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Lloyd Mayer

Publications and source records attributed to Lloyd Mayer.

10 recordsLinked to original sources
PubMed2003

Orthotopic tracheal allografts undergo reepithelialization with recipient-derived epithelium.

BACKGROUND: While the rejection of heterotopic tracheal allografts is characterized by complete airway obliteration, the rejection of orthotopic allografts leads to airway edema and cellular infiltrate of the lamina propria, but is not associated with obliteration. We hypothesized that orthotopic tracheal allografts undergo reepithelialization with recipient-derived mucosa and that this process prevents airway obliteration. METHODS: Thirty mice were randomly assigned to 6 experimental groups. BALB/c donor tracheal segments were transplanted orthotopically or heterotopically into syngeneic BALB/c or major histocompatability mismatched allogeneic C57BL/6 recipients. Recipients of allogeneic grafts were divided into a nonimmunosuppression group and an immunosuppression group (cyclosporine, 7 mg/kg per day). Twenty-one days after transplantation, histological assessment, immunohistochemistry for CD4 and CD8 lymphocyte infiltration and major histocompatibility-specific immunohistochemistry were performed on the grafts to assess rejection and donor or recipient origin of tissue. RESULTS: Untreated heterotopic allografts underwent complete airway obliteration by day 21. This response was prevented with cyclosporine immunosuppression. Untreated orthotopic allografts, however, demonstrated edema and lymphocytic infiltrate of the lamina propria resulting in clinical stridor without airway obliteration. Immunosuppressed orthotopic allografts did not develop edema or infiltrate of the lamina propria and consequently stridor did not occur. Immunohistochemical analysis demonstrated migration of recipient-derived mucosa into the donor allograft segment in both the untreated and treated orthotopic groups. CONCLUSIONS: Airway obliteration characteristic of rejecting heterotopic tracheal allografts does not occur in the orthotopic allografts. Migration of recipient mucosa into the donor allograft appears to prevent airway obliteration in the orthotopic allografts. These findings suggest that the orthotopic tracheal transplantation model more accurately represents the biological behavior of clinical tracheal allografts than the traditional heterotopic model.

Airway Obstruction↗
PubMed2003

Tacrolimus for the treatment of fistulas in patients with Crohn's disease: a randomized, placebo-controlled trial.

BACKGROUND & AIMS: This study determined the effectiveness of tacrolimus for the treatment of Crohn's disease fistulas. METHODS: The study was a randomized, double-blind, placebo-controlled, multicenter clinical trial. Forty-eight patients with Crohn's disease and draining perianal or enterocutaneous fistulas were randomized to treatment with oral tacrolimus 0.2 mg. kg(-1). day(-1) or placebo for 10 weeks. The primary outcome measure was fistula improvement as defined by closure of >/=50% of particular fistulas that were draining at baseline and maintenance of that closure for at least 4 weeks. A secondary outcome measure was fistula remission as defined by closure of all fistulas and maintenance of that closure for at least 4 weeks. RESULTS: Forty-three percent of tacrolimus-treated patients had fistula improvement compared with 8% of placebo-treated patients (P = 0.004). Ten percent of tacrolimus-treated patients had fistula remission compared with 8% of placebo-treated patients (P = 0.86). Adverse events significantly associated with tacrolimus, including headache, increased serum creatinine level, insomnia, leg cramps, paresthesias, and tremor, were managed with dose reduction. CONCLUSIONS: Oral tacrolimus 0.2 mg. kg(-1). day(-1) is effective for fistula improvement, but not fistula remission, in patients with perianal Crohn's disease. Adverse events associated with tacrolimus can be managed by dose reduction. Lower doses of tacrolimus should be evaluated.

Adolescent↗
PubMed2003

Meeting summary: Signal transduction pathways in immune and inflammatory cells. November 30-December 3, 2000, Amelia Island, Florida, U.S.A.

