Donor MHC Class I Peptides in Conjunction With Self-Epitopes Induce Donor-Specific Tolerance in a Dose-Dependent Manner But Unable to Abrogate Chronic Rejection

2005 ◽  
Vol 37 (4) ◽  
pp. 1937-1939 ◽  
Author(s):  
N.V. Semiletova ◽  
X.-D. Shen ◽  
D.M. Feldman ◽  
R.W. Busuttil ◽  
J.W. Kupiec-Weglinski ◽  
...  
Keyword(s):  
Mhc Class I ◽  
Chronic Rejection ◽  
Class I ◽  
Dependent Manner ◽  
Donor Specific Tolerance ◽  
Dose Dependent ◽  
Specific Tolerance

scholarly journals Antibodies to MHC Class I Induce Autoimmunity: Role in the Pathogenesis of Chronic Rejection

2008 ◽  
Vol 182 (1) ◽  
pp. 309-318 ◽  
Author(s):  
Naohiko Fukami ◽  
Sabarinathan Ramachandran ◽  
Deepti Saini ◽  
Michael Walter ◽  
William Chapman ◽  
...  
Keyword(s):  
Mhc Class I ◽  
Chronic Rejection ◽  
Class I

Role of MHC class I and CD8+ T cells in the pathogenesis of chronic rejection

2001 ◽  
Vol 33 (1-2) ◽  
pp. 319 ◽  
Author(s):  
H Sun ◽  
V Subbotin ◽  
J Woodward ◽  
L Valdivia ◽  
J.J Fung ◽  
...  
Keyword(s):  
T Cells ◽  
Mhc Class I ◽  
Cd8 T Cells ◽  
Chronic Rejection ◽  
Class I

Donor-Specific Tolerance Induction through Expansion of DCregs and Tregs by a Liposomal Formulation of KRN7000 (RGI-2001).

Blood ◽  
2008 ◽  
Vol 112 (11) ◽  
pp. 2332-2332
Author(s):  
Omar Duramad ◽  
Amy Laysang ◽  
Jun Li ◽  
Yasuyuki Ishii ◽  
Reiko Namikawa
Keyword(s):  
Bone Marrow ◽  
Bone Marrow Transplantation ◽  
Immune Responses ◽  
Treg Cells ◽  
Liposomal Formulation ◽  
Spleen Cells ◽  
Inkt Cells ◽  
Donor Specific Tolerance ◽  
Dose Dependent ◽  
Specific Tolerance

Abstract Pharmacological induction of donor-specific tolerance would provide significant benefits in both organ transplantation and bone marrow transplantation settings. We investigated the ability of alpha-galactosylceramide (α-GC) in inducing donor-specific tolerance when given in a liposomal formulation. α-GC is a ligand for CD1d molecules expressed on antigen-presenting cells. Upon presentation by CD1d to invariant natural killer T (iNKT) cells, α-GC induces the rapid release of Th1, Th2, or immune regulatory cytokines and initiation of multiple downstream cellular events such as T cell polarization and expansion of dendritic cell subsets. Previously, using RGI-2001 (a liposomal formulation of a synthetic derivative of α-GC, KRN7000), we have demonstrated that the activation of iNKT cells by RGI-2001 induces expansion of regulatory dendritic cells (DCreg) and subsequent generation of antigen-specific Foxp3+ regulatory T (Treg) cells in the presence of target antigens. In the present study, we examined the effects of RGI-2001 on immune responses against alloantigens using a murine in vivo experimental system. In brief, Balb/c (H-2d) recipients were primed with 5x10e6 C57BL/6 (H-2b) whole spleen cells (WSC) with varying doses of RGI-2001 (0.002 to 20 μg/mouse) given intravenously. Seven days later, WSC from the Balb/c recipients were examined for their cellular composition by FACS analysis. Subtle but reproducible dose-dependent increases were noted in the percentage of the LinnegCD11cintCD45RB+ dendritic cell (DC) population, known to be enriched for regulatory DC (DCreg). Since RGI-2001 induces an increase in the total spleen cells, the absolute DCreg cell numbers in RGI-2001-treated spleen increased in a statistically significant manner as compared with untreated controls. As for the percentages of CD4+Foxp3+ Treg cells, no apparent differences were observed. However, an analysis using the Ki67 cycling cell specific nuclear marker revealed a clear dose-dependent increase in the cycling cell fraction among CD4+Foxp3+ Treg cells. These results together confirmed that RGI-2001 induces expansion of DCregs and Tregs. Next, we investigated the effects of RGI-2001 on immune responses against the donor alloantigens. The WSC of the recipient mice were restimulated in vitro with the mitomycin C-treated, T cell depleted donor (C57BL/6) WSC, and the levels of proliferation were measured by MTT colorimetric assay (one-way MLR). It was found that RGI-2001 treatment reproducibly and significantly suppressed proliferation of host WSC in response to donor alloantigens. A dose of 2μg/mouse of RGI-2001 induced in average ~30% reduction in host WSC proliferation. IL-2 production was also reduced to ~50%, further indicating the suppressive effects of RGI-2001. Notably, it was confirmed that suppressive effect of RGI- 2001 was restricted to the responses towards donor specific alloantigens, as no suppression in proliferation nor IL-2 production was noted when a third party (C3H) WSC was used as the stimulators. Collectively, the results suggest that RGI-2001, when administered together with allogeneic donor cells, can induce donor specific tolerance by expanding DCregs and inducing antigen-specific Tregs. RGI-2001 may have a potential to be a novel therapy to prevent organ rejection as well as GvHD in bone marrow transplantation.

