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Biomedical subjects

Pedram Hamrah

Publications and source records attributed to Pedram Hamrah.

17 recordsLinked to original sources
PubMed2006

Nonvascular VEGF receptor 3 expression by corneal epithelium maintains avascularity and vision.

Transparency of the cornea, the window of the eye, is a prerequisite for vision. Angiogenesis into the normally avascular cornea is incompatible with good vision and, therefore, the cornea is one of the few tissues in the human body where avascularity is actively maintained. Here, we provide evidence for a critical mechanism contributing to corneal avascularity. VEGF receptor 3, normally present on lymphatic and proliferating blood vascular endothelium, is strongly constitutively expressed by corneal epithelium and is mechanistically responsible for suppressing inflammatory corneal angiogenesis.

Animals↗
PubMed2006

Ocular infection secondary to gemella.

PURPOSE: To report four cases of ocular infection caused by Gemella species. METHODS: Microbial identification was carried out using the MicroScan Walkaway system (Dade Behring) and/or Vitek-2 (bioMérieux) and susceptibility testing with either Kirby-Bauer disc diffusion and/or Vitek-2. The paper is presented as an interventional case report. RESULTS: Four patients developed infection due to Gemella species. All responded to vancomycin or fortified aminoglycosides and broad-spectrum antibiotics. CONCLUSION: Gemella spp. can cause opportunistic infections in the eye.

Adolescent↗
PubMed2005

Early ocular chemokine gene expression and leukocyte infiltration after high-risk corneal transplantation.

PURPOSE: To determine the differential gene expression of chemokine species and leukocyte infiltration of grafts in the early pre-rejection postoperative period after high-risk (HR) compared to normal-risk (NR) corneal transplantation. METHODS: Fully mismatched and syngeneic corneal grafts were performed in NR (avascular) and HR (vascularized) recipient beds of BALB/c murine hosts. Gene expression levels of a panel of chemokines were determined by a multiprobe ribonuclease protection assay system. The profiles of infiltrating cells into the corneal grafts at the same times were determined immunohistochemically. RESULTS: Compared to NR transplantation, HR eyes exhibited significantly higher mRNA levels for macrophage inflammatory protein (MIP)-2 and monocyte chemotactic protein-1 (MCP-1) on day 1, and for eotaxin on days 1 and 3 after transplantation. By day 6 after transplantation, still well before graft rejection, significantly higher levels of RANTES, eotaxin, MIP-1alpha, MIP-1beta, MIP-2, and MCP-1 were detected in HR eyes. The overexpression of MIPs in HR eyes correlated with a significant increase in the number of infiltrating macrophages (p<0.01), and neutrophils (p<0.05) in HR compared to NR recipients. Low levels of eosinophil and mast cell infiltration were observed in all grafts, with a modest increase in mast cell infiltration (p<0.05) in HR compared to NR grafts. CONCLUSIONS: These results suggest that increased expression of gene products for select chemokines, in particular those that mediate recruitment of innate immune cells, in the early period after HR corneal transplantation is related to the enhanced leukocytic infiltration of grafts observed in HR keratoplasty.

Animals↗
PubMed2005

CCR5 chemokine receptor mediates recruitment of MHC class II-positive Langerhans cells in the mouse corneal epithelium.

PURPOSE: To characterize the chemokines and chemokine receptors that mediate the effect of proinflammatory cytokines, interleukin (IL)-1 and tumor necrosis factor (TNF)-alpha, on the recruitment of MHC class II(+) Langerhans cells (LCs) in the corneal epithelium. METHODS: A standard model for corneal LC recruitment, application of cautery to the central corneal surface was used, and the differential gene expression levels of a panel of chemokines and chemokine receptors were determined by RNase protection assay. Chemokine receptor-knockout mice were used to evaluate the recruitment of MHC class II(+) LCs to the corneal epithelium. To determine the sensitivity of selected chemokines to IL-1 and TNF-alpha stimulation, the chemokine gene expression pattern was analyzed after blockade of IL-1 and TNF receptors. RESULTS: CCR1, -2, and -5 were overexpressed in corneas after cauterization. Topical administration of soluble TNF receptor I and IL-1 receptor antagonist, which abrogated corneal LC recruitment, significantly suppressed the gene transcription levels of the ligands of CCR1 and/or -5, regulated on activation normal T-cell expressed and secreted (RANTES), macrophage inflammatory protein (MIP)-1alpha, and MIP-1beta. The recruitment of major histocompatibility complex (MHC) class II(+) LC was significantly suppressed in CCR5(-/-) mice and blockade of RANTES and MIP-1beta, but not in CCR1(-/-), CCR2(-/-)/MIP-1alpha(-/-), or MIP-1alpha(-/-) mice. The evaluation of epithelial CD11c(+) LC cells by confocal microscopy revealed coexpression for CCR5 primarily among B7(-) (CD80(-)/CD86(-)) subsets of these LCs but not among the mature B7(+) subsets of CD11c(+) LCs. CONCLUSIONS: These data suggest that CCR5 plays a critical role in mediating recruitment and mobilization of MHC class II(+) LCs into the corneal epithelium. Targeting CCR5 and its ligands may be a new strategy for modulating immunity.

