Tumor necrosis factor-alpha antitumor and immunomodulatory effects

In the first part of this thesis we examined the possibilities of using the cytokine tumor necrosis factor-alpha (TNFcx) for the latter aproach. Although multiple studies have been performed regarding the antitumor action of TNFcx, it is still not clear whether TNFcx has sufficient potential to be used as immunotherapeutic agent in vivo. In this part of this thesis an answer to this important question is given Whereas cancer immunotherapy might benefit from immunostimulation with cytokines such as TNFa, immunosuppression through the inhibition of the release or activities of cytokines might be to the advantage of recipients of organ grafts. Rejection of a donor organ by a recipient is known to be an immunological process in which various cells of the immune system work together. Immune cells recognize the graft, either directly or indirectly, as being "non-self', and according to their task, they generate an immune response to rid the recipient of the "non-self' graft. Cytokines play a crucial role in this proces. Inhibition of cytokine production via cyclosporin-A delays or prevents graft rejection. The role of the cytokine interleukin-2 has been well established in this proces. Less attention has been paid to the involvement of TNFa. Maury and Teppo (1987) demonstrated that TNFa is present in the serum of patients with rejecting kidney grafts. This, however, did not prove that TNFa is actually involved in the process of graft rejection. Therefore experiments were performed in rats to assess the significance of TNFa

Utilization of the Aerial Photogrammetric Information on the Agrigultural Modernizaton (I) : On the Radio-controlled Nearby Aerial Photogrammetric Equipmentst

Aerial photogrammetry is the information science of measurement by means of space photographs, ordinary aerial photographs and nearby aerial photographs. It has been developed to the greatest extent in the field of topographic mapping from aerial photography, but there are many other applications of this science. Research work in aerial photogrammetry at the Kagawa University and Kobe University, has been focussed on the trial production and utilization of radio-controlled nearby aerial photogrammetric equipments since 1969. This paper deals with construction and principle of operation on the radio-controlled photogrammetric equipments (No. K-1 : model airplane, No. K-2 : model airship)

Injection of recombinant tumor necrosis factor directly into liver metastases: an experimental and clinical approach

__Abstract__ Systemic treatment with tumor necrosis factor (TNF) is associated with side-effects, limiting its clinical use in the treatment of malignancies. To investigate the feasibility of other routes of administration experimental and clinical studies were started to establish the toxicity and antitumor activity of TNF after intratumoral (i.t.) injection. In a rat model for colon adenocarcinoma, tumor fragments, implanted subcutaneously or under the hepatic capsule, were treated with TNF injected i.v. or i.t. A dosage of 40 μg/kg was lethal when given i.v., but not i.t. Injection of TNF (40 μg/kg) directly into the tumor resulted in inhibition of tumor growth in the subcutaneous as well as subhepatic tumor model. A phase I study was started in patient

The antitumour activity of the interferon inducer bropirimine is partially mediated by endogenous tumour necrosis factor α

Pyrimidinones, like 2-amino-5-bromo-6-phenyl-4-pyrimidinone (bropirimine), are potent immunomodulators. Natural killer cell activity and macrophage cytotoxicity are increased after bropirimine treatment, an effect exerted through induction of cytokines. Up to now, the interferons have been supposed to be the main mediators but we have found that tumour necrosis factor α (TNFα) can also be an important mediator of the bropirimine antitumour effects. Increased serum levels of TNFα were seen in rats after intraperitoneal administration of 200 mg/kg bropirimine on 2 consecutive days. We also found that the tumour-growth-inhibiting effect of the drug on a colon carcinoma in rats could be reduced about 40% by giving the rats rabbit anti-TNFα serum just prior to drug treatment. These results indicate that bropirimine can induce the release of TNFα in vivo and that this endogenous TNFα may be important as far as the antitumour effect of the drug is concerned.</p

Intrathymic injection of alloantigen may lead to hyperacute rejection and prolonged graft survival of heart allografts in the rat