CAL-101, a Potent Selective Inhibitor of the p110δ Isoform of Phosphatidylinositol 3-kinase, Attenuates Pathway Signaling, Induces Apoptosis, and Overcomes Signals From the Microenvironment In Cellular Models of Hodgkin Lymphoma

Blood ◽  
2010 ◽  
Vol 116 (21) ◽  
pp. 3926-3926 ◽  
Author(s):  
Sarah A Meadows ◽  
Adam Kashishian ◽  
Dave Johnson ◽  
Volker Diehl ◽  
Brian Lannutti
Keyword(s):  
Hodgkin Lymphoma ◽  
Cell Lines ◽  
Stromal Cells ◽  
Specific Inhibitor ◽  
Lymphocytic Leukemia ◽  
Class I ◽  
Clinical Activity ◽  
Dependent Manner ◽  
Cellular Models ◽  
Dose Dependent

Abstract Abstract 3926 Phosphatidylinositide 3-kinases (PI3Ks) are a family of lipid kinases that are involved in signaling events which control a diverse number of cellular processes. The class I kinases contain 4 isoforms designated p110α, β, δ, γ, and are activated by cell surface receptors. Aberrant regulation of the PI3K signaling pathway is frequently observed in human malignancies including those of hematological origin. CAL-101 is an oral p110δ-specific inhibitor which has shown preclinical and clinical activity in non-Hodgkin lymphoma (NHL) and chronic lymphocytic leukemia (CLL). This compound is a potent p110δ inhibitor (EC50 of 65 nM in a whole-blood assay) with >200-fold selectivity over the other class I PI3K isoforms and no activity against Class II and III PI3K family members or other PI3K-related proteins, including mTOR and DNA-PK. Prior in vitro NHL studies revealed that CAL-101 induces caspase-dependent apoptosis, and inhibits CD40L-, BAFF-, CXCL12- and CXCL13-derived survival signals in cellular models (Lannutti BJ, et al., Blood 2010). To investigate the potential role of p110δ in Hodgkin lymphoma (HL) we screened a number of HL cell lines for p110δ isoform expression and constitutive PI3K pathway activation. We report high levels of p110δ protein and activated Akt in 5 of 5 HL cell lines evaluated (L428, L540, L591, L1236, KM-H2). Inhibition of p110δ with CAL-101 treatment of cell lines resulted in a reduction of Akt phosphorylation and a decrease in cellular viability. Because previous studies have established the importance of signals from the microenvironment for the survival and proliferation of malignant cells as well as for their resistance to standard therapies, we investigated the effect of p110δ inhibition by CAL-101 in HL cell line-stroma cocultures. In this setting, CAL-101 overcame tumor cell growth induced by coculture of HL cells with bone marrow stromal cells. In addition, CAL-101 induced dose-dependent apoptosis of HL cells at 48 hours. Furthermore, stromal cell coculture resulted in increased CCL5, CCL17, and CCL22 levels; productions of these chemokines by HL cells cultured in the presence of stromal cells were reduced by CAL-101 in a dose-dependent manner. These results indicate that specific inhibition of p110δ may disrupt signals between HL cells and their microenvironment, thereby providing the preclinical rationale for clinical evaluation of CAL-101 as a novel therapeutic approach in patients with Hodgkin lymphoma. Disclosures: Meadows: Calistoga Pharmaceuticals: Employment. Kashishian:Calistoga Pharmaceuticals: Employment. Johnson:Calistoga Pharmaceuticals: Employment. Lannutti:Calistoga Pharmaceutical Inc.: Employment.

scholarly journals Vaccination with Trypomastigote Surface Antigen 1-Encoding Plasmid DNA Confers Protection against Lethal Trypanosoma cruzi Infection

