Biomedical subjects

Jeffrey D Carter

Publications and source records attributed to Jeffrey D Carter.

5 recordsLinked to original sources

PubMed2006

Combined treatment with lisofylline and exendin-4 reverses autoimmune diabetes.

Type 1 diabetes mellitus (T1DM) is an autoimmune disease leading to near complete pancreatic beta-cell destruction. New evidence suggests that beta-cell regeneration is possible, but ongoing autoimmune damage prevents restoration of beta-cell mass. We tested the hypothesis that simultaneously blocking autoimmune cytokine damage and supplying a growth-promoting stimulus for beta-cells would provide a novel approach to reverse T1DM. Therefore, in this study we combined lisofylline to suppress autoimmunity and exendin-4 to enhance beta-cell proliferation for treating autoimmune-mediated diabetes in the non-obese diabetic (NOD) mouse model. We found that this combined therapy effectively reversed new-onset diabetes within a week of therapy, and even maintained euglycemia up to 145 days after treatment withdrawal. The therapeutic effect of this regimen was associated with improved beta-cell metabolism and insulin secretion, while reducing beta-cell apoptosis. It is possible that such combined therapy could become a new strategy to defeat T1DM in humans.

Animals↗

PubMed2005

Viral IL-10-mediated immune regulation in pancreatic islet transplantation.

Protection of transplanted pancreatic islet grafts in recipients with autoimmune diabetes depends on the suppression of autoimmune recurrence and allogeneic rejection. The aim of this study was to investigate the efficiency of viral IL-10 gene delivery in the prevention of autoimmune recurrence following islet transplantation. We evaluated the effectiveness of a systemically delivered adeno-associated viral vector (AAV vIL-10) carrying viral IL-10 in protecting islet engraftment. We observed significant prolongation of graft survival after treatment with AAV vIL-10 when using islets from donors lacking autoimmunity. We found that the mechanism of vIL-10-mediated protection was associated with suppression of T cell activation and that donor immune cells that were simultaneously transferred with the islet grafts could induce autoimmune recurrence. AAV vIL-10 gene transfer suppressed previously activated T cells and protected grafted islets from autoimmune-mediated destruction. We conclude that vIL-10 can regulate autoimmune activity and that transfer of its gene may have potential for therapeutic islet transplantation.

Adenoviridae↗

PubMed2005

Inflammatory blockade improves human pancreatic islet function and viability.

The pathogenesis of pancreatic beta-cell death in diabetes mellitus is still under investigation. Inflammation is likely to be one of the factors responsible for beta-cell death during disease development. In this study, we have used a novel antiinflammatory compound, Lisofylline (LSF), to investigate the role of inflammatory blockade in protecting human pancreatic islets. LSF is a small synthetic molecule that reduces inflammatory cytokine production and action, improves beta-cell mitochondrial metabolism, and regulates immune activities. The present study has demonstrated that the treatment of human islets with LSF not only allows the retention of glucose responsiveness and insulin secretion in the presence of multiple proinflammatory cytokines, but also enhances basal insulin secretion of beta cells in vitro. LSF also significantly reduces islet apoptosis, protects beta cells from proinflammatory cytokine damage, and maintains cellular viability. In a mouse transplantation model, insulin independence could be reached in diabetic recipient mice by implantation of 30% fewer islets when LSF was used in islet culture compared to the control group. These results demonstrate that LSF profoundly enhances beta-cell function, and suggest the potential of using inflammatory blockade, such as LSF, to improve beta-cell function for islet transplantation.

Anti-Inflammatory Agents, Non-Steroidal↗

PubMed2004

The novel anti-inflammatory agent lisofylline prevents autoimmune diabetic recurrence after islet transplantation.

BACKGROUND: Pancreatic islet transplantation has become a promising treatment for type 1 diabetes. However, autoimmune reactivity destroys engrafted islets in type 1 diabetic recipients. The authors' previous studies demonstrated that a novel anti-inflammatory agent, lisofylline (LSF), suppressed autoimmune reactivity and protected nonobese diabetic (NOD) mice from diabetes. In this study, the authors investigated the potential of LSF in preventing autoimmune diabetes recurrence after islet transplantation. METHODS: Spontaneously diabetic NOD mice received NOD severe combined immunodeficiency islet transplants and were treated with daily LSF injections at 50 mg/kg for 3 weeks. Blood glucose levels were monitored. Serum cytokine levels were measured at 1 and 3 weeks after engraftment. Nephrectomy of the islet-implanted kidney was performed in LSF-treated recipients. Histology of islet grafts was assessed at the end of the study. The effect of LSF on beta-cell function was studied in vitro. RESULTS: Without immunosuppressants and insulin, the LSF-treated recipient mice maintained euglycemia significantly longer than the saline-treated recipients (mean, >65 days in the LSF-treated group vs. 6 days in saline controls; P=0.0004). Serum levels of interferon-gamma were markedly reduced in LSF-treated recipients at 1 and 3 weeks posttransplant. Diabetes recurred in the LSF-treated recipients after removing the islet-implanted kidneys. Immunohistochemistry showed retention of insulin-positive cells in the grafts of the LSF-treated recipients. LSF preserved beta-cell insulin secretory function in the presence of inflammatory cytokines in vitro. CONCLUSIONS: This study demonstrates that autoimmune diabetes recurrence after islet transplantation could be prevented by treatment with LSF. LSF and its analogues may have the potential to prevent islet autoimmune destruction in clinical transplantation.

Animals↗

PubMed2004

Autoimmune diabetes is blocked in Stat4-deficient mice.

Signal transducers and activators of transcription (STAT) proteins are activated in response to many cytokines, growth factors and hormones. STAT4 mediates IL-12 signaling and regulates T helper 1 (Th1) cell differentiation. Both IL-12 and Th1 cell activation participate in the development of autoimmune diabetes. In this study, we investigated the role of STAT4 in autoimmune diabetes. We crossbred Stat4 deficient (Stat4-/-) mice with nonobese diabetic (NOD) mice to generate the Stat4-/- NOD model. In Stat4-/- NOD mice, serum levels of both IFN-gamma and IL-2 were significantly reduced as compared to the controls. Insulin secretion in pancreatic islets was preserved in Stat4-/- NOD mice. Significantly, disruption of Stat4 activation completely prevented the development of spontaneous diabetes in NOD mice. This study reveals the important role of STAT4 in autoimmune diabetes pathogenesis.

Animals↗