Throughout this symposium, recurrent themes were highlighted that may provide important clues to the pathogenesis of mucosal inflammation and IBD. First, the mucosal immune system is unique: Studies describing signaling paradigms in peripheral immunocytes should be re-explored in the gut where the rules that govern cell signaling may not be the same. Paradigms are a point of departure to characterize similarities and differences in mucosal immunity. A good example is a differential requirement for costimulation through CD2 in lamina propria T cells compared with peripheral T cells. Furthermore, a new definition of T-cell "costimulation" is beginning to emerge. Costimulatory molecules may function to overcome physical barriers by allowing cognate interactions between other molecules or by targeting signaling complexes to membrane microdomains. This concept also relates to another recurrent theme: Interactions between signaling pathways and the cytoskeleton are functionally important. Finally, we were introduced to the novel concept of metabolic parameters as a readout for signal transduction in the immune system. In the recent past, cell signaling has been viewed as a linear exercise, connecting a cell surface receptor to a series of intermediate molecules to a program of gene expression. However, signal transduction is in fact a three-dimensional exercise in cell biology. The future challenge, as pointed out in the keynote address, is to integrate reductionist models into reality and describe networks of signal transduction pathways in complex biosystems. "Threshold" responses were emphasized, with a small incremental increase or decrease in enzymatic activity leading to an on-off phenomenon referred to as a "molecular switch." In IBD, minute genetically determined differences in enzymatic activity may be critical. This point emphasizes the power of a genetic approach in IBD. Without strong genetic evidence, it is unlikely that fuctional assays will clarify the importance of small differences in enzymatic activity that may have dramatic biologic consequences. This symposium identified recently described signal transduction molecules that may be attractive therapeutic targets in IBD. Characterization of signaling molecules such as SLP-76, SLAM, SAP, and Fyb in the mucosal immune system will be an important area of future research. Ultimately, well-developed scientific hypotheses need to be tested in human beings. This paradigm was perhaps best illustrated by PPARgamma, where reductionist models and mouse experiments have recently lead to small trials suggesting proof of concept in human IBD. This meeting also emphasized a renewed interest in innate immunity in IBD and inflammation research. The role of enteric flora in initiating and perpetuating inflammation in animal models of IBD suggests at some level the importance of the innate immune response. The role of TLRs and bacterial interactions were discussed, as was NF-kappaB as the prominent transcription factor target of innate immune activation. Numerous bridges between innate and adaptive immunity were highlighted, including IL-10, IL-12, IL-18, and IFN-gamma. Their production during an innate immune response can profoundly affect functional T-cell responses in humans. In conclusion, the challenge of understanding signal transduction in IBD is one of integrating well-characterized inflammatory pathways into a complex biologic system that is inhabited by diverse cell types that communicate, and is characterized by interactions with a complex microbial environment. Making sense of this complexity is a daunting task that will require a multifactorial approach utilizing reductionist systems, mouse models, genetic studies, and ultimately human clinical trials.

Animals↗
PubMed2003

The incidence and management of infusion reactions to infliximab: a large center experience.

OBJECTIVE: To assess the incidence and management of infusion reactions to infliximab, a chimeric monoclonal antibody that targets human tumor necrosis factor-alpha, in patients with Crohn's disease treated at a large infusion center. METHODS: A total of 165 consecutive patients who received 479 infliximab infusions in the Division of Clinical Immunology Infusion Center at Mount Sinai Medical Center from July, 1998 to January, 2001 were evaluated. Specific treatment protocols for initial and subsequent acute infusion reactions were followed and the outcomes documented. RESULTS: The overall incidence of infusion reactions to infliximab was 6.1% (29 of 479) of infusions, affecting 9.7% (16 of 165) of patients. Mild, moderate, or severe acute reactions occurred in 3.1% (15 of 479), 1.2% (six of 479), and 1.0% (five of 479) of infliximab infusions, respectively. Use of treatment protocols resulted in rapid resolution of all acute reactions to infliximab. With the prophylaxis protocol, all patients who experienced an initial mild or moderate acute reaction were able to receive additional infusions. Four patients experienced a total of five severe acute reactions. Three patients were retreated: two patients had no further problems, whereas one patient had a second severe acute reaction that rapidly resolved with treatment. Suggesting that acute infusion reactions are not type I hypersensitivity reactions, in 11 patients who experienced 14 acute infusion reactions, serum tryptase levels were normal. Delayed infusion reactions occurred in 0.6% (three of 479) of infusions. CONCLUSIONS: Infliximab infusions were accompanied by acute reactions in approximately 5% of infusions. These reactions did not seem to be true IgE-mediated type I hypersensitivity events. Using appropriate treatment protocols, these reactions were effectively treated and prevented upon retreatment in nearly all patients. Delayed reactions were rare, occurring in <1% of infusions.

