IMMUNE AND NATURAL ANTIBODIES TO SYNGENEIC MURINE PLASMA CELL TUMORS

Cytotoxic antibody to a plasma cell tumor antigen was produced in syngeneic BALB mice by immunization with viable or inactivated plasma cell tumors. Antibody with the same specificity was found in the sera of normal BALB and other strains of mice. This natural antibody reacted with an antigen with characteristics indistinguishable from the previously described alloantigen, PC.1, and with viral envelope antigen, χVEA. The incidence of cytotoxic reactivity and the antibody titers reached a peak in normal BALB mice at 3–4 months of age, and were lower in 9–12-month old mice. The sera of germfree mice had lower reactivity; but when the mice were transferred to conventional conditions, their sera soon became as active as those of conventional mice. A virus common to all plasma cell tumors, which is present in latent form in some normal tissues of BALB and other PC.1 positive strains, is suggested as the cause for the PC.1 antigen and for the appearance of natural antibody to it. The considerable evidence for the close association of a virus with plasma cell tumors is presented

Shared determinants between virus-infected and trinitrophenyl-conjugated H-2-identical target cells detected in cell-mediated lympholysis

Infection of H-2-identical mice with either lymphocytic choriomeningitis (LCM) virus, vaccinia virus, or paramyxo (Sendai) virus resulted in the generation of specifically sensitized cytotoxic T lymphocytes (CTL). CTL generated in vitro against 2,4,6-trinitrophenyl (TNP)-conjugated syngeneic stimulator cells were specifically cytotoxic for TNP-conjugated H-2K(D) region identical targets. Both LCM and vaccinia-induced CTL, however, were found to be strongly cytotoxic towards TNP-conjugated, H-2K(D) region-identical target cells. In contrast, Sendai virus-induced CTL did not lyse TNP-conjugated, syngeneic target cells. Inhibition experiments using cold targets suggested that shared antigenic determinants can be detected on either LCM virus-infected and TNP-conjugated targets, which are not present on the cell surface 6f normal target cells

Enhanced MHC I antigen expression on tumour target cells is inversely correlated to lysis by allogenic but not by xenogenic NK cells

Relationship between the levels of MHC class 1 antigen expressed on tumour cells and their susceptibility to allogenic and xenogenic NK cells was investigated. Mouse and human natural killer-resistance inducing factor (NK-RIF) preparations were used for augmenting/inducing MHC 1 antigen expression on murine YAC and human K562 tumour cells, respectively YAC cells with augmented MHC I antigen expression became relatively resistant to lysis by murine NK cells but not to rat NK cells. Similarly, induction of MHC I antigens on K562 cells reduced their susceptibility to human NK cells but not to monkey NK cells. These results indicate that the inverse correlation of MHC I antigen expression and NK susceptibility does not hold true for xenogenic pairs of NK effector and target cells

EVIDENCE OF SUPPRESSOR CELL ACTIVITY IN SPLEENS OF MICE BEARING PRIMARY TUMORS INDUCED BY MOLONEY SARCOMA VIRUS

Spleens from Moloney sarcoma virus (MSV) tumor-bearing C57BL/6N mice contained four times the normal number of mononuclear cells and displayed a markedly elevated "spontaneous" (mitogen-independent) DNA synthesis on a per cell basis. The number of macrophages were increased three-fold while there was a slight reduction in the percentage of T lymphocytes. The phytohemagglutinin (PHA) response on a per cell basis of spleens from tumor-bearing mice was decreased about 90% when compared with normal control mice. The primary in vitro immune response to sheep red blood cells was also suppressed to levels of less than 10% of normals. The PHA response could be restored by purification of MSV spleen cells by rayon adherence columns and by removal of phagocytic cells by an iron/magnet technique. The activity of suppressor cells in MSV spleens was demonstrated in mixtures with syngeneic normal spleen cells where a marked impairment of the PHA response was observed. Spleen cells from tumor-free nude mice and normal spleen cells treated by anti-θ serum plus guinea pig complement (C'), both totally unreactive to PHA, had no such effect. The inhibitor cell in MSV spleens was shown to be insensitive to inactivation by anti-θ plus C', but could be removed by the adherence columns and the iron/magnet technique. These data suggest that this suppressor cell is a cell of the monocyte/macrophage series. Suggestive evidence was also presented that the suppressor cells belong to a proliferating population in MSV spleens. Similar suppressor cells have been previously demonstrated in spleens of mice during a variety of immune responses. Our data show, that a tumor, although stimulating the immune system, nevertheless may be suppressive on certain immune functions through the activation of suppressor cells

Changes of liver-resident NK cells during liver regeneration in rats

To determine the role of NK cells in regulation of tissue growth, the phenotype and function of liver-resident NK cells were studied after 70% partial hepatectomy in rats. The process of liver regeneration was generally completed by clay 14. In contrast, the number of liver resident NK cells (NKR-P1(bright)) was restored as early as day 3 after partial hepatectomy. However, spontaneous functions of liver resident NK cells, including killing of YAC-1 and P815 targets, Ab-dependent cellular cytotoxicity, and redirected killing via NKR-P1, were continuously suppressed throughout the entire period of liver regeneration (from 3 h to 14 days). Augmentation of NK cytotoxicity against P815 targets and induction of NK cell adherence to plastic following 24 h of IL-2 stimulation showed a similar pattern of suppression. However, IL-2-induced augmentation of YAC-1 killing, proliferation and generation of adherent NK cells, and LAK activity in 5- to 7-day cultures were found to be suppressed only during the first 24 h and increased between days 2 and 7 after hepatectomy. Sorted NK cells (≥95% NKR-P1(bright)) from liver-resident mononuclear leukocytes 24 h after partial hepatectomy showed the same pattern of suppression as unsorted mononuclear leukocytes. In contrast to liver- resident NK cells, no significant changes were detected in peripheral blood or spleen NK cells of rats following partial hepatectomy. Of particular interest, in normal liver, hepatocytes were resistant to NK lysis, while resident NK cells were cytotoxic for various NK-sensitive targets. In contrast, during the early period of liver regeneration, when hepatocytes were sensitive to lysis by liver resident NK cells of normal rats, NK cells obtained from regenerating liver tissues were unable to mediate cytotoxicity. At the final phase of liver regeneration (days 7-14 after hepatectomy), both resistance of hepatocytes to killing by NK cells and cytotoxicity of liver- resident lymphocytes against hepatocytes from regenerating liver were simultaneously restored. In vivo depletion of NK cells by injection of rats with anti-NKR-P1 mAb resulted in a significant augmentation of liver regeneration subsequent to partial hepatectomy. Our data suggest that liver- resident NK cells may he involved in regulation of the extent of liver regeneration