1998 ◽  
Vol 66 (11) ◽  
pp. 5073-5081 ◽  
Author(s):  
Benjamin Wizel ◽  
Nisha Garg ◽  
Rick L. Tarleton
Keyword(s):  
Trypanosoma Cruzi ◽  
Mhc Class I ◽  
Surface Antigen ◽  
Plasmid Dna ◽  
Protective Immunity ◽  
Tandem Repeats ◽  
Class I ◽  
Dependent Manner ◽  
Dna Encoding ◽  
Ctl Responses

ABSTRACT DNA vaccination was evaluated with the experimental murine model ofTrypanosoma cruzi infection as a means to induce antiparasite protective immunity, and the trypomastigote surface antigen 1 (TSA-1), a target of anti-T. cruzi antibody and major histocompatibility complex (MHC) class I-restricted CD8+ cytotoxic T-lymphocyte (CTL) responses, was used as the model antigen. Following the intramuscular immunization ofH-2b and H-2d mice with a plasmid DNA encoding an N-terminally truncated TSA-1 lacking or containing the C-terminal nonapeptide tandem repeats, the antibody level, CTL response, and protection against challenge with T. cruzi were assessed. In H-2b mice, antiparasite antibodies were induced only by immunization with the DNA construct encoding TSA-1 containing the C-terminal repeats. However, both DNA constructs were efficient in eliciting long-lasting CTL responses against the protectiveH-2Kb -restricted TSA-1515–522epitope. In H-2d mice, inoculation with either of the two TSA-1-expressing vectors effectively generated antiparasite antibodies and primed CTLs that lysed T. cruzi-infected cells in an antigen-specific, MHC class I-restricted, and CD8+-T-cell-dependent manner. When TSA-1 DNA-vaccinated animals were challenged with T. cruzi, 14 of 22 (64%)H-2b and 16 of 18 (89%)H-2d mice survived the infection. The ability to induce significant murine anti-T. cruzi protective immunity by immunization with plasmid DNA expressing TSA-1 provides the basis for the application of this technology in the design of optimal DNA multicomponent anti-T. cruzi vaccines which may ultimately be used for the prevention or treatment of Chagas’ disease.

scholarly journals The Association between Low Muscle Mass and Hepatic Steatosis in Asymptomatic Population in Korea

Life ◽  
2021 ◽  
Vol 11 (8) ◽  
pp. 848
Author(s):  
Goh-Eun Chung ◽  
Hyo-Eun Park ◽  
Min-Joo Kim ◽  
Min-Sun Kwak ◽  
Jong-In Yang ◽  
...  
Keyword(s):  
Hepatic Steatosis ◽  
Muscle Mass ◽  
Liver Stiffness ◽  
Bioelectrical Impedance ◽  
Class Ii ◽  
Class I ◽  
Dependent Manner ◽  
Nonalcoholic Fatty Liver ◽  
Increased Risk ◽  
Dose Dependent

Background: An association between low muscle mass and nonalcoholic fatty liver disease (NAFLD) has been suggested. We investigated this relationship using controlled attenuation parameter (CAP). Methods: A retrospective cohort of subjects had liver FibroScan® (Echosens, Paris, France) and bioelectrical impedance analyses during health screening exams. Low muscle mass was defined based on appendicular skeletal muscle mass/body weight ratios of one (class I) or two (class II) standard deviations below the sex-specific mean for healthy young adults. Results: Among 960 subjects (58.1 years; 67.4% male), 344 (45.8%, class I) and 110 (11.5%, class II) had low muscle mass. After adjusting for traditional metabolic risk factors, hepatic steatosis, defined as a CAP ≥ 248 dB/m, was associated with low muscle mass (class I, odds ratio (OR): 1.96, 95% confidence interval (CI): 1.38–2.78; class II, OR: 3.33, 95% CI: 1.77–6.26). A dose-dependent association between the grade of steatosis and low muscle mass was also found (class I, OR: 1.88, for CAP ≥ 248, <302; OR: 2.19, in CAP ≥ 302; class II, OR: 2.33, for CAP ≥ 248, <302; OR: 6.17, in CAP ≥ 302). High liver stiffness was also significantly associated with an increased risk of low muscle mass (class I, OR: 1.97, 95% CI: 1.31–2.95; class II, OR: 2.96, 95% CI: 1.51–5.78). Conclusion: Hepatic steatosis is independently associated with low muscle mass in a dose-dependent manner. The association between hepatic steatosis and low muscle mass suggests that particular attention should be given to subjects with NAFLD for an adequate assessment of muscle mass.

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