Antibodies, Monoclonal↗
PubMed2003

The kinetics and pattern of tracheal allograft re-epithelialization.

Extensive tracheal defects may pose a life-threatening dilemma. Although tracheal transplantation may represent a reconstructive solution, very little is known regarding the immunobiology and behavior of tracheal allografts. The objective of this study was to assess the pattern and kinetics of re-epithelialization of orthotopic tracheal allografts in immunosuppressed recipients. Thirty-eight age-matched mice were randomly assigned to five experimental groups. BALB/c donor tracheal segments were orthotopically transplanted into either syngeneic BALB/c or MHC mismatched allogeneic C57BL/6 recipients with and without immunosuppression. On post-transplant days 7, 14, 28, 48, and 62, animals from each group were evaluated by serial histology, electron microscopy, and serial immunohistochemical analysis for mucosal phenotype, re-epithelialization pattern, and lymphocyte subpopulations. Nonimmunosuppressed recipients underwent recipient-derived basal cell re-epithelialization by Day 48, with differentiation into a sparse population of ciliated columnar epithelium by Day 62, whereas immunosuppressed recipients underwent basal cell re-epithelialization 28 d after transplantation and differentiation into a dense population of ciliated columnar epithelium by Day 48. The re-epithelialization process occurred in a definable pattern that was significantly enhanced with the addition of immunosuppression. Orthotopic tracheal transplants undergo progressive re-epithelialization with recipient-derived basal cells that differentiate into ciliated columnar epithelium in a definable pattern that is enhanced with the addition of immunosuppression.

Animals↗
PubMed2003

Mucosal immunity.

Food allergy is the manifestation of an abnormal immune response to antigen delivered by the oral route. Normal mucosal immune responses are generally associated with suppression of immunity. A normal mucosal immune response relies heavily on a number of factors: strong physical barriers, luminal digestion of potential antigens, selective antigen sampling sites, and unique T-cell subpopulations that effect suppression. In the newborn, several of these pathways are not matured, allowing for sensitization rather than suppression. With age, the mucosa associated lymphoid tissue matures, and in most individuals this allows for generation of the normal suppressed tone of the mucosa associated lymphoid tissue. As a consequence, food allergies are largely outgrown. This article deals with the normal facets of mucosal immune responses and postulates how the different processes may be defective in food-allergic patients.

Animals↗
PubMed2002

Complex formation of the interferon (IFN) consensus sequence-binding protein with IRF-1 is essential for murine macrophage IFN-gamma-induced iNOS gene expression.

This study describes the role of the interferon (IFN) consensus sequence-binding protein (ICSBP or IRF-8) in iNOS gene expression by murine macrophages. An ICSBP binding site in the iNOS promoter region (-923 to -913) was identified using an electrophoretic mobility shift assay and chromatin co-immunoprecipitation. Overexpression of ICSBP greatly enhanced IFN-gamma-induced iNOS promoter activation in RAW264.7 cells, and IFN-gamma-induced iNOS promoter activation was abolished in ICSBP-/- macrophages. Furthermore, transduction of retrovirus-ICSBP in ICSBP-/- macrophages rescued IFN-gamma-induced iNOS gene expression. However, transduction of retrovirus-ICSBP in the absence of IFN-gamma activation did not induce iNOS expression in either RAW264.7 cells or ICSBP-/- macrophages. Interestingly, ICSBP alone transduced into ICSBP-/- macrophages did not bind to IFN-stimulated response element site (-923 to -913) of the iNOS promoter region, although following activation with IFN-gamma, a DNA.protein complex was formed that contains ICSBP and IRF-1. Co-transduction of ICSBP with IRF-1 clearly induces nitric oxide production. In addition, interleukin-4 inhibits IFN-gamma-induced iNOS gene expression by attenuating the physical interaction of ICSBP with IRF-1. Complex formation of ICSBP with IRF-1 is essential for iNOS expression, and interleukin-4 attenuates the physical interaction of ICSBP with IRF-1 resulting in the inhibition of INOS gene expression.