The recent reports describing the beneficial effect of intrathymic (IT) inoculation of donor antigen on subsequent allograft survival prompted us to study this phenomenon in the high responder WAG to BN rat strain combination as well as in the low-responder BN to WAG combination. Previously in the WAG to BN model, we found that a donor-specific blood transfusion (DST) given 1 week before the heterotopic heart transplantation led to accelerated rejection in 5 days, whereas in the reverse model, a DST consistently led to marked prolongation of graft survival. These opposing phenomena led us to determine whether the effects of DST in the two rat strain combinations mentioned above would also occur after IT injection of donor type cells.[...]In conclusion we demonstrated that, similarly as following DST, the ability to induce prolonged acceptance of heart allografts by IT injection of donor-type cells is highly dependent on the donor-host combination used. The remarkable finding that IT injection can also lead to sensitization and even hyperacute rejection indicates that caution should be exercised with this ambiguous procedure

Intrathymic injection of alloantigen may lead to hyperacute rejection and prolonged graft survival of heart allografts in the rat

The recent reports describing the beneficial effect of intrathymic (IT) inoculation of donor antigen on subsequent allograft survival prompted us to study this phenomenon in the high responder WAG to BN rat strain combination as well as in the low-responder BN to WAG combination. Previously in the WAG to BN model, we found that a donor-specific blood transfusion (DST) given 1 week before the heterotopic heart transplantation led to accelerated rejection in 5 days, whereas in the reverse model, a DST consistently led to marked prolongation of graft survival. These opposing phenomena led us to determine whether the effects of DST in the two rat strain combinations mentioned above would also occur after IT injection of donor type cells.[...]In conclusion we demonstrated that, similarly as following DST, the ability to induce prolonged acceptance of heart allografts by IT injection of donor-type cells is highly dependent on the donor-host combination used. The remarkable finding that IT injection can also lead to sensitization and even hyperacute rejection indicates that caution should be exercised with this ambiguous procedure

Ketanserin reduces graft arteriosclerosis after allogeneic aorta transplantation in rats

The serotonin-2 receptor antagonist ketanserin has been suggested to diminish arteriosclerotic development by its effect on platelet function and on vascular smooth muscle cells. We investigated the ability of ketanserin in reducing immune-mediated arteriosclerosis using the BN-WAG and WAG-BN rat aortic transplantation models, Ketanserin (10 mg/kg/day) administered in drinking water significantly reduced posttransplant arteriosclerotic thickening of the intima in the BN-WAG rat model to 102 ± 23 μm as compared with 171 ± 60 μm in untreated BN-WAG allografts 8 weeks posttransplantation (p &lt; 0.05). In the opposite WAG-BN combination, at 4 weeks posttransplantation, no significant reduction in intimal thickening was attained (112 ± 42 vs. 152 ± 49 μm). Platelet aggregation to increasing amounts of collagen did not show a correlation between the effect of ketanserin on platelet function and reduction in intimal thickening. Ketanserin had no effect on systolic blood pressure or mononuclear cell infiltration. We conclude that ketanserin reduces graft arteriosclerosis by a mechanism other than by inhibition of platelet function, decrease in blood pressure, or immunosuppression. Because of this antiarteriosclerotic effect, ketanserin therapy might be beneficial to the long-term survival of vascular allografts.</p

Ketanserin reduces graft arteriosclerosis after allogeneic aorta transplantation in rats

The serotonin-2 receptor antagonist ketanserin has been suggested to diminish arteriosclerotic development by its effect on platelet function and on vascular smooth muscle cells. We investigated the ability of ketanserin in reducing immune-mediated arteriosclerosis using the BN-WAG and WAG-BN rat aortic transplantation models, Ketanserin (10 mg/kg/day) administered in drinking water significantly reduced posttransplant arteriosclerotic thickening of the intima in the BN-WAG rat model to 102 ± 23 μm as compared with 171 ± 60 μm in untreated BN-WAG allografts 8 weeks posttransplantation (p &lt; 0.05). In the opposite WAG-BN combination, at 4 weeks posttransplantation, no significant reduction in intimal thickening was attained (112 ± 42 vs. 152 ± 49 μm). Platelet aggregation to increasing amounts of collagen did not show a correlation between the effect of ketanserin on platelet function and reduction in intimal thickening. Ketanserin had no effect on systolic blood pressure or mononuclear cell infiltration. We conclude that ketanserin reduces graft arteriosclerosis by a mechanism other than by inhibition of platelet function, decrease in blood pressure, or immunosuppression. Because of this antiarteriosclerotic effect, ketanserin therapy might be beneficial to the long-term survival of vascular allografts.</p