210 results match your criteria: "Institute for Cellular Therapeutics.[Affiliation]"

Hematopoietic stem cell transplantation (HSCT) has been utilized for treatment of many hematologic malignancies, genetic and metabolic disorders, and hemoglobinopathies such as sickle cell disease and thalassemia. It also induces donor-specific tolerance to organ and tissue transplants. The widespread success of HSCT is hampered by the toxicities of immunosuppression and development of graft-versus-host disease (GVHD).

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Allogeneic islet transplantation is an important therapeutic approach for the treatment of type 1 diabetes. Clinical application of this approach, however, is severely curtailed by allograft rejection primarily initiated by pathogenic effector T cells regardless of chronic use of immunosuppression. Given the role of Fas-mediated signaling in regulating effector T cell responses, we tested if pancreatic islets can be engineered ex vivo to display on their surface an apoptotic form of Fas ligand protein chimeric with streptavidin (SA-FasL) and whether such engineered islets induce tolerance in allogeneic hosts.

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Background: Currently, the donor-recipient matching process for vascularized composite tissue allotransplantation (VCTA) closely follows the standard practices for solid organ transplantation. Sensitization is considered a contraindication to VCTA. However, the role of sensitization in VCTA rejection is largely unstudied.

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Background/aims: OVE26 (OVE) mice provide a valuable model of advanced diabetic nephropathy (DN), but they take 8 months to develop moderate interstitial fibrosis and reduced glomerular filtration rate (GFR). The aim of this project was to produce a more rapid and advanced model of DN.

Methods: Uninephrectomy was applied to OVE and FVB mice at 2 months of age.

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Mechanism of impaired NLRP3 inflammasome priming by monophosphoryl lipid A.

Sci Signal

May 2011

Department of Microbiology and Immunology and Institute for Cellular Therapeutics, University of Louisville School of Medicine, 570 South Preston Street, Louisville, KY 40202, USA.

Monophosphoryl lipid A (MLA), a nontoxic derivative of the endotoxin lipopolysaccharide (LPS), has been approved in the United States for use as a vaccine adjuvant. LPS and MLA are ligands of Toll-like receptor 4 (TLR4), and it has been unclear why LPS triggers toxic inflammation, whereas MLA generates safe and effective immunostimulation. Signaling downstream of TLR4 is mediated by the adaptor proteins TRIF [Toll-interleukin-1 (IL-1) receptor (TIR) domain-containing adaptor-inducing interferon-β], which is required for adaptive immune outcomes, and MyD88 (myeloid differentiation marker 88), which is responsible for many proinflammatory effects.

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CD8-positive/T-cell receptor-negative (CD8(+)/TCR(-)) graft facilitating cells (FCs) are a novel cell population in bone marrow that potently enhance engraftment of hemopoietic stem cells (HSCs). Previously, we showed that the CD11c(+)/B220(+)/CD11b(-) plasmacytoid-precursor dendritic cell (p-preDC) FC subpopulation plays a critical but nonredundant role in facilitation. In the present study, we investigated the mechanism of FC function.

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Stem cell-based strategies for the treatment of type 1 diabetes mellitus.

Expert Opin Biol Ther

January 2011

University of Louisville, Institute for Cellular Therapeutics, Louisville, KY 40202-1760, USA.

Importance Of The Field: β-Cell regeneration and β-cell preservation are two promising therapeutic approaches for the management of patients with type 1 diabetes (T1D). Stem cell-based strategies to address the problems of shortage in β cells, autoimmune and alloimmune responses have become an area of intense study.

Areas Covered In This Review: This review focuses on the progress that has been made in obtaining functional, insulin-producing cells from various types of stem/progenitor cells, including the current knowledge on the immunomodulatory roles of hematopoietic stem cell and multipotent stromal cell in the therapies for T1D.

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Stem cell-based therapeutic applications in retinal degenerative diseases.

Stem Cell Rev Rep

June 2011

Institute for Cellular Therapeutics, University of Louisville, 570 S. Preston Street, Suite 404, Louisville, KY 40202-1760, USA.

Retinal degenerative diseases that target photoreceptors or the adjacent retinal pigment epithelium (RPE) affect millions of people worldwide. Retinal degeneration (RD) is found in many different forms of retinal diseases including retinitis pigmentosa (RP), age-related macular degeneration (AMD), diabetic retinopathy, cataracts, and glaucoma. Effective treatment for retinal degeneration has been widely investigated.