Animals↗
PubMed2004

Vascular endothelial growth factor receptor-3 mediates induction of corneal alloimmunity.

There are no studies so far linking molecular regulation of lymphangiogenesis and induction of adaptive immunity. Here, we show that blockade of vascular endothelial growth factor receptor-3 (VEGFR-3) signaling significantly suppresses corneal antigen-presenting (dendritic) cell trafficking to draining lymph nodes, induction of delayed-type hypersensitivity and rejection of corneal transplants. Regulating the function of VEGFR-3 may therefore be a mechanism for modulating adaptive immunity in the periphery.

Animals↗
PubMed2004

Expression of vascular endothelial growth factor receptor-3 (VEGFR-3) on monocytic bone marrow-derived cells in the conjunctiva.

Vascular endothelial growth factor-3 (VEGFR-3), also known as Fms-like tyrosine kinase receptor 4 (FLT-4), was thought to be expressed exclusively on the lymphatic endothelium, high endothelial venules, and rarely on vascular endothelium. It plays a critical role in the development of lymphatics and cancer metastasis. Very recently, however, VEGFR-3 expression has been identified on dendritic cells (DCs) in the inflamed cornea, and related to the trafficking of these cells to lymphoid organs. The current study was performed to evaluate the expression of VEGFR-3 in the conjunctiva. The conjunctiva and limbus of normal and inflamed murine eyes were excised and stained for VEGFR-3. Immunofluorescence double staining for CD11b, CD11c, CD31, CD45, GR-1, CD3, CD80, LYVE-1 and class II major histocompatibility complex (MHC) antigen expression, using confocal microscopy, was performed to further phenotype the VEGFR-3+ cells. VEGFR-3 and LYVE-1 expression was observed on lymphatic, but not blood vessel, endothelium. In addition, we also detected expression of VEGFR-3 on non-endothelial CD45+ bone marrow-derived cells in the conjunctiva of normal and, in an increased number, in inflamed eyes. These cells were uniformly CD11b+, CD3-, and Gr-1-, suggesting a monocytic origin, similar to the VEGFR-3+ cells in the cornea. Nearly half of the VEGFR-3+ cells were also positive for MHC class II expression, and none were positive for CD80 (B7-1), indicating their relative immature status. In contrast to the recently described VEGFR3+ corneal cells, however, VEGFR-3+ conjunctival cells did not express the DC marker CD11c. We conclude that in addition to its known role in lymphangiogenesis, VEGFR-3 is also expressed by a conjunctival monocyte/macrophage lineage, implicating a potential relationship between lymphangiogenesis and leukocyte trafficking in the ocular surface.

Animals↗
PubMed2003

Alterations in corneal stromal dendritic cell phenotype and distribution in inflammation.

