FURTHER STUDIES OF ANTIGENIC COMPETITION : III. A MODEL TO ACCOUNT FOR THE PHENOMENON BASED ON A DEFICIENCY OF CELL-TO-CELL INTERACTION IN IMMUNE LYMPHOID CELL POPULATIONS

A striking correlation between the capacity of an antigen to nonspecifically suppress humoral immune responses of subsequently administered antigens which are non-cross-reacting, i.e. to manifest antigenic competition and produce enlargement of spleen size through cell proliferation, was found. Increase in spleen size was always accompanied by a drop in the normal proportion of thymus-derived cells to non-thymus-derived cells. Various means of altering the immune response to the initial antigen, and hence, the capacity of that antigen to suppress in a model of antigenic competition were performed and correlated with changes in spleen size and in the proportion of θ-positive cells in the spleen. In all instances, when the experimental condition reduced or abolished antigenic competition, the increase in spleen size and reduction in the proportion of θ-positive cells in the spleen was reduced or abolished. Furthermore, under conditions in which the suppressive capacity of the initial antigen was unaltered, the increase in spleen size and reduction in θ-proportion occurred normally. Finally, the better the suppression in a model of antigenic competition, the greater the increase in spleen size and reduction in the proportion of θ-positive cells. On the basis of these observations, it appears that there is a relationship between spleen enlargement through clonally restricted cell proliferation and the expression of antigenic competition; one cannot have the latter without the former. It is postulated that the immunological lesion associated with antigenic competition resides at the level of interference with cell interaction between thymus-derived antigen-reactive cells and marrow-derived antibody-forming cells. This occurs as a result of a relative "diluting out" of cells of both populations carrying antigenic specificity differing from the one(s) which induced the dilution effect in the first place. The net effect of this is to decrease the chance of a "hit" or interaction between a marrow-derived and thymus-derived cell of the same specificities. This mechanism, which is compatible with theories of clonal selection, and which in fact is dependent upon them, supports the view that the term "antigenic competition" is a misnomer; there is no competition by the antigens for anything. The term "antigen-induced suppression" is suggested as a more suitable alternative

CLASSIFICATION OF THYMUS-DERIVED AND MARROW-DERIVED LYMPHOCYTES BY DEMONSTRATION OF THEIR ANTIGEN-BINDING CHARACTERISTICS

Antigen-binding cells of T and B origin can readily be determined by quantitating the number of sheep erythrocytes per rosette after glutaraldehyde fixation. The T1 and T2 populations have low antigen-binding properties and are very unstable without fixation. The B1 and B2 populations are stable and correlate with precursor and secretory cells. Fixation of rosettes permits a sensitive test for studying differentiation of T and B cells

Impact of Metronomic UFT/Cyclophosphamide Chemotherapy and Antiangiogenic Drug Assessed in a New Preclinical Model of Locally Advanced Orthotopic Hepatocellular Carcinoma

AbstractHepatocellular carcinoma (HCC) is an intrinsically chemotherapy refractory malignancy. Development of effective therapeutic regimens would be facilitated by improved preclinical HCC models. Currently, most models consist of subcutaneous human tumor transplants in immunodeficient mice; however, these do not reproduce the extensive liver disease associated with HCC or metastasize. To address this deficiency, we developed an orthotopic model. Human HCC cells were transfected with the gene encoding secretable β-subunit human choriogonadotropin (β-hCG), which was used as a surrogate marker of tumor burden. The HCC cells were implanted into the left liver lobe of severe combined immunodeficient (SCID) mice, after which the efficacy of different therapies was evaluated on established, but liver-confined human Hep3B cell line HCC. Treatments included sorafenib or metronomic chemotherapy using cyclophosphamide (CTX), UFT, an oral 5-fluorouracil prodrug, or doxorubicin either alone or in various combinations, with or without an antiangiogenic agent, DC101, an anti-vascular endothelial growth factor receptor-2 antibody. Sorafenib inhibited tumor growth in a dose-dependent manner but caused severe weight loss in SCID mice, thus necessitating use of DC101 in subsequent experiments. Although less toxicity was observed using either single or doublet metronomic chemotherapy without any added antiangiogenic agent, none, provided survival benefit. In contrast, significantly improved overall survival was observed using various combinations of metronomic chemotherapy regimens such as UFT + CTX with DC101. In conclusion, using this model of liver-confined but advanced HCC suggests that the efficacy of a targeted antiangiogenic drug or metronomic chemotherapy can be mutually enhanced by concurrent combination treatment

Id1 Restrains p21 Expression to Control Endothelial Progenitor Cell Formation

Loss of Id1 in the bone marrow (BM) severely impairs tumor angiogenesis resulting in significant inhibition of tumor growth. This phenotype has been associated with the absence of circulating endothelial progenitor cells (EPCs) in the peripheral blood of Id1 mutant mice. However, the manner in which Id1 loss in the BM controls EPC generation or mobilization is largely unknown. Using genetically modified mouse models we demonstrate here that the generation of EPCs in the BM depends on the ability of Id1 to restrain the expression of its target gene p21. Through a series of cellular and functional studies we show that the increased myeloid commitment of BM stem cells and the absence of EPCs in Id1 knockout mice are associated with elevated p21 expression. Genetic ablation of p21 rescues the EPC population in the Id1 null animals, re-establishing functional BM-derived angiogenesis and restoring normal tumor growth. These results demonstrate that the restraint of p21 expression by Id1 is one key element of its activity in facilitating the generation of EPCs in the BM and highlight the critical role these cells play in tumor angiogenesis