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Sensitization to major histocompatibility complex (MHC) alloantigens is critical in transplantation rejection. The mechanism of sensitization to minor histocompatibility antigens (Mi-HAg) has not been thoroughly explored. We used a mouse model of allosensitization to Mi-HAg to study the Mi-HAg sensitization barrier in bone marrow transplantation (BMT).

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Article Synopsis
  • Cervical cancer is a major cause of death among women globally, and existing HPV vaccines do not effectively treat the disease, highlighting the need for new therapeutic vaccines.
  • The HPV E7 oncoprotein is a promising target for these vaccines, but its low antigenicity necessitates the use of strong adjuvants to boost effectiveness.
  • Research showed that a new engineered adjuvant, SA-4-1BBL, in combination with an HPV-16 E7 vaccine significantly eliminated tumors in 70% of treated mice by enhancing immune responses, particularly involving NK cells, which are crucial for the therapy's success.
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Tumor cells engineered to codisplay on their surface 4-1BBL and LIGHT costimulatory proteins as a novel vaccine approach for cancer immunotherapy.

Cancer Gene Ther

October 2010

Institute for Cellular Therapeutics, Department of Microbiology and Immunology and James Graham Brown Cancer Center, University of Louisville, Louisville, KY 40202, USA.

Primary tumor cells genetically modified to express a collection of immunological ligands on their surface may have the utility as therapeutic autologous cancer vaccines. However, genetic modification of primary tumor cells is not only cost, labor and time intensive, but also has safety repercussions. As an alternative, we developed the ProtEx technology that involves generation of immunological ligands with core streptavidin (SA) and their display on biotinylated cells in a rapid and efficient manner.

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Article Synopsis
  • Therapeutic subunit vaccines targeting tumor-associated antigens (TAAs) are promising for cancer treatment, but their effectiveness is limited by weak immunogenicity, necessitating strong adjuvants.
  • Researchers developed a soluble form of the costimulatory ligand 4-1BBL, combined with streptavidin (SA-4-1BBL), which enhances immune responses by improving the uptake and presentation of TAAs to immune cells.
  • In animal studies, vaccines using SA-4-1BBL showed significant therapeutic effects against specific cancers by boosting T-cell responses and altering the balance of immune cell populations in tumors, highlighting its potential as an innovative component in cancer immunotherapy.
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Background: The role of bone marrow (BM)-derived cells in pancreatic beta-cell regeneration remains unresolved. We examined whether BM-derived cells are recruited to the site of moderate pancreatic injury and contribute to beta-cell regeneration.

Methods: Low-dose streptozotocin (STZ) treatment was used to induce moderate pancreatic damage and hyperglycemia.

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Background: Mixed chimerism induces donor-specific tolerance to composite tissue allotransplants (CTAs). In the present studies, we used a nonmyeloablative conditioning approach to establish chimerism and promote CTA acceptance.

Methods: Wistar Furth (RT1A(u)) rats were conditioned with 600 to 300 cGy total body irradiation (TBI, day-1), and 100 x 10(6) T-cell-depleted ACI (RT1A(abl)) bone marrow cells were transplanted on day 0, followed by a 11-day course of tacrolimus and one dose of antilymphocyte serum (day 10).

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A novel form of 4-1BBL has better immunomodulatory activity than an agonistic anti-4-1BB Ab without Ab-associated severe toxicity.

Vaccine

December 2009

Institute for Cellular Therapeutics, Department of Microbiology and Immunology, and James Brown Cancer Center, University of Louisville, KY 40202, United States.

Agonistic Abs to select costimulatory members of CD28 and TNFR family have shown efficacy in various preclinical cancer immunotherapeutic settings. However, the use of agonistic Abs is often associated with severe toxicity due to non-specific activation of lymphocytes. We hypothesized that natural costimulatory ligands may serve as more potent and safer alternative to agonistic Abs for immunotherapy.

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Costimulation as a platform for the development of vaccines: a peptide-based vaccine containing a novel form of 4-1BB ligand eradicates established tumors.

