Dendritic Cells Exposed to MVA-Based HIV-1 Vaccine Induce Highly Functional HIV-1-Specific CD8+ T Cell Responses in HIV-1-Infected Individuals

Currently, MVA virus vectors carrying HIV-1 genes are being developed as HIV-1/AIDS prophylactic/therapeutic vaccines. Nevertheless, little is known about the impact of these vectors on human dendritic cells (DC) and their capacity to present HIV-1 antigens to human HIV-specific T cells. This study aimed to characterize the interaction of MVA and MVA expressing the HIV-1 genes Env-Gag-Pol-Nef of clade B (referred to as MVA-B) in human monocyte-derived dendritic cells (MDDC) and the subsequent processes of HIV-1 antigen presentation and activation of memory HIV-1-specific T lymphocytes. For these purposes, we performed ex vivo assays with MDDC and autologous lymphocytes from asymptomatic HIV-infected patients. Infection of MDDC with MVA-B or MVA, at the optimal dose of 0.3 PFU/MDDC, induced by itself a moderate degree of maturation of MDDC, involving secretion of cytokines and chemokines (IL1-ra, IL-7, TNF-α, IL-6, IL-12, IL-15, IL-8, MCP-1, MIP-1α, MIP-1β, RANTES, IP-10, MIG, and IFN-α). MDDC infected with MVA or MVA-B and following a period of 48 h or 72 h of maturation were able to migrate toward CCL19 or CCL21 chemokine gradients. MVA-B infection induced apoptosis of the infected cells and the resulting apoptotic bodies were engulfed by the uninfected MDDC, which cross-presented HIV-1 antigens to autologous CD8+ T lymphocytes. MVA-B-infected MDDC co-cultured with autologous T lymphocytes induced a highly functional HIV-specific CD8+ T cell response including proliferation, secretion of IFN-γ, IL-2, TNF-α, MIP-1β, MIP-1α, RANTES and IL-6, and strong cytotoxic activity against autologous HIV-1-infected CD4+ T lymphocytes. These results evidence the adjuvant role of the vector itself (MVA) and support the clinical development of prophylactic and therapeutic anti-HIV vaccines based on MVA-B

New Insight on Human Type 1 Diabetes Biology: nPOD and nPOD-Transplantation

The Juvenile Diabetes Research Foundation (JDRF) Network for Pancreatic Organ Donors with Diabetes (JDRF nPOD) was established to obtain human pancreata and other tissues from organ donors with type 1 diabetes (T1D) in support of research focused on disease pathogenesis. Since 2007, nPOD has recovered tissues from over 100 T1D donors and distributed specimens to approximately 130 projects led by investigators worldwide. More recently, nPOD established a programmatic expansion that further links the transplantation world to nPOD, nPOD-Transplantation; this effort is pioneering novel approaches to extend the study of islet autoimmunity to the transplanted pancreas and to consent patients for postmortem organ donation directed towards diabetes research. Finally, nPOD actively fosters and coordinates collaborative research among nPOD investigators, with the formation of working groups and the application of team science approaches. Exciting findings are emerging from the collective work of nPOD investigators, which covers multiple aspects of islet autoimmunity and beta cell biology

Virus Infections: Lessons from Pancreas Histology

Type 1 diabetes mellitus is a chronic autoimmune disease resulting from the progressive immune-mediated destruction of pancreatic β cells in genetically susceptible individuals, with the likely contribution of environmental factors, among which viruses have been extensively studied. The pathologic hallmark of the disease is insulitis—a process characterized by islet infiltration of immunocompetent cells that has been well characterized in animal models of islet autoimmunity, and to a lesser extent, in humans. Insulitis characterization has provided valuable information to gain insights into the disease pathogenesis. We review the recent literature on the viral contribution to β-cell destruction and dysfunction in type 1 diabetes, with particular reference to the pathology of the pancreatic islet in humans and in animal models of the disease

Pathologic changes in human islets

PURPOSE OF REVIEWThis paper reviews the most recent articles on human islet inflammation in type 1 and type 2 diabetes, in recurrent autoimmunity and alloimmunity, which can result in pancreatic graft failure. Finally, we examine data supporting the hypothesis that islet destruction is accompanied by regenerative phenomena aimed at restoring beta cell mass. RECENT FINDINGSType 1 diabetesApplication of high-resolution magnetic resonance imaging and fluorescence of long circulating nanoparticles was successfully used in evaluating islet inflammation in animal models of autoimmune diabetes. Among environmental factors in type 1 diabetes, enteroviral beta-cell infection was reported in some Finnish type 1 diabetic patients. Finally, a family of modulators of cytokine signaling was reported to occur in human islets.Pancreatic islet transplantationSeveral observations suggested that (a) interventions to activate, amplify, or sustain intra-islet endothelial cells may facilitate islet revascularization; and (b) the development of strategies aimed at preventing upregulation of proinflammatory molecules can improve islet transplantation.Type 2 diabetesMultiple factors such as proinflammatory cytokines, high glucose and free fatty acids can contribute to islet inflammation in type 2 diabetes. Accordingly, type 2 diabetic islets show increased apoptotic phenomena and a series of functional defects.Beta-cell regenerationA number of reports observed beta-cell neogenesis in rodent and in human pancreas. Newly formed beta-cells likely derive either from ductal cells or as results of proliferation phenomena from pre-existing beta cells. SUMMARYIncreasing evidence supports the hypothesis that islet inflammation together with beta-cell dysfunction is a common feature to both type 1 and type 2 diabetes