Accelerated Metastasis after Short-Term Treatment with a Potent Inhibitor of Tumor Angiogenesis

SummaryHerein we report that the VEGFR/PDGFR kinase inhibitor sunitinib/SU11248 can accelerate metastatic tumor growth and decrease overall survival in mice receiving short-term therapy in various metastasis assays, including after intravenous injection of tumor cells or after removal of primary orthotopically grown tumors. Acceleration of metastasis was also observed in mice receiving sunitinib prior to intravenous implantation of tumor cells, suggesting possible “metastatic conditioning” in multiple organs. Similar findings with additional VEGF receptor tyrosine kinase inhibitors implicate a class-specific effect for such agents. Importantly, these observations of metastatic acceleration were in contrast to the demonstrable antitumor benefits obtained when the same human breast cancer cells, as well as mouse or human melanoma cells, were grown orthotopically as primary tumors and subjected to identical sunitinib treatments

Antiangiogenic and anticolorectal cancer effects of metronomic irinotecan chemotherapy alone and in combination with semaxinib

Metronomic chemotherapy refers to the administration of chemotherapy at low, nontoxic doses on a frequent schedule with no prolonged breaks. The aim of the study is to rationally develop a CPT-11 metronomic regimen in preclinical settings of colon cancer. In vitro cell proliferation, apoptosis and thrombospondin-1/vascular endothelial growth factor (TSP-1/VEGF) expression analyses were performed on endothelial (HUVEC, HMVEC-d) and colorectal cancer (HT-29, SW620) cells exposed for 144 h to metronomic concentrations of SN-38, the active metabolite of CPT-11. HT-29 human colorectal cancer xenograft model was used, and tumour growth, microvessel density and VEGF/TSP-1 quantification was performed in tumours. In vitro and in vivo combination studies with the tyrosine inhibitor semaxinib were also performed. SN-38 preferentially inhibited endothelial cell proliferation alone and interacted synergistically with semaxinib; it induced apoptosis and increased the expression and secretion of TSP-1. Metronomic CPT-11 alone and combined with semaxinib significantly inhibits tumour growth in the absence of toxicity, which was accompanied by decreases in microvessel density and increases in TSP-1 gene expression in tumour tissues. In vitro results show the antiangiogenic properties of low-concentration SN-38, suggesting a key role of TSP-1 in this effect. In vivo, the CPT-11 metronomic schedule is effective against tumour and microvessel growth without toxic effect on mice

Effect of treatment of gestational diabetes mellitus on pregnancy outcomes

Copyright © 2005 Massachusetts Medical Society.Background: We conducted a randomized clinical trial to determine whether treatment of women with gestational diabetes mellitus reduced the risk of perinatal complications. Methods: We randomly assigned women between 24 and 34 weeks’ gestation who had gestational diabetes to receive dietary advice, blood glucose monitoring, and insulin therapy as needed (the intervention group) or routine care. Primary outcomes included serious perinatal complications (defined as death, shoulder dystocia, bone fracture, and nerve palsy), admission to the neonatal nursery, jaundice requiring phototherapy, induction of labor, cesarean birth, and maternal anxiety, depression, and health status. Results: The rate of serious perinatal complications was significantly lower among the infants of the 490 women in the intervention group than among the infants of the 510 women in the routine-care group (1 percent vs. 4 percent; relative risk adjusted for maternal age, race or ethnic group, and parity, 0.33; 95 percent confidence interval, 0.14 to 0.75; P=0.01). However, more infants of women in the intervention group were admitted to the neonatal nursery (71 percent vs. 61 percent; adjusted relative risk, 1.13; 95 percent confidence interval, 1.03 to 1.23; P=0.01). Women in the intervention group had a higher rate of induction of labor than the women in the routine-care group (39 percent vs. 29 percent; adjusted relative risk, 1.36; 95 percent confidence interval, 1.15 to 1.62; P<0.001), although the rates of cesarean delivery were similar (31 percent and 32 percent, respectively; adjusted relative risk, 0.97; 95 percent confidence interval, 0.81 to 1.16; P=0.73). At three months post partum, data on the women’s mood and quality of life, available for 573 women, revealed lower rates of depression and higher scores, consistent with improved health status, in the intervention group. Conclusions: Treatment of gestational diabetes reduces serious perinatal morbidity and may also improve the woman’s health-related quality of life.Caroline A. Crowther, Janet E. Hiller, John R. Moss, Andrew J. McPhee, William S. Jeffries and Jeffrey S. Robinso

Metastases: the glycan connection

An association between protein glycosylation and tumorigenesis has been recognized for over 10 years. Associations linking the importance of glycosylation events to tumor biology, especially the progression to metastatic disease, have been noted over many years, Recently, a mouse model in which β1,6-N-acetylglucosaminyltransferase V (a rate-limiting enzyme in the N-glycan pathway) has been knocked out, was used to demonstrate the importance of glycosylation in tumor progression. By crossing mice lacking this enzyme with a transgenic mouse model of metastatic breast cancer, metastatic progression of the disease was dramatically reduced. These experiments provide in vivo evidence for the role of N-linked glycosylation in metastatic breast cancer and have significant implications for the development of new treatment strategies