BACKGROUND: The normal corneal stroma is endowed with large numbers of resident dendritic cells (DCs). The purpose of this study was to examine the phenotype and distribution of these cells in inflammation. METHODS: Normal and inflamed murine corneas were excised at different time points and immunofluorescence staining with multiple antibodies was performed by confocal microscopy on whole-mounted corneal stromas to characterize and evaluate the distribution of DCs in inflammation. RESULTS: CD11c+CD11b+ myeloid DCs were present throughout the anterior stroma. In the periphery of the normal cornea, nearly one half were major histocompatibility complex (MHC) class II+CD80+CD86+, while they were uniformly MHC class II-CD80-CD86- in the center. In inflammation, in addition to a significant increase in the number of DCs, a majority up-regulated their expression of MHC class II, CD80, and CD86, indicating their state of maturation. The up-regulation of MHC class II and costimulatory molecules on DCs was seen as early as 24 hours after induction of inflammation or transplantation. In addition to the CD11c+DCs in the anterior stroma, a CD11c-CD11b+ population of monocytes/macrophages was present almost exclusively in the posterior stroma of the cornea. These cells were found throughout all layers of the stroma, and in increased numbers, after induction of inflammation. CONCLUSION: The present study demonstrates, for the first time, the phenotypic changes and distribution of resident stromal DCs in corneal inflammation. Clinical Relevance These novel data suggest that the cornea is capable of participating in immune and inflammatory responses by virtue of its own heterogeneous population of DCs.

Animals↗
PubMed2003

Novel expression of vascular endothelial growth factor receptor (VEGFR)-3 and VEGF-C on corneal dendritic cells.

Vascular endothelial growth factor-3 (VEGFR-3) plays a critical role in embryonic cardiovascular development and is thought to be expressed exclusively on the lymphatic endothelium, high endothelial venules, and rarely on adult vascular endothelium. Recent evidence also suggests expression of VEGFR-3 on some tumor-associated macrophages. We have studied the expression of VEGFR-3, its ligand VEGF-C and the co-receptor neuropilin-2, in normal and inflamed corneas and characterized the phenotype and distribution of VEGFR-3(+) cells. Our data demonstrate, for the first time, the expression of VEGFR-3 on corneal dendritic cells (DC) and its up-regulation in inflammation. VEGFR-3(+) DC are CD11c(+)CD45(+)CD11b(+), and are mostly major histocompatibility (MHC) class II(-)CD80(-)CD86(-), indicating immature DC of a monocytic lineage. During inflammation, there is rapid increase in the number of VEGFR-3(+) DC in the cornea associated with heightened membranous expression as compared to a mostly intracellular expression in uninflamed tissue. VEGFR-3(+) DC in normal corneas are VEGF-C(-)neuropilin-2(-), but express VEGF-C in inflammation. Interestingly, similar cells are absent both in the normal and inflamed skin. These data demonstrate, for the first time, the expression of VEGFR-3 and VEGF-C on tissue DC, which implicate a novel potential relationship between lymphangiogenesis and leukocyte trafficking in the eye.

Angiogenesis Inducing Agents↗
PubMed2003

The corneal stroma is endowed with a significant number of resident dendritic cells.

PURPOSE: Dendritic cells (DCs) comprise a system of highly efficient antigen-presenting cells (APCs) that initiate immune responses. The purpose of this study was to examine the normal stroma for the presence of DCs and other bone marrow (BM)-derived cells. METHODS: Normal uninflamed corneas of BALB/c and other murine strains were excised, and immunofluorescence single- and double-staining for multiple markers was performed for examination by confocal microscopy. Corneal buttons were placed in culture and immunocytochemistry and flow cytometry performed. RESULTS: MHC class II(+)CD80(+)CD86(+) cells were found in the periphery of the anterior normal stroma. These cells were CD45(+), CD11c(+)CD11b(+) suggesting a BM-derived and monocytic DC lineage. In a surprising finding, significant numbers of MHC class II(-)CD80(-)CD86(-) cells were found in the center of the anterior stroma. These cells were also CD45(+)CD11c(+)CD11b(+) but CD3(-), GR-1(-), keratan sulfate(-), and CD8alpha(-), reflecting an immature precursor phenotype of myeloid DC. In addition to DC subsets in the anterior stroma, a CD11c(-)CD11b(+) population of BM-derived cells was found primarily in the posterior stroma, representing monocytes/macrophages. These cells were rarely present in the anterior third of the normal stroma. Further, CD14(+) precursor-type DCs were found throughout the stroma. These in vivo findings were not strain specific and were confirmed by immunocytochemistry and flow cytometry analyses of cells derived from corneal explants and by transmission electron microscopy. CONCLUSIONS: This study demonstrates that, in addition to the known Langerhans cells in the corneal epithelium, at least three BM-derived cell subsets reside in the normal corneal stroma.