Cancer Res

May 2009

Institute for Cellular Therapeutics, Department of Microbiology and Immunology, and James Graham Brown Cancer Center, University of Louisville, Louisville, KY 40202, USA.

Vaccines represent an attractive treatment modality for the management of cancer primarily because of their specificity and generation of immunologic memory important for controlling recurrences. However, the efficacy of therapeutic vaccines may require formulations that not only generate effective immune responses but also overcome immune evasion mechanisms employed by progressing tumor. Costimulatory molecules play critical roles in modulating innate, adaptive, and regulatory immunity and have potential to serve as effective immunomodulatory components of therapeutic vaccines.

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Composite tissue allotransplantation (CTA) transplantation is currently being performed with increasing frequency in the clinic. The feasibility of the procedure has been confirmed in over 40 successful hand transplants, 3 facial reconstructions, and vascularized knee, esophageal, abdominal wall, and tracheal allografts. The toxicity of chronic, nonspecific immunosuppression remains a major limitation to the widespread availability of CTA and is associated with opportunistic infections, nephrotoxicity, end-organ damage, and an increased rate of malignancy.

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There is an increased risk of failure of engraftment following nonmyeloablative conditioning. Sensitization resulting from failed bone marrow transplantation (BMT) remains a major challenge for secondary BMT. Approaches to allow successful retransplantation would have significant benefits for BMT candidates living with chronic diseases.

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Apoptosis as a mechanism of T-regulatory cell homeostasis and suppression.

Immunol Cell Biol

June 2009

Department of Microbiology and Immunology, Institute for Cellular Therapeutics, University of Louisville, Louisville, KY, USA.

Activation-induced cell death is a general mechanism of immune homeostasis through negative regulation of clonal expansion of activated immune cells. This mechanism is involved in the maintenance of self- and transplant tolerance through polarization of the immune responses. The Fas/Fas-ligand interaction is a major common executioner of apoptosis in lymphocytes, with a dual role in regulatory T cell (Treg) function: Treg cell homeostasis and Treg cell-mediated suppression.

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Science of composite tissue allotransplantation.

Transplantation

September 2008

Institute for Cellular Therapeutics, University of Louisville, Louisville, KY 40202-1760, USA.

The science of composite tissue allotransplantation (CTA) is rooted in progressive thinking by surgeons, fueled by innovative solutions, and aided by understanding the immunology of tolerance and rejection. These three factors have allowed CTA to progress from science fiction to science fact. Research using preclinical animal models has allowed an understanding of the antigenicity of complex tissue transplants and mechanisms to promote graft acceptance.

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The development of non-infectious subunit vaccines greatly increases the safety of prophylactic immunization, but also reinforces the need for a new generation of immunostimulatory adjuvants. Because adverse effects are a paramount concern in prophylactic immunization, few new adjuvants have received approval for use anywhere in the developed world. The vaccine adjuvant monophosphoryl lipid A is a detoxified form of the endotoxin lipopolysaccharide, and is among the first of a new generation of Toll-like receptor agonists likely to be used as vaccine adjuvants on a mass scale in human populations.

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The critical role played by Fas ligand (FasL) in immune homeostasis renders this molecule an attractive target for immunomodulation to achieve tolerance to auto- and transplantation Ags. Immunomodulation with genetically modified cells expressing FasL was shown to induce tolerance to alloantigens. However, genetic modification of primary cells in a rapid, efficient, and clinically applicable manner proved challenging.

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Objective: Plasmacytoid precursor dendritic cell facilitating cells (p-preDC FCs) play a critical role in facilitation of syngeneic and allogeneic hematopoietic stem cell (HSC) engraftment. Here, we evaluated the phenotype and function of CD8(+)/TCR(-) FCs from NOD mice.

Research Design And Methods: The phenotype of CD8(+)/TCR(-) FCs was analyzed by flow cytometry using sorted FCs from NOD, NOR, or B6 mice.

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Background: Fms-related tyrosine kinase 3 (Flt3)-ligand (FL) promotes the proliferation, differentiation, development, and mobilization of hematopoietic cells. We previously found that FL-mobilized hematopoietic stem cells (HSC) engraft efficiently, whereas FL-expanded bone marrow HSC do not. The function of FL-mobilized c-Kit(+) Sca-1(+)Lin(-)(KSL) subpopulations has not been systematically evaluated.

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