Treatment of C57BL/6 mice with one transfusion BALB/c spleen cells and anti-CD154 (anti-CD40-ligand) antibody permits islet grafts to survive indefinitely skin for approximately 50 d without further intervention. The protocol induces long-term allograft survival, but the mechanism is unknown. We now report: (a) addition thymectomy permitted allografts > 100 d, suggesting that graft rejection in euthymic results from thymic export alloreactive T cells. (b) Clonal deletion not underlying as...

The c-Jun N-terminal kinase (JNK) signal transduction pathway is activated in response to the exposure of cells environmental stress. Components JNK signaling interact with JIP1 scaffold protein. located neurites primary hippocampal neurons. However, stress, accumulates soma together and phosphorylated c-Jun. Disruption Jip1 gene mice by homologous recombination prevented activation caused excitotoxic stress anoxic vivo vitro. These data show that protein a critical component MAP-kinase pathway.

To investigate the role of RT6+ T cells in pathogenesis diabetes BB/W rats, we treated animals from diabetes-resistant (DR) subline with anti-RT6.1 lymphocytotoxic mAb. This depleted greater than 95% peripheral but did not substantially reduce levels circulating or vitro response spleen to mitogen. Treatment 30-d-old DR rats this way: induced insulitis and diabetes, rendered nondiabetic RT6-depleted susceptible adoptive transfer by acutely diabetic yielded cell populations capable...

Abstract A two-element protocol consisting of one donor-specific transfusion (DST) plus a brief course anti-CD154 mAb greatly prolongs the survival murine islet, skin, and cardiac allografts. To study mechanism allograft survival, we determined fate tracer populations alloreactive transgenic CD8+ T cells in normal microenvironment. We observed that DST prolonged deleted cells. Neither component alone did so. Skin was also recipients treated with depleting anti-CD8 C57BL/6-CD8 knockout mice...

Objectives. We tested the effectiveness of a community-based, literacy-sensitive, and culturally tailored lifestyle intervention on weight loss diabetes risk reduction among low-income, Spanish-speaking Latinos at increased risk. Methods. Three hundred twelve participants from Lawrence, Massachusetts, were randomly assigned to care (IC) or usual (UC) between 2004 2007. The was implemented by trained individuals community. Each participant followed for 1 year. Results. participants’ mean age...

Diabetes-prone Bio-breeding/Worcester (DP) rats exhibit a severe T cell lymphopenia and autoimmune pancreatic insulitis. The present results indicate that the is due in large part, if not entirely, to absence of RT-6+ peripheral subset, which includes members both helper/inducer (W3/25) suppressor/cytotoxic (OX 8) antigenic phenotypes. Delineation causal mechanism(s) for selective cells DP may provide important insights into cellular basis insulin-dependent diabetes mellitus syndrome these animals.

Abstract Sensitization to donor Ags is an enormous problem in clinical transplantation. In islet allograft model, presensitization of recipients through donor-specific transfusion (DST) 4 wk before transplantation results accelerated rejection. We demonstrate that combined DST with anti-CD154 (CD40L) therapy not only prevents the deleterious produced by pretransplant it also induces broad alloantigen-specific tolerance and permits subsequent engraftment or cardiac grafts without further...

Combined treatment with antibody against CD40 ligand and one transfusion of donor splenocytes prolonged survival fully mismatched BALB/c skin allografts on C57BL/6 recipients, ≈20% grafts surviving >100 days. In vitro alloresponsiveness in treated animals was reduced the immediate post-transplantation period, but by day 100 increased despite presence a successful allograft. The alloreactivity confirmed vivo adoptive transfer, which suggests that our protocol had induced either state "split...

ABSTRACT Treatment with a 2-week course of anti-CD154 antibody and single transfusion donor leukocytes (a donor-specific or DST) permits skin allografts to survive for >100 days in thymectomized mice. As clinical trials this methodology humans are contemplated, concern has been expressed that viral infection graft recipients may disrupt tolerance the allograft. We report acute lymphocytic choriomeningitis virus (LCMV) induced allograft rejection mice treated DST if inoculated shortly...

