Publications by authors named "Barbara J Whalen"

3 Publications

  • Page 1 of 1

Leptin treatment confers clinical benefit at multiple stages of virally induced type 1 diabetes in BB rats.

Autoimmunity 2011 Mar 9;44(2):137-48. Epub 2010 Aug 9.

Department of Medicine, University of Massachusetts Medical School, Worcester, MA 01605, USA.

The adipokine, leptin, regulates blood glucose and the insulin secretory function of beta cells, while also modulating immune cell function. We hypothesized that the dual effects of leptin may prevent or suppress the autoreactive destruction of beta cells in a virally induced rodent model of type 1 diabetes. Nearly 100% of weanling BBDR rats treated with the combination of an innate immune system activator, polyinosinic:polycytidylic acid (pIC), and Kilham rat virus (KRV) become diabetic within a predictable time frame. We utilized this model to test the efficacy of leptin in preventing diabetes onset, remitting new onset disease, and preventing autoimmune recurrence in diabetic rats transplanted with syngeneic islet grafts. High doses of leptin delivered via an adenovirus vector (AdLeptin) or alzet pump prevented diabetes in>90% of rats treated with pIC+KRV. The serum hyperleptinemia generated by this treatment was associated with decreased body weight, decreased non-fasting serum insulin levels, and lack of islet insulitis in leptin-treated rats. In new onset diabetics, hyperleptinemia prevented rapid weight loss and diabetic ketoacidosis, and temporarily restored euglycemia. Leptin treatment also prolonged the survival of syngeneic islets transplanted into diabetic BBDR rats. In diverse therapeutic settings, we found leptin treatment to have significant beneficial effects in modulating virally induced diabetes. These findings merit further evaluation of leptin as a potential adjunct therapeutic agent for treatment of human type 1 diabetes.
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http://dx.doi.org/10.3109/08916934.2010.482116DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4172446PMC
March 2011

A DNA vaccine prime followed by a liposome-encapsulated protein boost confers enhanced mucosal immune responses and protection.

J Immunol 2008 May;180(9):6159-67

Oral Vaccine Institute, 10 New Bond Street, Worcester, MA 01606, USA.

A variety of DNA vaccine prime and recombinant viral boost immunization strategies have been developed to enhance immune responses in humans, but inherent limitations to these strategies exist. There is still an overwhelming need to develop safe and effective approaches that raise broad humoral and T cell-mediated immune responses systemically and on mucosal surfaces. We have developed a novel mucosal immunization regimen that precludes the use of viral vectors yet induces potent T cell responses. Using hepatitis B surface Ag (HBsAg), we observed that vaccination of BALB/c mice with an i.m. HBsAg-DNA vaccine prime followed by an intranasal boost with HBsAg protein encapsulated in biologically inert liposomes enhanced humoral and T cell immune responses, particularly on mucosal surfaces. Intranasal live virus challenge with a recombinant vaccinia virus expressing HBsAg revealed a correlation between T cell immune responses and protection of immunized mice. A shortened immunization protocol was developed that was successful in both adult and neonatal mice. These results support the conclusion that this new approach is capable of generating a Th-type-1-biased, broad spectrum immune response, specifically at mucosal surfaces. The success of this design may provide a safe and effective vaccination alternative for human use.
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http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3633597PMC
http://dx.doi.org/10.4049/jimmunol.180.9.6159DOI Listing
May 2008

Type 1 cytokines polarize thymocytes during T cell development in adult thymus organ cultures.

J Autoimmun 2003 Feb;20(1):27-42

Department of Medicine, University of Massachusetts Medical School, Biotech II, Suite 218, 373 Plantation Street, Worcester, MA 01605, USA.

Peripheral T cells can be polarized towards type 1 or type 2 cytokine immune responses during TCR engagement. Because T cell selection by peptide plus self-MHC in the thymus requires TCR engagement, we hypothesized that type 1 cytokines may polarize developing T cells. We cultured thymi from BBDR rats in adult thymus organ cultures (ATOC) under type 1 cytokine conditions in the absence of exogenous antigen. Type 1 cytokine-conditioned ATOC generated cells that spontaneously secreted high levels of IFNgamma, but not IL-4. A second exposure to type 1 cytokines further increased IFNgamma secretion by these cells, most of which were blasts that expressed the activation markers CD25, CD71, CD86, and CD134. Studies using blocking antibodies and pharmacological inhibitors suggested that both IL-18 and cognate TCR-MHC/ligand interactions were important for activation. Blocking anti-MHC class I plus anti-MHC class II antibodies, neutralizing anti-IL-18 antibody, and the p38 MAP-kinase inhibitor SB203580 each reduced IFNgamma production by approximately 75-80%. Cyclosporin A, which prevents TCR signaling, inhibited IFNgamma production by approximately 50%. These data demonstrate that exposure to type 1 cytokines during intrathymic development can polarize differentiating T cells, and suggest a mechanism by which intrathymic exposure to type 1 cytokines may modulate T cell development.
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http://dx.doi.org/10.1016/s0896-8411(02)00091-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7125593PMC
February 2003