalis by human polymorphonuclear leukocytes requires specific immunoglobulin G. 
Infection and Immunity  1991;59(6):2097-2104.
No studies to date clearly define the interactions between Porphyromonas gingivalis and human peripheral blood polymorphonuclear leukocytes (PMN), nor has a protective role for antibody to P. gingivalis been defined. Using a fluorochrome phagocytosis microassay, we investigated PMN phagocytosis and killing of P. gingivalis as a function of P. gingivalis-specific antibody. Sera from a nonimmune rabbit and a healthy human subject were not opsonic for virulent P. gingivalis A7436, W83, and HG405; phagocytosis of these strains (but not 33277) required opsonization with hyperimmune antiserum (RaPg). Diluting RaPg with a constant complement source decreased proportionally the number of P. gingivalis A7436 cells phagocytosed per phagocytic PMN. Enriching for the immunoglobulin G fraction of RAPg A7436 enriched for opsonic activity toward A7436. An opsonic evaluation of 18 serum samples from adult periodontitis patients revealed that only 3 adult periodontitis sera of 17 with elevated immunoglobulin G to P. gingivalis A7436 were opsonic for A7436 and, moreover, that the serum sample with the highest enzyme-linked immunosorbent assay titer was most opsonic (patient 1). However, the opsonic activity of serum from patient 1 was qualitatively and not just quantitatively different from that of the nonopsonic human sera (but was less effective opsonin than RaPg). Strain variability was observed in resistance of P. gingivalis to phagocytosis, and opsonization was strain specific for some, but not all, strains tested. An evaluation of killing of A7436 revealed that serum killing and extracellular killing of P. gingivalis were less effective alone when compared with intracellular PMN killing alone.
PMCID: PMC257971  PMID: 2037370
13.  A novel mouse model to study the virulence of and host response to Porphyromonas (Bacteroides) gingivalis. 
Infection and Immunity  1991;59(4):1255-1263.
We describe here the development of a mouse subcutaneous chamber model that allows for the examination of host-parasite interactions as well as the determination of gross pathology with Porphyromonas (Bacteroides) gingivalis challenge. When inoculated into stainless-steel chambers implanted subcutaneously in female BALB/c mice, P. gingivalis W83, W50, and A7436 (10(8) to 10(10) CFU) caused cachexia, ruffling, general erythema and phlegmonous, ulcerated, necrotic lesions, and death. P. gingivalis W50/BEI, HG405, and 33277 (10(10) CFU) produced localized abscesses in the mouse chamber model with rejection of chambers at the injection site. Analysis of chamber fluid from 33277-, HG405-, and W50/BEI-infected mice by cytocentrifugation revealed inflammatory cell debris, polymorphonuclear leukocytes, and high numbers of dead bacteria. In contrast, fluid from A7436-, W50-, and W83-infected mice revealed infiltration predominantly of polymorphonuclear leukocytes and live bacteria. Bacteria were found primarily associated with polymorphonuclear leukocytes in the fluid from W50-, HG405-, and W83-infected mice but not from A7436-infected mice. Viable isolates were recoverable from the chamber fluid through day 3 for W50/BEI, day 5 for 33277, day 6 for HG405, day 7 for W50, day 14 for W83, and day 26 for A7436. All strains induced a systemic immunoglobulin G response in serum and chamber fluid samples. The use of this model will allow us to examine the virulence of P. gingivalis as defined by the interaction of host response to localized infection with P. gingivalis.
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PMCID: PMC257836  PMID: 2004807
14.  Metastic carcinoma of ciliary body 
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PMCID: PMC1322493  PMID: 16692045

Results 1-14 (14)