Abstract Ag-specific immune tolerance results from the induction of cellular mechanisms that limit T cell responses to selective Ags. One these is characterized by attenuated proliferation and decreased IL-2 production in fully stimulated CD4+ Th cells denoted anergy. We report identification early growth response gene (Egr-2; Krox-20), a zinc-finger transcription factor, as key protein required for anergy cultured cells. Gene array screening revealed high Egr-2 expression distinctly...

Virus infection is hypothesized to be an important environmental "trigger" of type 1 diabetes in humans. We used the BBDR rat model investigate relationship between viral and autoimmune diabetes. rats are diabetes-free Ab-free housing, but disease develops approximately 30% infected with Kilham virus (KRV) through a process that does not involve pancreatic beta cells. Pretreatment polyinosinic-polycytidylic (poly(I:C)), ligand TLR3, acts synergistically induce 100% KRV-infected rats. The...

Abstract Costimulation blockade protocols are effective in prolonging allograft survival animal models and entering clinical trials, but how environmental perturbants affect graft remains largely unstudied. We used a costimulation protocol consisting of donor-specific transfusion anti-CD154 mAb to address this question. observed that lymphocytic choriomeningitis virus infection at the time shortens survival. Lymphocytic 1) activates innate immunity, 2) induces allo-cross-reactive T cells, 3)...

Abstract Viral infections are associated epidemiologically with the expression of type 1 diabetes in humans, but mechanisms underlying this putative association unknown. To investigate role viruses diabetes, we used a model viral induction autoimmune genetically susceptible biobreeding diabetes-resistant (BBDR) rats. BBDR rats do not develop viral-Ab-free environments, ∼25% animals infected parvovirus Kilham rat virus (KRV) via mechanism that does involve β cell infection. Using model,...

The Bio-Breeding/Worcester (BB/W) rat develops spontaneous autoimmune diabetes similar to human insulin-dependent mellitus. Transfusions of whole blood from the nondiabetic W-line BB/W rats prevent syndrome in diabetes-prone recipients. We report three experiments designed determine which component is protective. In all experiments, 23 35 d age were given four or six weekly intravenous injections. first experiment, animals received either saline transfusions erythrocytes, white cells, plasma...

To determine the influence of infectious agents on initiation diabetes in spontaneously diabetic Bio-Breeding/Worcester (BB/W) rat, susceptible rats were raised a germ-free environment. Between 2 and 3 mo age, 12 pups became diabetic. Histologic examination pancreas revealed insulitis or end-stage islets. Culture smears from various tissues negative for bacteria parasites. Serum vital antibody titers all known rat viruses undetectable. These data suggest that syndrome BB/W is not dependent...

Allogeneic hematopoietic chimerism leading to central tolerance has significant therapeutic potential. Realization of that potential been impeded by the need for myeloablative conditioning host and development graft-versus-host disease (GVHD). To surmount these impediments, we have adapted a costimulation blockade–based protocol developed solid organ transplantation use in stem cell transplantation. The combines donor-specific transfusion (DST) with anti-CD154 mAb. When applied...

Apoptosis is a regulated cell death program controlled by extrinsic and intrinsic signaling pathways. The pathway involves stress signals that activate pro-apoptotic members of the Bcl-2 family, inducing permeabilization mitochondria release apoptogenic factors. These proteins localize to outer mitochondrial membrane. Ian4, membrane protein with GTP-binding activity, normally present in thymocytes, T cells, B cells. We others have recently discovered mutation rat Ian4 gene results severe...

Previous studies have shown that multiple transfusions of spleen cells from histocompatible nondiabetic donors prevent autoimmune diabetes mellitus in diabetes-prone (DP) BioBreeding/Worcester (BB/Wor) rats. In this study, a single transfusion greater than or equal to 50 x 10(6) either diabetes-resistant (DR) BB/Wor Wistar-Furth (WF) rats substantially reduced the incidence when given DP 27 46 days old but not 61 old. Transfusion and protection were associated with appearance RT6+ donor...