Michael J. Brunda

IL-12 Administration Leads to a Transient Depletion of T Cells, B Cells, and APCs and Concomitant Abrogation of the HLA-A2.1-Restricted CTL Response in Transgenic Mice

The injection of a mixture of bona fide T cell epitopes can lead to the occurrence of immunodominance, meaning that the immune response is focused on the recognition of a single epitope or a small portion of the epitopes injected. We have previously demonstrated that the administration of rIL-12 can counteract immunodominance in BALB/c mice. In this study, we show that the administration of rIL-12 to HLA-A2.1 transgenic mice (A2kb mice) abrogates specifically the immune response against HLA-A2.1-restricted HIV epitopes in the spleen. This lack of immune response is most probably due to a transient depletion of B cells, T cells, macrophages, and dendritic cells in this organ. Therefore, our study explains the mechanism of immunosuppression by rIL-12 in vivo.

In vitro immunisation against human tumour cells with bacterial extracts.

LYMPHOCYTES from normal persons can become immunised to a variety of tumour cells by exposure to tumour cells in vitro1–5. Since close antigenic relationships between microorganisms and some tumour cells have been demonstrated6–9, studies were carried out to see if bacterial antigens could similarly immunise lymphocytes from normal persons in vitro against some tumour cells. The experiments reported here indicate that not only is this possible, but that the cytotoxicity of bacterial immunised lymphocytes is sometimes greater than when lymphocytes are sensitised by intact tumour cells.

SUPPRESSION OF MURINE NATURAL KILLER CELL ACTIVITY BY NORMAL PERITONEAL MACROPHAGES

Publisher Summary This chapter discusses suppression of murine natural killer (NK) cell activity by normal peritoneal macrophages. It has been suggested that natural killer (NK) cells have a wide range of biological activities, including immunosurveillance against neoplastic cells, protection against viral infections, and production of lymphokines such as interferon (IFN). In an experiment discussed in the chapter, the possibility that normal macrophages regulate NK activity was examined, as NK activity is present in normal animals. To examine the ability of various Mφ populations to suppress NK activity, Mφ from the peritoneal cavity and spleen of both normal and Corynebacterium Parvum (C. parvum)-injected mice were compared. The results demonstrate that normal peritoneal Mφ have the ability to suppress either spontaneously maintained or IFN-augmented NK activity in vitro. Although the potential in vivo regulatory role of Mφ on NK activity has not been established, it is tempting to speculate that peritoneal Mφ may control the level of NK cell-mediated cytotoxicity. Normal peritoneal Mφ has the ability to suppress NK activity in vitro and this ability is altered by injection of C. parvum.

Influence of adoptively transferred thioglycollate-elicited peritoneal macrophages on metastasis formation in mice with depressed or stimulated NK activity

The effect of thioglycollate-elicited macrophages (TG-Mφ) on natural killer (NK)-cell activity and metastases formation in mice was investigated. Intravenously (i.v.) inoculated TG-Mφ inhibited spleen NK activity of normal mice and abrogated polyinosinic: polycytidylic (poly I∶C) induced augmentation of NK cell function. TG-Mφ also inhibited the clearance of i.v.-injected radiolabeled B16 melanoma cells from the lungs of normal or poly I∶C stimulated mice. Formation of experimental B16 melanoma metastases was dramatically increased in mice pretreated with TG-Mφ. Administration of TG-Mφ increased metatasis formation to a greater extent than anti-asialo GM1 serum, while anti-asGM1 serum was more efficient than TG-Mφ in depressing spleen NK cell activity. When mice with low NK reactivity (beige mice or mice treated with anti-asialo GM1 serum) were inoculated with TG-Mφ, there was a substantial additive augmenting effect on metastasis formation in the lungs. Treatment with poly I∶C elevated NK-cell activity and had profound antimetastatic effects in normal but not in TG-Mφ pretreated mice. The metastasis augmenting effect of TG-Mφ was fully expressed in poly I∶C-treated mice as well as in athymic nude mice. Inoculation of proteose peptone-elicited macrophages (PMφ), unlike TG-Mφ, did not depress NK activity or augment metastasis formation in normal or poly I∶C-treated mice. However, since the inhibition of NK activity in TG-Mφ-treated mice was relatively weak, and a substantial additional increase in metastases was observed in NK-depressed mice after transfusion of TG-Mφ, it seems unlikely that the TG-Mφ-induced inhibition of NK reactivity is entirely responsible for the augmented formation of metastases. Further studies revealed that i.v. inoculation of TG-Mφ, but not PMφ, induced intravascular inflammatory reactions, and damage to endothelial cells and basement membrane of the lung vasculature. These reactions may contribute to increased tumor cell extravasation and metastasis formation in mice pretreated with TG-Mφ.