Animals↗
PubMed2003

Corneal immunity is mediated by heterogeneous population of antigen-presenting cells.

Corneal antigen-presenting cells (APC), including dendritic cells (DC), were thought to reside exclusively in the peripheral cornea. Here, we present recent data from our group demonstrating that the central cornea is indeed endowed with a heterogeneous population of epithelial and stromal DC, which function as APC. Although the corneal periphery contains mature and immature resident bone marrow-derived CD11c(+) DC, the central cornea is endowed exclusively with immature and precursor DC, both in the epithelium and the stroma, wherein Langerhans cells and monocytic DC reside, respectively. During inflammation, a majority of resident DC undergo maturation by overexpressing major histocompatibility complex class II and B7 (CD80/CD86) costimulatory molecules. In addition to the DC, macrophages are present in the posterior corneal stroma. In transplantation, donor-derived DC are able to migrate to host cervical lymph nodes and activate host T cells via the direct pathway when allografts are placed in inflamed host beds. These data revise the tenet that the cornea is immune-privileged as a result of lack of resident lymphoreticular cells and suggest that the cornea is capable of diverse cellular mechanisms for antigen presentation.

Animals↗
PubMed2002

Draining lymph nodes of corneal transplant hosts exhibit evidence for donor major histocompatibility complex (MHC) class II-positive dendritic cells derived from MHC class II-negative grafts.

To examine the widely accepted dogmas that corneal grafts lack passenger leukocytes or cells capable of migrating directly to lymph nodes (LNs), we tracked the migration of corneal graft-derived transgenic green fluorescent protein (GFP; Ia(b)) cells into the draining LNs of allogeneic (Ia(d)) recipients. GFP(+) cells were identified in cervical LNs several hours after transplantation, and this traffic was significantly enhanced when grafts were placed in inflamed recipient beds. Draining cells were Ia(b+), CD45(+), and CD11c(+), and examination of ungrafted corneas revealed numerous similarly CD45(+)CD11c(+)CD3(-)CD8alpha(-) cells that uniformly lacked major histocompatibility complex (MHC) class II expression; transmission electron microscopy confirmed the presence of morphologically similar cells. After transplantation, or placement in culture, these CD11c(+) cells became class II(+) in a time-dependent manner and were capable of allostimulatory function. However, the stimulatory capacity of these cornea-derived dendritic cells (DCs) was suppressed compared with splenic controls. These results demonstrate for the first time that the cornea is endowed with resident DCs that are universally MHC class II(-) but that are capable of expressing class II antigen after surgery and migrating to draining LNs of allografted hosts. These data refute the tenet that the cornea is immune privileged due to lack of resident lymphoreticular cells or due to antigenic sequestration from systemic immunity.

Animals↗
PubMed2002

Mechanisms of immunotherapeutic intervention by anti-CD154 (CD40L) antibody in high-risk corneal transplantation.

This study aimed to determine the effects of anti-CD154 on T cell cytokine profiles and ocular chemokine gene expression after high-risk corneal transplantation and to specifically determine if CD154 blockade is associated with a switch from a Th1 to a Th2 alloimmune response. Mice were used as recipients of syngeneic or multiple minor H or MHC antigen-mismatched corneal grafts. Recipient beds were neovascularized (high-risk). Hosts were randomized to receive either anti-CD154 antibody or control immunoglobulin (Ig) perioperatively. Two weeks after corneal transplantation, allospecific delayed-type hypersensitivity (DTH) was evaluated. Frequencies of interferon-gamma (IFN-gamma)-, interleukin-2 (IL-2)-, IL-4-, and IL-5-secreting T cells in the hosts were measured by enzyme-linked immunospot (ELISPOT) assay. Ocular chemokine gene expression in anti-CD154-treated and control hamster Ig-treated groups was determined using a multiprobe ribonuclease protection assay (RPA). Leukocyte infiltration of corneal grafts was evaluated microscopically. Anti-CD154-treated mice did not exhibit allospecific DTH. The frequencies of Th1 cytokine-producing but not Th2 cytokine-producing T cells were significantly reduced in anti-CD154-treated hosts. Postoperative mRNA levels of RANTES and macrophage inflammatory protein-1beta (MIP-1beta) in anti-CD154-treated eyes were substantially suppressed compared with hamster Ig-treated controls. Leukocyte infiltration was profoundly suppressed in grafts of anti-CD154-treated hosts. These data demonstrate that blockade of the CD40-CD154 costimulatory pathway after corneal transplantation inhibits Th1-mediated responses but does not induce a switch to a Th2-specific response. In addition, anti-CD154 therapy suppresses ocular chemokine gene expression and leukocytic infiltration into allografts.