Animals↗
PubMed2002

Orthotopic tracheal transplantation in the murine model.

BACKGROUND: Before tracheal transplantation can be clinically applied for the reconstruction of life-threatening airway defects, the immunobiology of this organ system must be better characterized. The availability of reagents and transgenic mice strains make the murine model ideal for this purpose. We have developed a reliable and reproducible method of orthotopic tracheal transplantation and characterized the kinetics of rejection. METHODS: Balb/c donor tracheal segments (five tracheal rings), were orthotopically transplanted into either syngeneic Balb/c recipients or allogeneic C57BL/6 recipients. Tracheal graft rejection was monitored by daily clinical airway assessment, in vivo cilia motility, and histologic examination using hematoxylin and eosin staining and CD8/CD4 immunohistochemistry. RESULTS: Two days after tracheal transplantation, allogenic recipients developed a persistent audible stridor that did not occur in the syngeneic experimental group. Whereas syngeneic tracheal autografts demonstrated normal mucociliary function after transplantation, allogeneic recipients failed to achieve normal mucociliary function. Normal histologic architecture persisted in the syngeneic grafts without evidence of lymphocytic infiltrate; however, the nonimmunosuppressed allogeneic grafts demonstrated a loss of normal ciliated respiratory epithelia and a CD8/CD4-positive lymphocytic infiltrate that peaked at 21 days after transplantation. CONCLUSIONS: The Balb/c (donor) to C57BL/6 (recipient) murine orthotopic tracheal transplant model offers a reliable method for the study of tracheal transplantation.

Animals↗
PubMed2002

Expansion of CD8+ T cells with regulatory function after interaction with intestinal epithelial cells.

BACKGROUND & AIMS: Regulatory T cells play a role in the control of immune responses in the intestinal mucosa and their absence may predispose to inflammatory bowel disease (IBD). We have previously shown that T cells activated by intestinal epithelial cells (IECs) are suppressive in function. Our goal was to characterize the phenotype and function of T cells proliferating after interaction with IECs. METHODS: Irradiated human IECs, isolated from normal resection specimens, were cultured with carboxy fluorescein succinimidyl ester (CFSE) labeled T cells. Flow cytometric analysis of T cells was performed at days 5-10. CD8+ T cells proliferating in culture with IECs were sorted and added to suppressive assays. RESULTS: The precursor frequency of T cells proliferating in response to IECs ranged from 0.3%-0.9%. Several subpopulations were shown to proliferate (CD8+CD28-/CD8+CD28+/CD4+CD25+), but one population (CD8+CD28-CD101+CD103+) appeared to be dependent on contact with the CD8 ligand gp180. After sorting, culture in the presence of interleukin (IL)-7 and IL-15 allowed for the generation of cell lines. IEC-activated CD8+ T cells, but not nonactivated CD8+ T cells, were suppressive in function. Suppression belonged to the CD101+CD103+ subset of IEC-activated CD8+ T cells and appeared to require cell contact. CD8+ lamina propria T cells also showed suppressive function, suggesting the presence of CD8+ regulatory T cells in the mucosa. CONCLUSIONS: IECs are able to induce the proliferation of a small fraction of CD8+ peripheral T cells. The CD8+CD28- subset of IEC-activated CD8+ T cells, which express CD101 and CD103, interacts with IECs through gp180 and has regulatory function.

Antigens, CD↗