Induction of Peptide-specific CTL Activity and Inhibition of Tumor Growth Following Immunization with Nanoparticles Coated with Tumor Peptide-MHC-I Complexes

Tumor peptides associated with MHC class I molecules or their synthetic variants have attracted great attention for their potential use as vaccines to induce tumor-specific CTLs. However, the outcome of clinical trials of peptide-based tumor vaccines has been disappointing. There are various reasons for this lack of success, such as difficulties in delivering the peptides specifically to professional Ag-presenting cells, short peptide halflife in vivo, and limited peptide immunogenicity. We report here a novel peptide vaccination strategy that efficiently induces peptide-specific CTLs. Nanoparticles (NPs) were fabricated from a biodegradable polymer, poly(D,L-lactic-co-glycolic acid), attached to H-2Kb molecules, and then the natural peptide epitopes associated with the H-2K b molecules were exchanged with a model tumor peptide, SIINFEKL (OVA 257-268 ). These NPs were efficiently phagocytosed by immature dendritic cells (DCs), inducing DC maturation and activation. In addition, the DCs that phagocytosed SIINFEKL-pulsed NPs potently activated SIINFEKL-H-2K b complex-specific CD8 + T cells via cross-presentation of SIINFEKL. In vivo studies showed that intravenous administration of SIINFEKL-pulsed NPs effectively generated SIINFEKLspecific CD8 + T cells in both normal and tumor-bearing mice. Furthermore, intravenous administration of SIINFEKL-pulsed NPs into EG7.OVA tumor-bearing mice almost completely inhibited the tumor growth. These results demonstrate that vaccination with polymeric NPs coated with tumor peptide-MHC-I complexes is a novel strategy for efficient induction of tumor-specific CTLs.

Polymeric Nanoparticles Containing Both Antigen and Vitamin D₃ Induce Antigen-Specific Immune Suppression

The active form of vitamin D3, 1,25-dihydroxyvitamin D₃ (aVD₃), is known to exert beneficial effects in the treatment of autoimmune diseases because of its immunosuppressive effects. However, clinical application of aVD₃ remains limited because of the potential side effects, particularly hypercalcemia. Encapsulation of aVD₃ within biodegradable nanoparticles (NPs) would enhance the delivery of aVD₃ to antigen presenting cells, while preventing the potential systemic side effects of aVD₃. In the present study, polymeric NPs containing ovalbumin (OVA) and aVD₃ (NP[OVA+aVD₃]) were prepared via the water-in-oil-in-water double emulsion solvent evaporation method, after which their immunomodulatory effects were examined. Bone marrow-derived immature dendritic cells (DCs) treated with NP(OVA+aVD₃) did not mature into immunogenic DCs but were converted into tolerogenic DCs, which express low levels of co-stimulatory molecules and MHC class II molecules, produce lower levels of pro-inflammatory cytokines while increasing the production of IL-10 and TGF-β, and induce the generation of Tregs. Intravenous injection with NP(OVA+aVD₃) markedly suppressed the generation of OVA-specific CTLs in mice. Furthermore, OVA-specific immune tolerance was induced in mice orally administered with NP(OVA+aVD₃). These results show that biodegradable NPs encapsulating both antigen and aVD₃ can effectively induce antigen-specific immune suppression.

Thapsigargin Increases IL-2 Production in T Cells at Nanomolar Concentrations

Thapsigargin (TGN) is a potent and selective inhibitor of sarco-endoplasmic Ca²⁺-ATPase, leading to rapid elevation of cytoplasmic Ca2+ concentration. Previous reports have shown that TGN increases the production of various cytokines from macrophages and dendritic cells. Here, we examine the effects of TGN on murine T cells. Nanomolar concentrations of TGN are a significant inducer of IL-2 production with full activity at 50 nM. Micromolar concentrations of TGN, however, are inhibitory to IL-2 production and T cell proliferation. The IL-2 production-inducing activity of TGN is much more prominent when T cells are primed with concanavalin A or anti-CD3 mAb, and is due to the increase of cytoplasmic Ca²⁺ concentration. TGN at 50 nM does not affect interferon-gamma or IL-4 production from T cells. Thus, the present study shows that low nanomolar concentrations of TGN could be useful in potentiating IL-2 production from antigen-primed T cells.

Clinical study for Patients with Cervical Cancer who had undergone Radical Hysterectomy / 대한산부인과학회잡지

OBJECTIVE: The purpose of this study was to analyze the clinical study for patients with cervical cancer who had undergone radical hysterectomy. METHOD: The subjects of this study were one hundred and sixty two patients with cervical cancer who had undergone radical hysterectomy at Eulji Medical College Hospital, Taejon, Korea, from January 1983 to December 1992. We reviewed the medical record retrospectively and analyzed the data. RESULT: The distribution of patients by age was found in the order of 50 decade and 60 decade, 40 decade. Those by the clinical stages were as follows: Stage Ia, 12 cases(7.4%); Stage Ib, 84 cases(51.9%); Stage IIa, 39 cases(24.1%); Stage IIb 27 cases(16.7%). The results of histopathologic type were distributed as follows: squamous cell carcinoma was 91.9%, adenocarcinoma was 4.9% and adenosquamous cell carcinoma was 3.1%. The histologic subtypes of squamous cell carcinoma(149 cases) were as follows: Large cell non-keratinizing type was 75.9%, large cell keratinizing type was 14.8% and small cell type was 1.2%. The frequancy of lymph node metastasis was 22.9% in stage I and 31.8% in stage II. The overall incidence of lymph node metastasis was 26.4%. The frequency of external radiation therapy done after radical hysterectomy was 63.5% in stage I and 75.8% in stage II. The 5-year survival rate was as follows: The Ia was 100%; Stage Ib, 95.2%(4cases); Stage IIa, 87.2%(5cases); Stage IIb, 77.8%(6cases). The incidence of recurrence was 7.4% and recurrent sites were vaginal stump , rectum and pelvic wall. CONCLUSION: The highest incidence of cervix cancer in age distribution was 50 decade(30.9%) and 60 decade(30.9%). The most common clinical stage was Ib(51.9%) and most frequent pathologic type was squamous cell carcinoma(91.9%). The overall incidence of lymph node metastasis was 26.4% and The most common site of recurrence was vaginal stump. The 5-year survival rate was 100% in the stage Ia, 95.2% in the stage Ib, 87.2% in the stage IIa, 77.8% in the stage IIb.

The Association between Unexplained Second-Trimester Human Chorionic Gonadotropin Elevations and Pregnancy Outcome / 대한산부인과학회잡지

We conducted this cohort analytic study to determine whether women with unexplained elevations of maternal serum hCG at 15-18 weeks' gestation are at increased risk for pregnancy complications and adverse perinatal outcomes. The inclusion criteria were a singleton gestation, a confirmed gestational age, and an hCG level greater than 2.0 multiples of the median (MoM). The exclusion criteria were fetal anomalies, an abnormal karyotype, molar pregnancy, and an MSAFP level greater than 2.5 multiples of the median (MoM). A group of randomly selected women with hCG levels under 2.0 MoM served as controls. Patients with elevated levels of hCG had a significantly higher risk for PIH (17.9% versus 4.5%; P <.05) and preterm delivery (17.9% versus 3.5%; P<, 05) than control. But no significant differences were observed in the incidence of intrauterine growth restriction and low birth weight and in the newborn weight. We suggested that pregnancies with unexplained elevated hCG levels should be regarded as high-risk pregnancies. And these patients require careful monitoring with adequate obstetric management.