Animals↗
PubMed2002

Novel characterization of MHC class II-negative population of resident corneal Langerhans cell-type dendritic cells.

PURPOSE: The presence of antigen-presenting cells (APCs) such as Langerhans cells (LCs), an epithelial form of dendritic cells (DCs), in corneal tissue is critical for generation of immune responses, including graft rejection and herpetic keratitis. The purpose of this study was to characterize the distribution and major histocompatibility complex (MHC) antigen expression of corneal LCs. METHODS: Normal and inflamed corneas were excised from BALB/c mice, and immunofluorescence staining for CD11c, CD11b, CD45, CD80 (B7.1), CD86 (B7.2), CD3, and MHC class II (Ia) was performed by confocal microscopy on wholemount corneal epithelium. RESULTS: CD11c(+) MHC class II-positive LCs were found in the limbus and corneal periphery, but not in the center of the normal cornea. These cells were CD45 positive, exhibiting bone marrow derivation, and CD3 and CD11b negative, confirming a DC lineage. Additionally, these cells were CD80 and CD86 negative, reflecting an immature phenotype. In the central and paracentral areas, however, significant numbers of CD11c(+) LCs were detected that expressed no MHC class II. It is important to note that although the density of the LCs declined from the limbus toward the center of the cornea, they were always present. In the inflamed cornea, the expression of MHC class II and costimulatory molecules CD80 and CD86 was significantly enhanced, and present in all parts of the cornea, in contrast to the normal cornea. CONCLUSIONS: The present study demonstrates for the first time the phenotype and distribution of MHC class II-negative LCs in the murine corneal epithelium. In the inflamed cornea, the LCs become activated as reflected by expression of B7 costimulatory markers. These changes in activation markers may provide additional information for devising novel immunomodulatory strategies.

Animals↗
PubMedDate not supplied

The hypertensive lower esophageal sphincter: a motility disorder with manometric features of outflow obstruction.

The aim of this study was to define the clinical presentation, motility characteristics, and prevalence and patterns of gastroesophageal reflux in patients with hypertensive lower esophageal sphincter (HTLES). HTLES was defined by a resting pressure measured at the respiratory inversion point on stationary manometry of greater than 26 mm Hg (ninety-fifth percentile of normal). One hundred consecutive patients (80 women, 20 men; mean age 54.7 years, range 23 to 89 years), diagnosed with HTLES at our institution between September 1996 and October 1999, were studied. Patients with achalasia or other named esophageal motility disorders or history of foregut surgery were excluded, but patients with both HTLES and "nutcracker esophagus" were included. The most common symptoms in patients with HTLES were regurgitation (75%), heartburn (71%), dysphagia (71%), and chest pain (49%). The most common primary presenting symptoms were heartburn and dysphagia. The intrabolus pressure, which is a manometric measure of outflow obstruction, was significantly higher in patients with HTLES compared to normal volunteers. The residual pressure measured during LES relaxation induced by a water swallow was also significantly higher than in normal persons. There were no significant associations between any of the relaxation parameters studied (residual pressure, nadir pressure, duration of relaxation, time to residual pressure) and either the presence or severity of any symptoms or the presence of abnormal esophageal acid exposure. Seventy-three patients underwent 24-hour pH monitoring, and 26% had increased distal esophageal acid exposure. Compared to a cohort of patients with gastroesophageal reflux disease but no HTLES (n=300), the total and supine periods of distal esophageal acid exposure were significantly lower in the patients with HTLES and abnormal acid exposure. Patients with HTLES frequently present with moderately severe dysphagia and typical reflux symptoms. Approximately one quarter of them have abnormal esophageal acid exposure on pH monitoring. Patients with HTLES have significantly elevated intrabolus and residual relaxation pressures on liquid boluses, suggesting that outflow obstruction is present.

Case-Control Studies↗